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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Evolution of Central Metabolic Pathways: The Playground of Non-Orthologous Gene Displacement - Sequence - Evolution - Function - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Sequence - Evolution - Function: Computational Approaches in Comparative Genomics">
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<meta name="citation_title" content="Evolution of Central Metabolic Pathways: The Playground of Non-Orthologous Gene Displacement">
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<meta name="citation_publisher" content="Kluwer Academic">
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<meta name="citation_date" content="2003">
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<meta name="citation_author" content="Eugene V Koonin">
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<meta name="citation_author" content="Michael Y Galperin">
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<meta name="DC.Title" content="Evolution of Central Metabolic Pathways: The Playground of Non-Orthologous Gene Displacement">
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<meta name="DC.Contributor" content="Eugene V Koonin">
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<meta name="DC.Contributor" content="Michael Y Galperin">
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<meta name="DC.Date" content="2003">
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<meta name="description" content="One of the central goals of functional genomics is the complete reconstruction of the metabolic pathways of the organisms, for which genome sequences have been obtained. As discussed in Chapter 1, there is no chance that all necessary biochemical experiments are ever done in any substantial number of organisms. Therefore, reconstructions made through comparative genomics, combined with the knowledge derived from experiments on model systems, are the only realistic path to a satisfactory understanding of the biochemical diversity of life and to the characterization of poorly studied and hard-to-grow organisms (including extremely important ones, e.g. the syphilis spirochete T. pallidum [243,887]).">
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<meta name="og:description" content="One of the central goals of functional genomics is the complete reconstruction of the metabolic pathways of the organisms, for which genome sequences have been obtained. As discussed in Chapter 1, there is no chance that all necessary biochemical experiments are ever done in any substantial number of organisms. Therefore, reconstructions made through comparative genomics, combined with the knowledge derived from experiments on model systems, are the only realistic path to a satisfactory understanding of the biochemical diversity of life and to the characterization of poorly studied and hard-to-grow organisms (including extremely important ones, e.g. the syphilis spirochete T. pallidum [243,887]).">
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match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK20266_"><span class="label">Chapter 7</span><span class="title" itemprop="name">Evolution of Central Metabolic Pathways: The Playground of Non-Orthologous Gene Displacement</span></h1><p class="fm-aai"><a href="#_NBK20266_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><p>One of the central goals of functional genomics is the complete reconstruction of the
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metabolic pathways of the organisms, for which genome sequences have been obtained. As
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discussed in <a href="/books/n/sef/A4/?report=reader">Chapter 1</a>, there is no chance
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that all necessary biochemical experiments are ever done in any substantial number of
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organisms. Therefore, reconstructions made through comparative genomics, combined with
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the knowledge derived from experiments on model systems, are the only realistic path to
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a satisfactory understanding of the biochemical diversity of life and to the
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characterization of poorly studied and hard-to-grow organisms (including extremely
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important ones, e.g. the syphilis spirochete <i>T. pallidum</i> [<a href="/books/n/sef/A727/?report=reader#A971">243</a>,<a href="/books/n/sef/A727/?report=reader#A1615">887</a>]).</p><p>In the pre-genomic era, metabolic reconstruction might have seemed to be a relatively
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easy task, given the overall similarity of the key metabolic enzymes in several model
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organisms, such as <i>E. coli</i>, <i>B. subtilis</i>, yeast,
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plants, and animals. Although cases of non-orthologous (unrelated or distantly related)
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enzymes catalyzing the same reaction, such as the two distinct forms of
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fructose-1,6-bisphosphate aldolases, phosphoglycerate mutases, and superoxide
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dismutases, have been known for a long time, these cases were generally perceived as
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rare and, more or less, inconsequential [<a href="/books/n/sef/A727/?report=reader#A915">187</a>,<a href="/books/n/sef/A727/?report=reader#A986">258</a>,<a href="/books/n/sef/A727/?report=reader#A999">271</a>,<a href="/books/n/sef/A727/?report=reader#A1277">549</a>]. The
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availability of complete genomes is gradually changing this perception, making us
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realize just how common these cases of analogous (as opposed to homologous) enzymes are
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in nature (see <a href="/books/n/sef/A22/?report=reader#A40">2.2.5</a>). The phenomenon of
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non-orthologous gene displacement turned out to be a major complication (but also a
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major source of unexpected findings) for the analysis of metabolic pathways, making it
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particularly hard to automate. Indeed, whenever an ortholog of a given metabolic enzyme
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from the model organisms is not detected in the organism of interest (the initial step
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of metabolic reconstruction, the identification of orthologs of known enzymes, can be
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automated almost completely), the process turns into “detective
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work”. The researcher needs to identify a set of gene products that, on the
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basis of their predicted biochemical activities, potentially could catalyze the reaction
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in question. Often, there is more than one such candidate, and the choice between these
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might not be possible without direct experiments. Furthermore, there is always a chance
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that, however plausible, all candidates detected in such searches are false, whereas the
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true culprit is a complete unknown. This makes metabolic reconstruction in the era of
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comparative genomics a less precise but much more exciting undertaking.</p><p>In this chapter, we show how a COG-based reconstruction of bacterial and archaeal
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metabolism helps organizing the existing data on microbial biochemistry, illuminates the
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remaining questions, suggests candidates for some of the “missing”
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enzymatic activities, and predicts the existence of novel enzymes that remain to be
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discovered. For each metabolic reaction, we list the COGs that are known to catalyze it
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or can be reasonably predicted to do so. We then compare the phyletic patterns of the
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corresponding COGs to see if the current set of COGs is sufficient to suggest candidate
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proteins to catalyze the given reaction in each organism with sequenced genome or still
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unexplained gaps remain in metabolic pathways.</p><div id="A372"><h2 id="_A372_">7.1. Carbohydrate Metabolism</h2><div id="A373"><h3>7.1.1. Glycolysis</h3><p>We have already used the COG approach to demonstrate the complementarity of the
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phyletic patterns of the three forms of phosphoglycerate mutase (see <a href="/books/n/sef/A22/?report=reader#A43">2.2.6</a>). <a href="/books/n/sef/A517/?report=reader#A520">Figure 7.1</a> shows the COGs that are known or predicted to include
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glycolytic enzymes and shows their phyletic patterns. This superposition of COGs
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and metabolic pathways provides a convenient framework for a detailed analysis
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of the phylogenetic distribution of each of the glycolytic enzymes and the
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general principles of evolution of carbohydrate metabolism. This figure shows,
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for example, that <i>R. prowazekii</i>, an obligate intracellular
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parasite and a relative of the mitochondria [<a href="/books/n/sef/A727/?report=reader#A758">30</a>], does not encode a single glycolytic enzyme. In contrast, all
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other organisms with completely sequenced genomes encode enzymes of the lower
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(tri-carbon) part of the pathway. This supports the notion that glycolysis is
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the central pathway of carbohydrate metabolism and makes comparative analysis of
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variants of this pathway all the more interesting.</p><div id="A374"><h4>Glucokinase (EC 2.7.1.2 )</h4><p>Fermentation of glucose starts with its phosphorylation, which is catalyzed
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by glucokinase. Although many bacteria bypass the glucokinase step by
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phosphorylating glucose concomitantly with its uptake by the PEP-dependent
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phosphotransferase system, some of them, including <i>E. coli</i>,
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encode a glucokinase (COG0837) that shares little sequence similarity with
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yeast and human enzymes. There is also another bacterial form, found in
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<i>S. coelicolor</i>, <i>Bacillus megaterium</i>,
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and other bacteria [<a href="/books/n/sef/A727/?report=reader#A760">32</a>,<a href="/books/n/sef/A727/?report=reader#A1523">795</a>].</p><p>Recently, <i>P. furiosus</i> has been reported to encode an
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ADP-dependent glucokinase [<a href="/books/n/sef/A727/?report=reader#A1163">435</a>].
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This enzyme has no detectable sequence similarity to any other glucokinase
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but shows significant structural similarity to enzymes of the ribokinase
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family [<a href="/books/n/sef/A727/?report=reader#A1111">383</a>]. In retrospect,
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several conserved motifs were detected in this new glucokinase and the
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ribokinase family proteins, which indicates a homologous relationship. Thus,
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a clear-cut case of non-orthologous gene displacement is observed: a
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ribokinase family enzyme has been recruited to replace the typical
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glucokinase. So far, the ADP-dependent glucokinase has been found only in
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<i>M. jannaschii</i> and in pyrococci. The existence of at
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least three distinct forms of glucokinase is remarkable, especially given
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that this is apparently not an essential component of glycolysis. Moving
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down the glycolytic pathway, we find similar examples of non-orthologous
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gene displacement for several other, essential enzymes.</p></div><div id="A375"><h4>Glucose-6-phosphate isomerase (EC 5.3.1.9)</h4><p>Bacteria and eukaryotes encode several distinct but homologous forms of
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glucose-6-phosphate isomerase (phosphoglucomutase) [<a href="/books/n/sef/A727/?report=reader#A1352">624</a>]. The classical (<i>E. coli</i>) form
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of the enzyme is found in Gram-negative bacteria and in the cytoplasm of the
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eukaryotic cell. A divergent version of this enzyme is found in
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Gram-positive bacteria including <i>B. subtilis</i>, in <i>T.
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maritima</i>, and some archaea, such as <i>M.
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jannaschii</i> and <i>Halobacterium</i> sp. [<a href="/books/n/sef/A727/?report=reader#A1194">466</a>,<a href="/books/n/sef/A727/?report=reader#A1489">761</a>]. The most divergent members of this family of
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glucose-6-phosphate isomerases were detected in <i>A. aeolicus</i>
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and another subset of archaea, including <i>M.
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thermoautotrophicum</i>, <i>A. pernix</i>, and
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<i>Thermoplasma</i> spp. No enzyme of this family seems to be
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encoded in the genomes of <i>A. fulgidus</i> or pyrococci.
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Instead, <i>P. furiosus</i> has been shown to encode a novel
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glucose-6-phosphate isomerase, which has highly conserved orthologs in
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<i>P. horikoshii</i> and in <i>A. fulgidus</i>, but
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so far not in any other organism [<a href="/books/n/sef/A727/?report=reader#A1059">331</a>]. Thus, two non-orthologous (in fact, apparently unrelated)
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versions of this enzyme together account for the phosphoglucomutase activity
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in all known microbial genomes, with the exception of <i>R.
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prowazekii</i> and <i>U. urealyticum</i>. As indicated
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above, the former does not encode any glycolytic enzymes, whereas the latter
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apparently obtains fructose-6-phosphate by importing fructose concomitantly
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with its phosphorylation through the fructose-specific phosphotransferase
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system, thus bypassing the phosphoglucomutase stage.</p></div><div id="A376"><h4>Phosphofructokinase (EC 2.7.1.11)</h4><p>The next glycolytic enzyme, phosphofructokinase, offers an even more
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interesting example of non-orthologous gene displacement. It is also an
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example of an enzyme where several “missing” enzyme
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forms have been discovered just in the past year.</p><p>The most common version of this enzyme, PfkA, is an ATP-dependent kinase of
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unique structure found in bacteria and many eukaryotes. Plants have a
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homologous enzyme, which, however, uses pyrophosphate as the phosphate
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donor. Altogether, homologs of PfkA are found in nearly all bacteria and
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eukaryotes but are conspicuously missing in <i>H. pylori</i> and
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in all archaeal genomes sequenced so far. In addition, <i>E.
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coli</i> encodes a second phosphofructokinase, PfkB, which is
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unrelated to PfkA and instead belongs to the ribokinase family of
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carbohydrate kinases.</p><p>A unique ADP-dependent phosphofructokinase has been described in <i>P.
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furiosus</i> [<a href="/books/n/sef/A727/?report=reader#A1581">853</a>].
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However, this enzyme appears to have a limited phyletic distribution: so
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far, it was found only in <i>M. jannaschii</i> and in pyrococci.
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This left the phosphofructokinase activity in other archaea unaccounted for
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and suggested that additional forms of this enzyme might exist. Very
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recently, a new ATP-dependent phosphofructokinase, which is a member of the
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ribokinase family but is not specifically related to PfkB, has been
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identified in <i>A. pernix</i> [<a href="/books/n/sef/A727/?report=reader#A1440">712</a>]. Close homologs of this protein (APE0012) were found in
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<i>Halobacterium</i> sp., <i>A. fulgidus</i>,
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<i>M. thermoautotrophicum</i>, and several other archaea.
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Therefore, it seems likely that these ribokinase family enzymes function as
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phosphofructokinases in all these archaea. Finally,
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<i>Thermoplasma</i> does not encode orthologs of any of the
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four forms of phosphofructokinase described above. This leaves two
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possibilities: either thermoplasmas lack phosphofructokinase altogether
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(along with fructose-1,6-bisphosphate aldolase; see below), or they might
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have yet another, fifth variant of this enzyme.</p></div><div id="A377"><h4>Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13)</h4><p>For more than 50 years now, it has been known that fructose-1,6-bisphosphate
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aldolase exists in two distinct forms, a metal-independent one (class I) in
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multicellular eukaryotes and a metal-dependent one (class II) in bacteria
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and yeast [<a href="/books/n/sef/A727/?report=reader#A915">187</a>,<a href="/books/n/sef/A727/?report=reader#A1277">549</a>,<a href="/books/n/sef/A727/?report=reader#A1609">881</a>].
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Certain organisms, such as <i>Euglena</i>, seem to have enzymes of
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both classes. Although these two enzyme forms have similar structures, they
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do not share any detectable sequence similarity [<a href="/books/n/sef/A727/?report=reader#A985">257</a>].</p><p>Sequence analysis of archaeal genomes and those of chlamydia showed that they
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encode neither a typical class I enzyme, nor a typical class II enzyme.
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Instead, chlamydia and all archaea, with the exception of thermoplasmas,
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encode orthologs of the recently described class I aldolase DhnA (FbaB) of
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<i>E. coli</i>, which is only distantly related to the regular
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class I enzymes and may be considered a third class of aldolases. Recently,
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fructose-1,6-bisphosphate aldolase activity was demonstrated in the
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<i>P. furiosus</i> homolog of DhnA; this enzyme has been
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referred to as a class IA aldolase [<a href="/books/n/sef/A727/?report=reader#A1498">770</a>]. The phyletic patterns of the bacterial-type class II
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aldolase (COG0191) and the DhnA-type aldolase (COG1830) are almost
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complementary, except that both types of aldolases are present in <i>E.
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coli</i> and <i>A. aeolicus</i>, and none of them is
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detectable in <i>X. fastidiosa</i> (<a class="figpopup" href="/books/NBK20266/figure/A378/?report=objectonly" target="object" rid-figpopup="figA378" rid-ob="figobA378">Figure 7.1</a>). <i>X. fastidiosa</i>, a plant
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pathogen, encodes a eukaryotic class I aldolase, which is specifically
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similar to the plant class I aldolase and probably has been acquired from
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the plant host via HGT. However, typical eukaryotic (class I)
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fructose-1,6-bisphosphate aldolase is also encoded in several other
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bacteria, in which cases the underlying evolutionary scenario is less
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clear.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA378" co-legend-rid="figlgndA378"><a href="/books/NBK20266/figure/A378/?report=objectonly" target="object" title="Figure 7.1" class="img_link icnblk_img figpopup" rid-figpopup="figA378" rid-ob="figobA378"><img class="small-thumb" src="/books/NBK20266/bin/ch7f1.gif" src-large="/books/NBK20266/bin/ch7f1.jpg" alt="Figure 7.1. Distribution of glycolysis (Embden-Meyerhoff-Parnas pathway) enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA378"><h4 id="A378"><a href="/books/NBK20266/figure/A378/?report=objectonly" target="object" rid-ob="figobA378">Figure 7.1</a></h4><p class="float-caption no_bottom_margin">Distribution of glycolysis (Embden-Meyerhoff-Parnas pathway)
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enzymes in organisms with completely sequenced genomes. Each rounded rectangle shows a glycolytic enzyme, denoted by its
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gene name and the COG number. Alternative enzymes catalyzing the
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same <a href="/books/NBK20266/figure/A378/?report=objectonly" target="object" rid-ob="figobA378">(more...)</a></p></div></div><p>Although most genomes encode only one type of fructose-1,6-bisphosphate
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aldolase, different forms of this enzyme do coexist in several organisms. In
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|
particular, the relatively large genome of the plant symbiont <i>M.
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|
loti</i> encodes fructose-1,6-bisphosphate aldolases of all three
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classes.</p><p>The nature of the aldolase, if any, in thermoplasmas remains unclear. The
|
|
apparent absence in these archaea of both phosphofructokinase and
|
|
fructose-1,6-bisphosphate aldolase might indicate that these organisms split
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hexoses into trioses exclusively via the Entner-Doudoroff pathway (see
|
|
below). Indeed, thermoplasmas encode close homologs of the recently
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|
described fructose-6-phosphate aldolase [<a href="/books/n/sef/A727/?report=reader#A1486">758</a>].</p><p>Finally, given that chlamydiae are important human pathogens and that the
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unusual class IA fructose-1,6-bisphosphate aldolase is the only aldolase
|
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encoded in their genomes, this presumably essential enzyme might be a
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promising target for anti-chlamydial drug therapy (see <a href="#A501">7.6</a>) [<a href="/books/n/sef/A727/?report=reader#A985">257</a>,<a href="/books/n/sef/A727/?report=reader#A994">266</a>].</p></div><div id="A379"><h4>Triose phosphate isomerase (EC 5.3.1.1)</h4><p>Triose phosphate isomerase is conserved in all organisms, with the exception
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of <i>Rickettsia</i>. Bacterial-eukaryotic and archaeal isomerases
|
|
form two clearly separated clusters [<a href="/books/n/sef/A727/?report=reader#A967">239</a>]. This gave rise to the notion that eukaryotic triose
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|
phosphate isomerases originated from the promitochondrial endosymbiont whose
|
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genes have been transferred into the nucleus of the eukaryotic host [<a href="/books/n/sef/A727/?report=reader#A1160">432</a>].</p></div><div id="A380"><h4>Glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12)</h4><p>Like triosephosphate isomerases, archaeal glyceraldehyde-3-phosphate
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dehydrogenases are homologous to those from bacteria and eukaryotes but form
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a well-defined cluster, suggesting the mitochondrial origin of this enzyme
|
|
in eukaryotes. In pyrococci and, probably, in several other archaea, the
|
|
main glycolytic flow goes through a different enzyme,
|
|
glyceraldehyde-3-phosphate:ferredoxin oxidoreductase, whereas
|
|
glyceraldehyde-3-phosphate dehydrogenase appears to be confined to
|
|
gluconeogenesis [<a href="/books/n/sef/A727/?report=reader#A1312">584</a>,<a href="/books/n/sef/A727/?report=reader#A1595">867</a>].</p><p>In <i>U. urealyticum</i>, the typical NADH-dependent
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|
glyceraldeldehyde-3-phosphate dehydrogenase is missing, and this reaction is
|
|
apparently catalyzed by a non-phosphorylating, NADP-dependent enzyme,
|
|
similar to the well-characterized enzymes from plants and
|
|
<i>Streptococcus mutans</i> [<a href="/books/n/sef/A727/?report=reader#A1054">326</a>,<a href="/books/n/sef/A727/?report=reader#A1272">544</a>]. These enzymes
|
|
belong to a large superfamily of NADP-dependent aldehyde dehydrogenases and
|
|
are unrelated to the phosphorylating glyceraldeldehyde-3-phosphate
|
|
dehydrogenase [<a href="/books/n/sef/A727/?report=reader#A1296">568</a>]. Remarkably, an
|
|
archaeal member of the non-phosphorylating glyceraldeldehyde-3-phosphate
|
|
dehydrogenase family uses NAD instead of NADP [<a href="/books/n/sef/A727/?report=reader#A852">124</a>].</p></div><div id="A381"><h4>Phosphoglycerate kinase (EC 2.7.2.3)</h4><p>Like triose phosphate isomerases and glyceraldehyde-3-phosphate
|
|
dehydrogenases, phosphoglycerate kinase is conserved in all organisms that
|
|
have glycolysis, and the sequences from bacteria and eukaryotes are closer
|
|
to each other than they are to their archaeal counterparts, suggesting the
|
|
mitochondrial origin of the eukaryotic enzyme.</p></div><div id="A382"><h4>Phosphoglycerate mutase (EC 5.4.2.1)</h4><p>The diversity of phosphoglycerate mutases was discussed earlier (see <a href="/books/n/sef/A22/?report=reader#A43">2.2.6</a>). We would only like to reiterate
|
|
that there are two unrelated forms of this enzyme,
|
|
2,3-bisphosphoglycerate-dependent (animal-type) and
|
|
2,3-bisphosphoglycerate-independent (plant-type), either one of which (or
|
|
both) can be found in various bacteria [<a href="/books/n/sef/A727/?report=reader#A866">138</a>]. Although <i>E. coli pgm</i> mutants devoid of
|
|
its principal (cofactor-dependent) form of phosphoglycerate mutase clearly
|
|
exhibit a mutant phenotype, a recent study of the second
|
|
(cofactor-independent) form of this enzyme showed that it accounts for as
|
|
much as 10% of the total phosphoglycerate mutase activity in
|
|
<i>E. coli</i> [<a href="/books/n/sef/A727/?report=reader#A972">244</a>].</p><p>Remarkably, neither form of phosphoglycerate mutase is encoded in any
|
|
archaeal genome available to date, with the sole exception of
|
|
<i>Halobacterium</i> spp., which has a typical
|
|
cofactor-independent enzyme, similar to the one in <i>B.
|
|
subtilis</i>. Sequence analysis of archaeal genomes showed that
|
|
they encode enzymes of the alkaline phosphatase superfamily that are
|
|
distantly related to the cofactor-independent phosphoglycerate mutase and
|
|
contain all the principal active-site residues [<a href="/books/n/sef/A727/?report=reader#A986">258</a>]. These enzymes were predicted to have a
|
|
phosphoglycerate mutase activity [<a href="/books/n/sef/A727/?report=reader#A986">258</a>]. This prediction was supported by the structural analysis
|
|
of the cofactor-independent phosphoglycerate mutase [<a href="/books/n/sef/A727/?report=reader#A989">261</a>,<a href="/books/n/sef/A727/?report=reader#A1122">394</a>] and
|
|
has been recently confirmed by direct experimental data [<a href="/books/n/sef/A727/?report=reader#A1036">308</a>,<a href="/books/n/sef/A727/?report=reader#A1594">866</a>]. Thus, like phosphofructokinase and
|
|
fructose-1,6-bisphosphate aldolase, phosphoglycerate mutase is found in
|
|
three different (unrelated or distantly related) variants.</p></div><div id="A383"><h4>Enolase (EC 4.2.1.11)</h4><p>Enolases encoded in bacterial, archaeal, and eukaryotic genomes are highly
|
|
conserved; phylogenetic trees for enolases show a “star
|
|
topology”, which precludes any definitive conclusions on the
|
|
evolutionary scenario for this enzyme. Pyrococci and <i>M.
|
|
jannaschii</i> encode additional, divergent paralogs of enolase
|
|
whose function(s) remains unknown.</p></div><div id="A384"><h4>Pyruvate kinase (EC 2.7.1.40)</h4><p>Pyruvate kinase, the terminal glycolytic enzyme, is not encoded in some
|
|
bacterial (<i>A. aeolicus</i>, <i>T. pallidum</i>) and
|
|
archaeal (<i>A. fulgidus</i>, <i>M.
|
|
thermoautotrophicum</i>) genomes. In these organisms, the pyruvate
|
|
kinase function is probably taken over by phosphoenolpyruvate synthase,
|
|
which is capable of catalyzing pyruvate formation by reversing its typical
|
|
reaction.</p><p>Pyruvate kinase, like phosphofructokinase (see above), is also missing in
|
|
<i>H. pylori</i>. Although a ribokinase-like
|
|
phosphofructokinase and phosphoenolpyruvate synthase could be considered as
|
|
possible bypasses for these enzymes, it seems more likely that glycolysis is
|
|
not functional in <i>H. pylori.</i> In contrast, this bacterium
|
|
encodes the complete set of enzymes involved in gluconeogenesis (<a href="/books/n/sef/A517/?report=reader#A523">Figure 8.2</a>). Such organization of
|
|
metabolism seems to make perfect sense for <i>H. pylori</i>, given
|
|
the challenge of maintaining near-neutral intracellular pH in the highly
|
|
acidic gastric environment. Sugar fermentation, resulting in intracellular
|
|
production of acid, would place an additional burden on the pH maintenance
|
|
mechanism, whereas gluconeogenesis converts organic acids into sugars and
|
|
thus removes H from the cytoplasm. For the purposes of energy production,
|
|
<i>H. pylori</i> apparently depends on fermentation of amino
|
|
acids and oligopeptides that are produced by gastric proteolysis and are
|
|
transported into the bacterial cells by ABC-type transporters. Amino acid
|
|
fermentation results in alkalinization of the cytoplasm and could relieve
|
|
part of the burden of pH maintenance in <i>H. pylori</i>. This
|
|
simple example shows that, even when seemingly plausible candidates for
|
|
missing steps in a pathway can be suggested, this should be done with
|
|
caution, and the resulting predicted pathways should be assessed against the
|
|
biological background of the respective organism.</p><p>After a string of recent publications [<a href="/books/n/sef/A727/?report=reader#A1059">331</a>,<a href="/books/n/sef/A727/?report=reader#A1111">383</a>,<a href="/books/n/sef/A727/?report=reader#A1498">770</a>], it appears that most glycolytic
|
|
enzymes have now been accounted for. While there are no clear candidates for
|
|
phosphofructokinase and fructose-1,6-bisphosphate aldolase in
|
|
<i>Thermoplasma</i> spp., the chances of discovering new
|
|
enzyme variants in this pathway appear very slim.</p></div></div><div id="A385"><h3>7.1.2. Gluconeogenesis</h3><p>With the exception of reactions catalyzed by phosphofructokinase and pyruvate
|
|
kinase, glycolytic reactions are reversible and function also in gluconeogenesis
|
|
(<a class="figpopup" href="/books/NBK20266/figure/A386/?report=objectonly" target="object" rid-figpopup="figA386" rid-ob="figobA386">Figure 7.2</a>). The reversal of the
|
|
latter reaction, i.e. conversion of pyruvate into phosphoenolpyruvate, can be
|
|
catalyzed by two closely related enzymes, phosphoenolpyruvate synthase and
|
|
pyruvate, phosphate dikinase. The only other reaction that is specific for
|
|
gluconeogenesis is the dephosphorylation of fructose-1,6-bisphosphate.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA386" co-legend-rid="figlgndA386"><a href="/books/NBK20266/figure/A386/?report=objectonly" target="object" title="Figure 7.2" class="img_link icnblk_img figpopup" rid-figpopup="figA386" rid-ob="figobA386"><img class="small-thumb" src="/books/NBK20266/bin/ch7f2.gif" src-large="/books/NBK20266/bin/ch7f2.jpg" alt="Figure 7.2. Distribution of gluconeogenesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA386"><h4 id="A386"><a href="/books/NBK20266/figure/A386/?report=objectonly" target="object" rid-ob="figobA386">Figure 7.2</a></h4><p class="float-caption no_bottom_margin">Distribution of gluconeogenesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div><div id="A387"><h4>Phosphoenolpyruvate synthase (EC 2.7.9.2)</h4><p>Phosphoenolpyruvate synthase (pyruvate, water dikinase, EC 2.7.9.2) and
|
|
pyruvate, phosphate dikinase (EC 2.7.9.1) catalyze two similar reactions of
|
|
phosphoenolpyruvate biosynthesis</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e1.jpg" alt="Image ch7e1.jpg" /></div><p>and have highly similar sequences. This enzyme is widely present in bacteria,
|
|
archaea, protists, and plants but is missing in animals, where PEP is
|
|
synthesized from oxaloacetates in a PEP carboxykinase-catalyzed
|
|
reaction.</p></div><div id="A388"><h4>Phosphoenolpyruvate carboxykinase (EC 4.1.1.32 and EC 4.1.1.49)</h4><p>Phosphoenolpyruvate carboxykinase exists in two unrelated forms, which
|
|
catalyze ATP-dependent (EC 4.1.1.49) or GTP-dependent (EC 4.1.1.32)
|
|
decarboxylation of oxaloacetate:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e2.jpg" alt="Image ch7e2.jpg" /></div><p>These forms show remarkably complex phyletic distributions. The GTP-dependent
|
|
form is found in animals and in a limited number of bacteria, such as
|
|
<i>Chlamydia</i> spp., <i>Mycobacterium</i> spp.,
|
|
<i>T. pallidum</i>, and the green sulfur bacterium
|
|
<i>Chlorobium limicola</i>. Among archaea, it is encoded only
|
|
in the genomes of pyrococci, thermoplasmas, and <i>Sulfolobus</i>.
|
|
In contrast, the ATP-dependent form of phosphoenolpyruvate carboxykinase is
|
|
found in plants, yeast, and many bacteria. The only complete archaeal genome
|
|
that has been found to encode the ATP-dependent form is that of <i>A.
|
|
pernix</i> (<a class="figpopup" href="/books/NBK20266/figure/A386/?report=objectonly" target="object" rid-figpopup="figA386" rid-ob="figobA386">Figure 7.2</a>).</p><p>Since the typical bacterial ATP-dependent phosphoenolpyruvate carboxykinase
|
|
appears to be unrelated to the GTP-dependent form found in humans, this key
|
|
enzyme of central metabolism might be an interesting drug target for such
|
|
pathogenic bacteria as <i>H. influenzae</i> and <i>C.
|
|
jejuni</i>(see <a href="#A501">7.6</a>).</p><p>There have also been reports of a third, pyrophosphate-dependent, form of
|
|
phosphoenolpyruvate carboxykinase [<a href="/books/n/sef/A727/?report=reader#A1547">819</a>], but they remain unconfirmed and no sequence so far has
|
|
been identified with this form. Absent this third form, phosphoenolpyruvate
|
|
carboxykinase appears to be missing in a large number of microorganisms,
|
|
leaving room for discovery of a new enzyme.</p></div><div id="A389"><h4>Fructose-1,6-bisphosphatase (EC 3.1.3.11)</h4><p>The best-studied form of fructose-1,6-bisphosphatase, found in <i>E.
|
|
coli</i>, yeast, and human (COG0158), has a limited phyletic
|
|
distribution: it is not encoded in the genomes of chlamydia, spirochetes,
|
|
Gram-positive bacteria, <i>A. aeolicus</i>, or <i>T.
|
|
maritima</i>. Among archaea, it is present only in
|
|
<i>Halobacterium</i> sp. A second form of this enzyme
|
|
(COG1494), originally described in cyanobacteria, has been reported to
|
|
function both as a fructose-1,6-bisphosphatase and as a
|
|
sedoheptulose-1,7-bisphosphatase [<a href="/books/n/sef/A727/?report=reader#A1551">823</a>,<a href="/books/n/sef/A727/?report=reader#A1552">824</a>].</p><p>This form also has a limited phyletic distribution, being found in a
|
|
relatively small number of bacteria (<a class="figpopup" href="/books/NBK20266/figure/A386/?report=objectonly" target="object" rid-figpopup="figA386" rid-ob="figobA386">Figure
|
|
7.2</a>). Although a member of this second family is encoded in
|
|
<i>B. subtilis</i>, this organism also has a distinct form of
|
|
fructose-1,6-bisphosphatase that is unrelated to the first two and is found
|
|
only in several other low-GC, Gram-positive bacteria [<a href="/books/n/sef/A727/?report=reader#A979">251</a>]. Finally, archaea encode yet another, fourth form
|
|
of this enzyme that belongs to the inositol monophosphatase family and only
|
|
recently has been shown to possess fructose-1,6-bisphosphatase activity
|
|
[<a href="/books/n/sef/A727/?report=reader#A1127">399</a>,<a href="/books/n/sef/A727/?report=reader#A1529">801</a>]. Like <i>B. subtilis</i>, several
|
|
bacterial genomes encode members of more than one protein family, which
|
|
include known or potential fructose-1,6-bisphosphatases; this makes it hard
|
|
to predict which of them actually has this function in gluconeogenesis. In
|
|
contrast, there is no clear candidate for this function in <i>A.
|
|
aeolicus</i>, <i>T. maritima</i>, <i>X.
|
|
fastidiosa</i>, <i>Chlamydia</i> spp., mycoplasmas,
|
|
spirochetes, and thermoplasmas. While the first three of these organisms and
|
|
<i>B. burgdorferi</i> encode enzymes of the inositol
|
|
monophosphatase family, they are not closely related to the archaeal
|
|
fructose-1,6-bisphosphatase (typified by the MJ0109 protein from <i>M.
|
|
jannaschii</i>) and might represent an independent case of enzyme
|
|
recruitment. Proteins that function as fructose-1,6-bisphosphatase in
|
|
<i>Chlamydia</i> spp., <i>Thermoplasma</i> spp.,
|
|
mycoplasmas, and <i>T. pallidum</i>, if any, remain to be
|
|
identified.</p></div></div><div id="A390"><h3>7.1.3. Entner-Doudoroff pathway and pentose phosphate shunt</h3><p>Alternative pathways for converting hexoses into trioses, the pentose phosphate
|
|
shunt and the Entner-Doudoroff pathway, are found in many organisms but cannot
|
|
be considered universal. Both of these pathways start from the NADP-dependent
|
|
oxidation of glucose-6-phosphate into phosphogluconolacton and proceed through
|
|
6-phosphogluconate (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.3</a>). Instead
|
|
of the standard Entner-Doudoroff pathway, some archaea encode the so-called
|
|
non-phosphorylating variant of this pathway, which starts from glucose and
|
|
includes unphosphorylated intermediates.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA391" co-legend-rid="figlgndA391"><a href="/books/NBK20266/figure/A391/?report=objectonly" target="object" title="Figure 7.3" class="img_link icnblk_img figpopup" rid-figpopup="figA391" rid-ob="figobA391"><img class="small-thumb" src="/books/NBK20266/bin/ch7f3.gif" src-large="/books/NBK20266/bin/ch7f3.jpg" alt="Figure 7.3. Distribution of enzymes of the pentose phosphate and Entner-Doudoroff pathways in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA391"><h4 id="A391"><a href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-ob="figobA391">Figure 7.3</a></h4><p class="float-caption no_bottom_margin">Distribution of enzymes of the pentose phosphate and
|
|
Entner-Doudoroff pathways in organisms with completely sequenced
|
|
genomes. Details are as in Figure
|
|
2.7. </p></div></div><div id="A392"><h4>Glucose-6-phosphate 1-dehydrogenase (EC 1.1.1.49)</h4><p>Glucose 6-phosphate dehydrogenase (Zwischenferment) primarily uses NADP as
|
|
the electron acceptor, although there have been reports of NAD-dependent
|
|
forms. This enzyme is found in many bacteria and eukaryotes but is not
|
|
encoded in any of the archaeal genomes sequenced to date. In addition, it is
|
|
missing in several bacteria, such as <i>M. leprae</i>, <i>B.
|
|
halodurans</i>, <i>S. pyogenes</i>, <i>C.
|
|
jejuni</i>, and mycoplasmas (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure
|
|
7.3</a>).</p></div><div id="A393"><h4>6-Phosphogluconolactonase (EC 3.1.1.31)</h4><p>Although this enzymatic activity had been characterized many years ago, the
|
|
gene for the lactonase remained unidentified until very recently, which was
|
|
due, in part, to the inherent instability of its substrate and, in part, to
|
|
the fact that this activity resides in a protein that is closely related to
|
|
glucosamine-6-phosphate isomerase/deaminase and might even combine both
|
|
activities [<a href="/books/n/sef/A727/?report=reader#A882">154</a>,<a href="/books/n/sef/A727/?report=reader#A1056">328</a>]. In humans, the lactonase is
|
|
fused to the glucose-6-phosphate dehydrogenase, forming the C-terminal
|
|
domain of a bifunctional enzyme. Interestingly, in <i>Plasmodium
|
|
falciparum</i>, the fusion partners switch places, with the
|
|
lactonase located at the N-terminus [<a href="/books/n/sef/A727/?report=reader#A1279">551</a>]. The lactonase is found largely in the same set of species
|
|
as glucose dehydrogenase, although it appears to be missing, additionally,
|
|
in <i>A. aeolicus</i> and <i>D. radiodurans</i>.</p></div><div id="A394"><h4>7.1.3.1. Pentose phosphate shunt</h4><div id="A395"><h5>6-Phosphogluconate dehydrogenase (decarboxylating, EC
|
|
1.1.1.44)</h5><p>6-Phosphogluconate dehydrogenase, the product of the <i>gnd</i>
|
|
gene in <i>E. coli</i>, is the upstream enzyme specific for
|
|
the pentose phosphate pathway. Of those organisms that encode
|
|
phosphogluconate dehydrogenase (COG0362), several (<i>M.
|
|
loti</i>, <i>B. subtilis</i>, <i>L.
|
|
lactis</i>) also encode its close paralog (COG1023), whose
|
|
function remains unknown but which is likely to have the same activity.
|
|
Phosphogluconate dehydrogenase has an even more narrow phylogenetic
|
|
distribution than phosphogluconolactonase, being additionally absent
|
|
from <i>S. pyogenes</i>, <i>X. fastidiosa</i>,
|
|
<i>H. pylori</i>, and <i>C. jejuni</i> (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.3</a>).</p></div><div id="A396"><h5>Pentose-5-phosphate-3-epimerase (EC 5.1.3.1)</h5><p>The next reaction of the pentose phosphate pathway, isomerization of
|
|
ribulose 5-phosphate into xylulose 5-phosphate, is catalyzed by
|
|
phosphoribulose epimerase. In addition to the pentose phosphate pathway,
|
|
this enzyme also participates in the interconversions of pentose
|
|
phosphates in the Calvin cycle, which accounts for its wider phyletic
|
|
distribution than seen for phosphogluconate dehydrogenase.</p></div><div id="A397"><h5>Ribose 5-phosphate isomerase (EC 5.3.1.6)</h5><p>Ribose-5-phosphate isomerase, which catalyzes interconversion of ribulose
|
|
5-phosphate and ribose 5-phosphate, is found in two apparently unrelated
|
|
forms, both of which, RpiA and RpiB, have been characterized in
|
|
<i>E. coli</i> [<a href="/books/n/sef/A727/?report=reader#A1521">793</a>]. RpiA is found in many bacteria, archaea, and
|
|
eukaryotes. In contrast, RpiB is limited to certain bacterial species
|
|
and is the sole form of ribose-5-phosphate isomerase in <i>B.
|
|
subtilis</i>, <i>M. tuberculosis</i>, <i>H.
|
|
pylori</i>, and several other bacteria. The phyletic patterns
|
|
of the two forms of the enzyme are largely complementary:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e3.jpg" alt="Image ch7e3.jpg" /></div><p>Like phosphoribulose epimerase, phosphoribose isomerase participates in
|
|
the Calvin cycle, which might explain its universal distribution.</p></div><div id="A398"><h5>Transketolase (EC 2.2.1.1)</h5><p>In eukaryotes and bacteria, transketolase is a single protein of
|
|
610–630 amino acid residues [<a href="/books/n/sef/A727/?report=reader#A1549">821</a>]. In archaea, however, this enzyme is either missing
|
|
altogether (e.g. <i>A. fulgidus</i>, <i>M.
|
|
thermoautotrophicum</i>) or is encoded by two separate genes
|
|
that may not even be adjacent (in <i>M. jannaschii</i>). The
|
|
hyperthermophilic bacterium <i>T. maritima</i> has both types
|
|
of genes, one full-length and one split gene, the latter probably
|
|
acquired from archaea via HGT. Transketolase shows high sequence
|
|
similarity to deoxyxylulose-5-phosphate synthase and other thiamine
|
|
pyrophosphate-dependent enzymes, which might point to a broad substrate
|
|
specificity of this enzyme, particularly in thermophiles.</p></div><div id="A399"><h5>Transaldolase (EC 2.2.1.2)</h5><p>Transaldolase is a protein of 310–330 amino acid residues,
|
|
which is present in eukaryotes and many bacteria and catalyzes the
|
|
transfer of the tri-carbon unit of sedoheptulose-7-phosphate to
|
|
glyceraldehyde-3-phosphate, producing fructose-6-phosphate and
|
|
erythrose-4-phosphate [<a href="/books/n/sef/A727/?report=reader#A1549">821</a>].
|
|
Archaea and some other bacteria encode a closely related but shorter
|
|
protein, about 210–230 aa long, which has recently been
|
|
demonstrated to function not as transaldolase, but as
|
|
fructose-6-phosphate aldolase, which splits fructose-6-phosphate into
|
|
glyceraldehyde-3-phosphate and dihydroxyacetone [<a href="/books/n/sef/A727/?report=reader#A1486">758</a>]. While <i>E. coli</i> encodes two
|
|
paralogous transaldolases (<i>talA</i>, <i>talB</i>)
|
|
and two paralogs of the smaller related enzyme (<i>talC</i>,
|
|
<i>mipB</i>), many other micro-prokaryotes, including
|
|
<i>B. subtilis</i>, <i>M. jannaschii</i>, and
|
|
<i>Thermoplasma</i> spp., encode only the latter protein.
|
|
Although the exact substrate specificity of these enzymes is not known,
|
|
enzymes from <i>B. subtilis</i> and <i>T.
|
|
maritima</i> have been reported to have transaldolase activity
|
|
[<a href="/books/n/sef/A727/?report=reader#A1486">758</a>]. Thus, different MipB
|
|
orthologs could have different (primary) activities, which makes
|
|
complete reconstruction of the pentose phosphate pathway in organisms
|
|
having these enzymes unrealistic at this time. Clearly, however, the
|
|
phyletic patterns of the enzymes of this pathway differ significantly,
|
|
which suggests the existence of still uncharacterized enzyme forms.</p></div></div><div id="A400"><h4>7.1.3.2. The Entner-Doudoroff pathway</h4><p>Conversion of 6-phosphogluconate into two tri-carbon molecules,
|
|
3-phosphoglyceraldehyde and pyruvate, via the Entner-Doudoroff pathway
|
|
includes only two steps, which are catalyzed by 6-phosphogluconate
|
|
dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase (the products of
|
|
<i>E. coli</i> genes <i>edd</i> and
|
|
<i>eda</i>, respectively (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.3</a>).</p><div id="A401"><h5>Phosphogluconate dehydratase (EC 4.2.1.12)</h5><p>Phosphogluconate dehydratase is a close paralog of dihydroxyacid
|
|
dehydratase, an enzyme of isoleucine/valine biosynthesis, which is
|
|
encoded in almost every genome. As a result, it is not easy to decide
|
|
which organisms encode phosphogluconate dehydratase. In <i>E.
|
|
coli</i> and several other proteobacteria, <i>edd</i>
|
|
and <i>eda</i> genes form operons. In other organisms, such as
|
|
<i>P. aeruginosa</i>, even though both these genes are
|
|
present, they are not adjacent, which complicates the identification of
|
|
phosphogluconate dehydratase.</p></div><div id="A402"><h5>2-Keto-3-deoxy-6-phosphogluconate aldolase (EC 4.1.2.14)</h5><p>KDPG aldolase has a much more narrow phyletic distribution than
|
|
phosphogluconate/dihydroxyacid dehydratase (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Fig 7.3</a>). Assuming that a functional
|
|
Entner-Doudoroff pathway requires the presence of each of these enzymes,
|
|
as well as glucose-6-phosphate dehydrogenase and
|
|
phosphogluconolactonase, the available genomic data suggest that the
|
|
pathway is limited to certain proteobacteria, <i>T.
|
|
maritima</i>, and some Gram-positive bacteria of the
|
|
Bacillus/Clostridium group.</p></div></div><div id="A403"><h4>7.1.3.3. Non-phosphorylated variants of the Entner-Doudoroff pathway</h4><p>While the standard Entner-Doudoroff pathway starts from glucose-6-phosphate
|
|
and proceeds through phosphorylated sugar intermediates, a variety of
|
|
bacteria and archaea possess so-called
|
|
“non-phosphorylated” variants of this pathway, which all
|
|
start from glucose and delay phosphorylation until later stages. The
|
|
simplest version of such a modified pathway includes glucose oxidation into
|
|
gluconate, followed by its phosphorylation into 6-phosphogluconate. The
|
|
resulting 6-phosphogluconate rejoins the standard Entner-Doudoroff pathway.
|
|
Another variant of the modified pathway includes an additional
|
|
non-phosphorylated step, dehydratation of gluconate into
|
|
2-keto-3-deoxygluconate, followed by its phosphorylation. In yet another
|
|
variant of this pathway, phosphorylation is delayed even further, until
|
|
after splitting of 2-keto-3-deoxygluconate into two tri-carbon molecules,
|
|
pyruvate and glyceraldehyde. The latter compound is then phosphorylated into
|
|
3-phosphoglyceraldehyde. Finally, phosphorylation can be delayed one step
|
|
further, with glyceraldehyde first oxidized into glycerate and then
|
|
phosphorylated into 2-phosphoglycerate.</p><div id="A404"><h5>Glucose 1-dehydrogenase (EC 1.1.1.47, 1.1.99.10)</h5><p>Glucose dehydrogenase, which catalyzes glucose oxidation into
|
|
glucono-1,5-lactone, is known in several variants, which use different
|
|
electron acceptors. Two non-orthologous NAD-dependent variants of this
|
|
enzyme (EC 1.1.1.47), typified by enzymes from <i>T.
|
|
acidophilum</i> [<a href="/books/n/sef/A727/?report=reader#A1125">397</a>]
|
|
and <i>Bacillus megaterium</i> [<a href="/books/n/sef/A727/?report=reader#A1657">929</a>], belong, respectively, to the Zn-containing
|
|
dehydrogenase family and to the short-chain reductases/dehydrogenases
|
|
family. One more variant of glucose dehydrogenase, which is present in
|
|
<i>E. coli</i> and several other bacteria, uses
|
|
pyrroloquinoline quinone as the electron acceptor [<a href="/books/n/sef/A727/?report=reader#A1365">637</a>]. Finally, the enzyme from
|
|
<i>Drosophila</i> (DHGL_DROME) is a flavoprotein that can
|
|
use a variety of electron acceptors [<a href="/books/n/sef/A727/?report=reader#A869">141</a>].</p></div><div id="A405"><h5>Gluconolactonase (EC 3.1.1.17)</h5><p>Only a single variant of gluconolactonase has been characterized so far
|
|
[<a href="/books/n/sef/A727/?report=reader#A1141">413</a>]. It has a patchy and
|
|
relatively narrow phyletic distribution (COG3386), suggesting that
|
|
alternative versions of this enzyme might exist.</p></div><div id="A406"><h5>Gluconate kinase (EC 2.7.1.12)</h5><p>Gluconate kinase is found in two distinct versions, one unique and the
|
|
other belonging to a large family of sugar kinases. This second form of
|
|
gluconate kinase has probably evolved from a glycerol kinase or a
|
|
xylulose kinase via enzyme recruitment (<a href="/books/n/sef/A22/?report=reader#A40">2.2.5</a>). Gluconate kinases of the first type are found in
|
|
yeast, <i>D. radiodurans</i>, <i>E. coli</i>, and
|
|
several other proteobacteria, whereas the second form is apparently
|
|
limited to <i>B. subtilis</i> and a handful of other
|
|
Gram-positive bacteria.</p></div><div id="A407"><h5>Gluconate dehydratase (EC 4.2.1.39)</h5><p>Although gluconate dehydratase activity has been described in bacteria
|
|
long ago [<a href="/books/n/sef/A727/?report=reader#A1027">299</a>] and can be
|
|
easily detected in archaea [<a href="/books/n/sef/A727/?report=reader#A1126">398</a>], the gene(s) for this enzyme has not been identified.
|
|
<i>E. coli</i>, some other bacteria, and
|
|
<i>Thermoplasma</i> spp. encode an enzyme with similar
|
|
activity, D-mannonate dehydratase (EC 4.2.1.8, the product of
|
|
<i>uxuA</i> gene), which converts mannonate into
|
|
2-keto-3-deoxygluconate. It is not known whether this enzyme can use
|
|
gluconate as a substrate. In any case, its narrow phyletic distribution
|
|
suggests that, even if UxuA functions as gluconate dehydratase in
|
|
<i>E. coli</i>, <i>M. loti</i>, <i>B.
|
|
subtilis</i>, and <i>Thermoplasma</i> spp., there
|
|
should exist a different form of this enzyme, which would participate in
|
|
the non-phosphorylated Entner-Doudoroff pathway in other archaea.</p></div><div id="A408"><h5>2-Keto-3-deoxygluconate aldolase</h5><p>Although splitting of 2-keto-3-deoxygluconate into pyruvate and
|
|
glyceraldehyde has been described long ago [<a href="/books/n/sef/A727/?report=reader#A744">16</a>], the first gene for 2-keto-3-deoxygluconate
|
|
has been identified only recently in the hyperthermophilic crenarchaeon
|
|
<i>S. solfataricus</i>. This enzyme is closely related to
|
|
N-acetyl-neuraminate lyase and belongs to the same superfamily of Schiff
|
|
base-dependent aldolases [<a href="/books/n/sef/A727/?report=reader#A854">126</a>].
|
|
Enzymes of this family (COG0329) are present in all archaeal genomes
|
|
sequenced so far, as well as in most bacteria. Although the exact
|
|
substrate specificity of each particular member of this family is not
|
|
yet clear, <i>Thermoplasma</i> spp. and <i>P.
|
|
abyssi</i> encode proteins that are highly similar to the
|
|
enzyme from <i>Sulfolobus</i> and can be confidently predicted
|
|
to catalyze this reaction.</p></div></div></div><div id="A409"><h3>7.1.4. The TCA cycle</h3><p>The tricarboxylic acid cycle (Krebs cycle) is the central metabolic pathway that
|
|
links together carbohydrate, amino acid, and fatty acid degradation and supplies
|
|
precursors for various biosynthetic pathways. Remarkably, the complete TCA
|
|
cycle, which has been studied in much detail in animal and yeast mitochondria,
|
|
<i>E. coli</i>, and <i>B. subtilis</i>, is only found in
|
|
a handful of microorganisms (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.4</a>).
|
|
Most organisms with completely sequenced genomes encode only a certain subset of
|
|
TCA cycle enzymes and, instead of performing the entire cycle, utilize only
|
|
fragments of it. Another remarkable feature is the diversity of this pathway:
|
|
cases of non-orthologous gene displacement are detectable for at least five of
|
|
the eight TCA cycle enzymes. A detailed analysis of the phyletic distribution
|
|
and evolution of the TCA cycle enzymes has been recently published by Huynen and
|
|
coworkers [<a href="/books/n/sef/A727/?report=reader#A1098">370</a>]. Most of their
|
|
conclusions remain valid, although the sequences of the genomes of two aerobic
|
|
archaea, the crenarchaeon <i>A. pernix</i> and the euryarchaeaon
|
|
<i>Halobacterium</i> sp., have substantially changed the notions
|
|
of what can and cannot be found in archaeal genomes. In an impressive
|
|
confirmation of early biochemical results on halobacterial metabolism [<a href="/books/n/sef/A727/?report=reader#A736">8</a>], both of these organisms have been
|
|
found to encode the complete set of TCA cycle enzymes as was the microaerophile
|
|
<i>Thermoplasma</i> spp. A reconstruction of the TCA cycle
|
|
reactions occurring in each organism can be a very interesting project, which we
|
|
recommend the readers to do on their own (see <a href="/books/n/sef/A646/?report=reader">Problems</a>). We concentrate here exclusively on the cases of
|
|
non-orthologous gene displacement.</p><div id="A410"><h4>Citrate synthase (EC 4.1.3.7)</h4><p>Citrate synthase is a highly conserved enzyme, which is encoded in most
|
|
bacterial, archaeal, and eukaryotic genomes (<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.3</a>). It serves as the principal port of entry of
|
|
acetyl-CoA into the TCA cycle and, in eukaryotes, is exclusively located in
|
|
the mitochondria. A very similar reaction is catalyzed by ATP:citrate lyase
|
|
(EC 4.1.3.8), which contains a citrate synthase-like domain at its
|
|
C-terminus.</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e4.jpg" alt="Image ch7e4.jpg" /></div><p>However, ATP:citrate lyase so far has been found exclusively in eukaryotes,
|
|
where it localizes in the cytoplasm and preferentially catalyzes the reverse
|
|
reaction, citrate cleavage.</p><p>Citrate synthase is missing in spirochetes and mycoplasmas, which do not
|
|
encode any enzymes of the TCA cycle. It is also missing in pyrococci,
|
|
<i>M. jannaschii</i>, <i>S. pyogenes</i>, and
|
|
<i>H. influenzae</i>, which encode unlinked branches of the
|
|
TCA cycle (<a class="figpopup" href="/books/NBK20266/figure/A411/?report=objectonly" target="object" rid-figpopup="figA411" rid-ob="figobA411">Figure 7.4</a>). It has been
|
|
suggested that the TCA cycle has evolved from two separate reductive
|
|
branches [<a href="/books/n/sef/A727/?report=reader#A1439">711</a>], which were
|
|
subsequently linked by (i) citrate synthase and (ii) either an
|
|
α-ketoglutarate dehydrogenase or an
|
|
α-ketoglutarate:ferredoxin oxidoreductase [<a href="/books/n/sef/A727/?report=reader#A1173">445</a>,<a href="/books/n/sef/A727/?report=reader#A1266">538</a>]. In
|
|
any case, due to the absence of known displacements, citrate synthase seems
|
|
to be a good indicator of the presence of a (nearly) complete TCA cycle in a
|
|
given organism.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA411" co-legend-rid="figlgndA411"><a href="/books/NBK20266/figure/A411/?report=objectonly" target="object" title="Figure 7.4" class="img_link icnblk_img figpopup" rid-figpopup="figA411" rid-ob="figobA411"><img class="small-thumb" src="/books/NBK20266/bin/ch7f4.gif" src-large="/books/NBK20266/bin/ch7f4.jpg" alt="Figure 7.4. Distribution of the TCA cycle enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA411"><h4 id="A411"><a href="/books/NBK20266/figure/A411/?report=objectonly" target="object" rid-ob="figobA411">Figure 7.4</a></h4><p class="float-caption no_bottom_margin">Distribution of the TCA cycle enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A412"><h4>Aconitase (EC 4.2.1.3)</h4><p>There are two distantly related, paralogous aconitases, referred to as
|
|
aconitase A and aconitase B, both of which are present in <i>E.
|
|
coli</i> and many other proteobacteria (<a class="figpopup" href="/books/NBK20266/figure/A411/?report=objectonly" target="object" rid-figpopup="figA411" rid-ob="figobA411">Figure 7.4</a>). Aconitase A has a much wider phyletic
|
|
distribution and is the form of the enzyme present in
|
|
α-proteobacteria <i>M. loti</i>, <i>C.
|
|
crescentus</i>, and <i>R. prowazekii</i>. Accordingly,
|
|
this is also the form of aconitase found in the mitochondria. Although
|
|
aconitase B has a much more narrow phyletic distribution, it is the only
|
|
form of the enzyme encoded in <i>Synechocystis</i> sp., <i>P.
|
|
multocida</i>, <i>H. pylori</i>, and <i>C.
|
|
jejuni</i>. </p><p>Aconitase is closely related to 3-isopropylmalate dehydratase, an enzyme of
|
|
leucine biosynthesis (see <a href="#A484">7.4.4</a>),
|
|
which sometimes makes its annotation of these enzymes in sequenced genomes
|
|
not entirely straightforward. However, <i>leu</i> genes are
|
|
usually found in a conserved operon, which helps make the correct
|
|
assignment.</p></div><div id="A413"><h4>Isocitrate dehydrogenase (EC 1.1.1.42)</h4><p>Like aconitase, isocitrate dehydrogenase is also found in two forms, which,
|
|
however, appear to be unrelated. The mitochondrial form of this enzyme, also
|
|
found in <i>E. coli</i> and many other bacteria and archaea, is
|
|
closely related to isopropylmalate dehydrogenase, an enzyme of leucine
|
|
biosynthesis (see <a href="#A484">7.4.4</a>), and it is
|
|
believed that it could have evolved via a duplication of the
|
|
<i>leuB</i> gene [<a href="/books/n/sef/A727/?report=reader#A1307">579</a>]. Again, genome annotation here has to rely on the genetic
|
|
context, i.e. on the presence or absence of adjacent <i>leu</i>
|
|
genes. In any case, the product of such a gene is very likely to have both
|
|
isocitrate dehydrogenase and isopropylmalate dehydrogenase activity. This
|
|
form is active as a homodimer, which distinguishes it from the second form,
|
|
referred to as monomeric isocitrate dehydrogenase. This second form was
|
|
originally found in <i>Vibrio</i> sp. [<a href="/books/n/sef/A727/?report=reader#A1542">814</a>] and was subsequently discovered in many other
|
|
bacteria [<a href="/books/n/sef/A727/?report=reader#A1531">803</a>]. It is the only form
|
|
of the enzyme encoded in the genomes of <i>M. leprae</i>,
|
|
<i>V. cholerae</i>, and <i>C. jejuni</i>.</p></div><div id="A414"><h4>2-Ketoglutarate dehydrogenase (EC 1.2.4.2)</h4><p>In mitochondria and many aerobic bacteria and archaea, decarboxylation of
|
|
α-ketoglutarate into the succinyl moiety of succinyl-CoA is
|
|
catalyzed by the thiamine pyrophosphate and lipoate-dependent
|
|
α-ketoglutarate dehydrogenase complex. In contrast, many anaerobic
|
|
bacteria and archaea utilize α-ketoglutarate ferredoxin
|
|
oxidoreductase, an unrelated enzyme [<a href="/books/n/sef/A727/?report=reader#A1173">445</a>,<a href="/books/n/sef/A727/?report=reader#A1266">538</a>].</p></div><div id="A415"><h4>Succinyl-CoA synthetase (EC 6.2.1.4, 6.2.1.5)</h4><p>Succinyl-CoA synthetases are divided into paralogous, highly similar
|
|
GTP-dependent and ATP dependent forms. Succinyl-CoA synthetase is a member
|
|
of a large family of acyl-CoA synthetases (NDP-forming), which also includes
|
|
acetyl-CoA synthetase found in many archaea and lower eukaryotes. For ATP
|
|
binding, these enzymes employ the ATP-grasp domain (<a href="/books/n/sef/A55/?report=reader#A100">Table 3.2</a>). Variants of this enzyme with shifted
|
|
substrate specificities are found in most phylogenetic lineages.</p></div><div id="A416"><h4>Succinate dehydrogenase/fumarate reductase (EC 1.3.99.1)</h4><p>Mitochondrial succinate dehydrogenase, which couples the oxidation of
|
|
succinate to fumarate with the reduction of ubiquinone to ubiquinol,
|
|
consists of four subunits carrying three iron-sulfur centers, a covalently
|
|
bound flavin and two b-type hemes (the history of the discovery of these
|
|
complexes is vividly described in [<a href="/books/n/sef/A727/?report=reader#A1501">773</a>]). The fumarate reductase (quinol:fumarate reductase)
|
|
complex also contains iron-sulfur centers and a covalently bound flavin but
|
|
usually consists of only two or three subunits. Succinate dehydrogenase is
|
|
part of the aerobic respiratory chain, whereas fumarate reductase is
|
|
involved in anaerobic respiration, with fumarate functioning as the terminal
|
|
electron acceptor. Accordingly, one or both of these enzymes is found in all
|
|
organisms, with the exception of pyrococci, spirochetes, and mycoplasmas
|
|
(<a class="figpopup" href="/books/NBK20266/figure/A411/?report=objectonly" target="object" rid-figpopup="figA411" rid-ob="figobA411">Figure 7.4</a>).</p></div><div id="A417"><h4>Fumarate hydratase (fumarase, EC 4.2.1.2)</h4><p>Like several other TCA cycle enzymes, fumarase is represented by two
|
|
unrelated forms. The mitochondrial form of this enzyme (class II) is also
|
|
encoded in many bacteria and in aerobic archaea, <i>A. pernix</i>
|
|
and <i>Halobacterium</i> sp. The second form of fumarase (class I)
|
|
consists of two subunits that are fused in most bacterial genomes but are
|
|
encoded by separate genes in archaea, <i>T. maritima</i> and
|
|
<i>A. aeolicus</i>. The two forms of fumarase have largely
|
|
complementary phyletic patterns:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e5.jpg" alt="Image ch7e5.jpg" /></div><p>The only archaeal genome that appears not to encode a fumarase is <i>T.
|
|
acidophilum</i>, whose fumarase homolog Ta0258 is much more closely
|
|
related to aspartate ammonia-lyase (COG1027) than to a typical fumarase
|
|
(COG0114). The actual activity of this <i>Thermoplasma</i> enzyme
|
|
has not been determined.</p></div><div id="A418"><h4>Malate dehydrogenase (EC 1.1.1.37)</h4><p>Malate dehydrogenase is also found in two forms, with the mitochondrial form
|
|
showing a much wider phyletic distribution. The second form of malate
|
|
dehydrogenase was originally described in archaea [<a href="/books/n/sef/A727/?report=reader#A736">8</a>,<a href="/books/n/sef/A727/?report=reader#A806">78</a>,<a href="/books/n/sef/A727/?report=reader#A1048">320</a>] and is often referred to as the
|
|
“archaeal” form of the enzyme. However, it is also
|
|
encoded in certain bacterial genomes, including three paralogous genes in
|
|
<i>E. coli</i> (<i>ybiC</i>, <i>yiaK</i>,
|
|
and <i>ylbC</i>) and <i>M. loti</i>. It is the only form
|
|
of malate dehydrogenase in pyrococci and in <i>P. aeruginosa</i>.
|
|
Remarkably, <i>M. thermoautotrophicus, M. jannaschii, B. subtilis, H.
|
|
influenzae</i>, and <i>P. multocida</i> encode both forms
|
|
of malate dehydrogenase ([<a href="/books/n/sef/A727/?report=reader#A1570">842</a>],
|
|
<a class="figpopup" href="/books/NBK20266/figure/A391/?report=objectonly" target="object" rid-figpopup="figA391" rid-ob="figobA391">Figure 7.3</a>). Why do these
|
|
organisms, with their relatively small genomes, need two paralogous forms of
|
|
this enzyme remains unclear. <i>U. urealyticum</i> and <i>T.
|
|
pallidum</i> do not encode either of the two forms of malate
|
|
dehydrogenase, in contrast to their respective relatives <i>M.
|
|
genitalium</i> and <i>B. burgdorferi</i>. Therefore, the
|
|
possibility remains that there exists yet another, third form of this
|
|
enzyme.</p></div></div></div><div id="A419"><h2 id="_A419_">7.2. Pyrimidine Biosynthesis</h2><p>In contrast to the pathways of carbohydrate metabolism discussed above, enzymes of
|
|
the pyrimidine biosynthesis pathway show a fairly consistent phyletic pattern,
|
|
although cases of non-orthologous gene displacement can be found here, too (see
|
|
<a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>
|
|
). The whole pathway, with the exception of the last three steps,
|
|
is missing in the obligate parasitic bacteria with small genomes: rickettsiae,
|
|
chlamydiae, spirochetes, and mycoplasmas, whereas bacteria and archaea with larger
|
|
genomes encode all or almost all enzymes of pyrimidine biosynthesis.</p><div id="A420"><h3>Carbamoyl phosphate synthase (EC 6.3.5.5)</h3><p>In bacteria and archaea, carbamoyl phosphate synthase consists of two subunits,
|
|
which in eukaryotes are fused into a single multifunctional CAD protein that
|
|
additionally contains dihydroorotase and aspartate carbamoyl-transferase
|
|
domains. The small subunit, encoded by the <i>carA</i> gene, is a
|
|
typical glutamine amidotransferase of the Triad family [<a href="/books/n/sef/A727/?report=reader#A1664">936</a>]. The large subunit consists of two ATP-grasp domains
|
|
(see <a href="/books/n/sef/A55/?report=reader#A98">3.3.3</a>) fused in the same polypeptide
|
|
chain [<a href="/books/n/sef/A727/?report=reader#A1119">391</a>,<a href="/books/n/sef/A727/?report=reader#A1528">800</a>,<a href="/books/n/sef/A727/?report=reader#A1569">841</a>]. In
|
|
<i>M. jannaschii</i> and <i>M. thermoautotrophicus</i>,
|
|
the large subunit is split into two proteins, which are encoded by different,
|
|
albeit adjacent, genes. In addition to the obligate parasites mentioned above,
|
|
carbamoyl phosphate synthase is missing in <i>P. horikoshii</i>,
|
|
<i>P. abyssi</i>, <i>Thermoplasma</i> spp., and
|
|
<i>H. influenzae</i> (<a href="/books/n/sef/A22/?report=reader#A35">Figure
|
|
2.7</a>). It is present, however, in <i>Pyrococcus
|
|
furiosus</i>, suggesting a relatively recent loss of this enzyme in the
|
|
other two pyrococci. In <i>P. abyssi</i>, carbamoyl phosphate
|
|
biosynthesis is carried out by an unrelated form of the enzyme, which is closely
|
|
related to carbamate kinase [<a href="/books/n/sef/A727/?report=reader#A1411">683</a>,<a href="/books/n/sef/A727/?report=reader#A1412">684</a>]. This second form is also
|
|
responsible for the carbamoyl phosphate synthase activity in <i>P.
|
|
furiosus</i> [<a href="/books/n/sef/A727/?report=reader#A929">201</a>,<a href="/books/n/sef/A727/?report=reader#A1420">692</a>] and might account for this activity
|
|
in <i>Thermoplasma</i> spp. Although both subunits of carbamoyl
|
|
phosphate synthase belong to large protein superfamilies and are similar to many
|
|
proteins with different substrate specificities, the sheer size of the large
|
|
subunit, which typically contains more than 1,050 amino acid residues, allows an
|
|
easy identification of this enzyme in genome analyses. However, caution is due
|
|
with respect to the annotation of any shorter proteins that give statistically
|
|
significant hits to the large subunit of carbamoyl phosphate synthase: these are
|
|
likely to be other ATP-grasp superfamily enzymes (see <a href="/books/n/sef/A55/?report=reader#A100">Table 3.2</a>).</p></div><div id="A421"><h3>Aspartate carbamoyltransferase (EC 2.1.3.2)</h3><p>Aspartate carbamoyltransferase, the second enzyme of pyrimidine biosynthesis, has
|
|
a wide distribution with a phyletic pattern, which is similar to that of
|
|
carbamoyl phosphate synthase but additionally includes pyrococci and
|
|
<i>Thermoplasma</i> spp. (<a href="/books/n/sef/A22/?report=reader#A35">Figure
|
|
2.7</a>). This enzyme, however, is lacking in <i>H.
|
|
influenzae</i> and in its close relative <i>P. multocida</i>.
|
|
In eukaryotes, aspartate carbamoyltransferase comprises the C-terminal domain of
|
|
the multifunctional CAD protein [<a href="/books/n/sef/A727/?report=reader#A1499">771</a>].</p></div><div id="A422"><h3>Dihydroorotase (EC 3.5.2.3)</h3><p>The well-characterized form of dihydroorotase (COG0418), encoded by the
|
|
<i>E. coli pyrC</i> gene [<a href="/books/n/sef/A727/?report=reader#A793">65</a>] and by the <i>URA4</i> gene in yeast [<a href="/books/n/sef/A727/?report=reader#A1053">325</a>], has a very limited phyletic
|
|
distribution (<a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>). In contrast,
|
|
the second form of this enzyme (COG0044) is almost universal, being present in
|
|
many bacteria, archaea, and eukaryotes [<a href="/books/n/sef/A727/?report=reader#A1414">686</a>]. In eukaryotes, this enzyme forms the middle portion of the
|
|
multifunctional CAD protein [<a href="/books/n/sef/A727/?report=reader#A1499">771</a>,<a href="/books/n/sef/A727/?report=reader#A1671">943</a>]. In yeast, however, this domain is
|
|
apparently inactive [<a href="/books/n/sef/A727/?report=reader#A1522">794</a>], most likely
|
|
because of the presence of the alternative form of dihydroorotase. Simlilar to
|
|
aspartate carbamoyltransferase, neither form of dihydroorotase is encoded in
|
|
<i>H. influenzae</i> or <i>P. multocida</i>. Notably,
|
|
the union of the phyletic patterns for the two forms of dihydroorotase is
|
|
identical to the phyletic pattern of aspartate carbamoyl-transferase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e6.jpg" alt="Image ch7e6.jpg" /></div></div><div id="A423"><h3>Dihydroorotate dehydrogenase (EC 1.3.3.1)</h3><p>Dihydroorotate dehydrogenase displays the same phyletic pattern as dihydroorotase
|
|
and aspartate carbamoyltransferase, with the addition of <i>H.
|
|
influenzae</i> and <i>P. multocida</i>. Both these bacteria
|
|
encode the enzymes for all downstream steps of pyrimidine biosynthesis.</p></div><div id="A424"><h3>Orotate phosphoribosyltransferase (EC 2.4.2.10)</h3><p>The phyletic pattern of orotate phosphoribosyltransferase differs from that of
|
|
dihydroorotate dehydrogenase in only one respect, the presence of a
|
|
<i>pyrE</i>-related gene in <i>C. pneumoniae</i>. The
|
|
function of the product of this gene in <i>C. pneumoniae</i> is
|
|
unknown, but given the absence in this organism of the enzymes for the upstream
|
|
and the downstream steps of the pathway, it is unlikely to function as orotate
|
|
phosphoribosyltransferase. Rather, this enzyme might be recruited to catalyze a
|
|
different phosphoribosyltransferase reaction. In eukaryotes, orotate
|
|
phosphoribosyltransferase is fused to the next enzyme of the pathway, OMP
|
|
decarboxylase, forming a two-domain UMP synthase. As a result, orotate
|
|
phosphoribosyltransferase and OMP decarboxylase are occasionally misannotated as
|
|
UMP synthases and vice versa [<a href="/books/n/sef/A727/?report=reader#A992">264</a>].</p></div><div id="A425"><h3>Orotidine-5′-monophosphate decarboxylase (EC 4.1.1.23)</h3><p>Although the phyletic pattern of OMP decarboxylase is identical to that of
|
|
dihydroorotate dehydrogenase, a closer look at COG0284 shows that it consists of
|
|
three distantly related families. Two of these include well-characterized
|
|
enzymes from <i>E. coli</i> and other bacteria [<a href="/books/n/sef/A727/?report=reader#A1584">856</a>] and from yeast and other eukaryotes [<a href="/books/n/sef/A727/?report=reader#A962">234</a>,<a href="/books/n/sef/A727/?report=reader#A1298">570</a>]. The third family includes OMP decarboxylases from archaea and
|
|
a small number of bacteria, such as <i>M. tuberculosis</i>, <i>M.
|
|
leprae</i>, and <i>Myxococcus xanthus</i> [<a href="/books/n/sef/A727/?report=reader#A740">12</a>,<a href="/books/n/sef/A727/?report=reader#A1167">439</a>]. Mycobacterial OMP decarboxylases seem to be sufficiently
|
|
distinct from those of eukaryotes and other bacteria to consider them promising
|
|
targets for antituberculine drugs [<a href="/books/n/sef/A727/?report=reader#A994">266</a>].</p></div><div id="A426"><h3>Uridylate kinase (EC 2.7.4.-, 2.7.4.14)</h3><p>There seem to be two distinct forms of uridylate kinase: one specific for UMP and
|
|
found in bacteria and archaea (COG0528) and another one that phosphorylates both
|
|
UMP and CMP and is found in eukaryotes [<a href="/books/n/sef/A727/?report=reader#A1356">628</a>,<a href="/books/n/sef/A727/?report=reader#A1467">739</a>]. The eukaryotic
|
|
form of the enzyme is closely related to bacterial adenylate kinase and could
|
|
have been recruited from an ancestral prokaryotic adenylate kinase. The
|
|
prokaryotic form of uridylate kinase is encoded in all bacterial and archaeal
|
|
genomes sequenced to date, including the ‘minimal’ (see
|
|
<a href="/books/n/sef/A22/?report=reader#A40">2.2.5</a>) genomes of mycoplasmas and
|
|
<i>Buchnera</i>.</p></div><div id="A427"><h3>Nucleoside diphosphate kinase (EC 2.7.4.6)</h3><p>Nucleotide diphosphate kinase (COG0105) is highly conserved in most bacteria,
|
|
archaea, and eukaryotes. Surprisingly, however, this enzyme is not encoded in
|
|
<i>T. maritima</i>, <i>L. lactis</i>, <i>S.
|
|
pyogenes</i>, and mycoplasmas. One could imagine that these organisms
|
|
employ a different nucleotide diphosphate kinase that might have been recruited,
|
|
just like the eukaryotic uridylate kinase, from the adenylate kinase family
|
|
(COG0563).</p><p>This, however, would not solve the problem for <i>T. maritima</i> and
|
|
mycoplasmas, which encode only a single enzyme of that family. It therefore
|
|
seems likely that nucleotide diphosphate kinase in these organisms has been
|
|
recruited from yet another kinase family. Indeed, a phyletic pattern search for
|
|
a protein that would be encoded in those four genomes, but not in other
|
|
organisms with relatively small genomes, such as chlamydiae, spirochetes, or
|
|
<i>H. pylori</i>, easily finds an uncharacterized (predicted)
|
|
kinase related to dihydroxyacetone kinase (COG1461), which appears to be a good
|
|
candidate for the role of nucleoside diphosphate kinase in these organisms:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e7.jpg" alt="Image ch7e7.jpg" /></div></div><div id="A428"><h3>CTP synthase (UTP-ammonia ligase, EC 6.3.4.2)</h3><p>CTP synthase is a two-domain protein, which consists of an N-terminal
|
|
nucleotide-binding synthetase domain and a C-terminal glutamine amidotransferase
|
|
domain. This enzyme is extremely highly conserved in bacteria, archaea, and
|
|
eukaryotes. It is missing only in the genomes of <i>M. genitalium</i>
|
|
and <i>M. pneumoniae</i>, which apparently make CTP from CDP or CMP in
|
|
a salvage pathway, rather than from UTP.</p><div id="A429"><h4>General notes on pyrimidine biosynthesis evolution</h4><p>Comparison of the phyletic patterns for the enzymes of pyrimidine
|
|
biosynthesis reveals two important evolutionary trends. First, there appears
|
|
to be a tendency toward decreasing the genome size by losing genes that have
|
|
ceased to be essential. Indeed, ample evidence indicates that mycoplasmas
|
|
evolved from a Gram-positive ancestor by way of massive gene loss associated
|
|
with their adaptation to parasitism. While bacilli, lactococci, and many
|
|
other Gram-positive bacteria carry the full set of genes of pyrimidine
|
|
biosynthesis, most of the <i>pyr</i> genes have been lost in the
|
|
mycoplasmal lineage. Similarly, many <i>pyr</i> genes apparently
|
|
have been lost in other parasitic bacteria with small genomes, such as
|
|
spirochetes, rickettsiae, and chlamydiae (<a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>).</p><p>The trend toward gene loss is much more pronounced for the initial steps of
|
|
the pyrimidine biosynthesis pathway than it is for the distal steps. Thus,
|
|
genes for the first three steps of pyrimidine biosynthesis from bicarbonate
|
|
and ammonia to dihydroorotate (<i>carA</i>, <i>carB</i>,
|
|
<i>pyrB</i>, and <i>pyrC</i>) are missing in
|
|
<i>H. influenzae</i>, but the genes for all the subsequent
|
|
steps of pyrimidine biosynthesis, from dihydroorotate to CTP, are present
|
|
(<a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>). This means that,
|
|
although <i>H. influenzae</i> is incapable of <i>de
|
|
novo</i> pyrimidine biosynthesis, it still can synthesize UTP and
|
|
CTP from dihydroorotate, orotate, or OMP. Spirochetes, chlamydiae,
|
|
rickettsiae, and mycoplasmas show an even deeper loss of pyrimidine
|
|
biosynthesis genes but nevertheless retain genes for the last three steps of
|
|
the pathway, the conversion of UMP into CTP. Thus, while depending on the
|
|
host for the supply of essential nutrients, this strategy allows the
|
|
parasite to preserve at least some metabolic plasticity. In particular,
|
|
every organism seems to encode enzymes to synthesize its own nucleoside
|
|
triphosphates (NTPs). For thermodynamic reasons, bacteria cannot import NTPs
|
|
directly, although intracellular bacterial parasites do encode ATP/ADP
|
|
translocases, which are capable of exchanging ADP generated by the parasite
|
|
for cytoplasmic ATP [<a href="/books/n/sef/A727/?report=reader#A1627">899</a>,<a href="/books/n/sef/A727/?report=reader#A1638">910</a>].</p></div></div></div><div id="A430"><h2 id="_A430_">7.3. Purine Biosynthesis</h2><p>Like pyrimidine biosynthesis enzymes, enzymes of the purine biosynthesis pathway
|
|
follow a consistent phylogenetic pattern, albeit with some inevitable complications
|
|
(<a class="figpopup" href="/books/NBK20266/figure/A431/?report=objectonly" target="object" rid-figpopup="figA431" rid-ob="figobA431">Figure 7.5</a>). With only a few exceptions,
|
|
enzymes that catalyze the common reactions of the pathway, which leads to the
|
|
formation of inosine-5′-monophosphate, are missing in parasitic bacteria
|
|
with small genomes, namely mycoplasmas, rickettsiae, chlamydiae, spirochetes,
|
|
<i>Buchnera</i> sp., and <i>H. pylori</i>, and,
|
|
interestingly, in the aerobic crenarchaeon <i>A. pernix</i>. Other
|
|
bacteria encode the complete set of purine biosynthesis enzymes, whereas the
|
|
distribution of these enzymes in archaeal genomes is more complex and has to be
|
|
discussed separately for each enzyme.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA431" co-legend-rid="figlgndA431"><a href="/books/NBK20266/figure/A431/?report=objectonly" target="object" title="Figure 7.5" class="img_link icnblk_img figpopup" rid-figpopup="figA431" rid-ob="figobA431"><img class="small-thumb" src="/books/NBK20266/bin/ch7f5.gif" src-large="/books/NBK20266/bin/ch7f5.jpg" alt="Figure 7.5. Distribution of purine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA431"><h4 id="A431"><a href="/books/NBK20266/figure/A431/?report=objectonly" target="object" rid-ob="figobA431">Figure 7.5</a></h4><p class="float-caption no_bottom_margin">Distribution of purine biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details as in Figure 2.7. </p></div></div><div id="A432"><h3>Phosphoribosylpyrophosphate synthetase (EC 2.7.6.1)</h3><p>PRPP synthetase (ribose-phosphate diphosphokinase) is an enzyme that is shared by
|
|
purine biosynthesis and histidine biosynthesis pathways. This enzyme is found in
|
|
most completely sequenced genomes, including those of mycoplasmas, spirochetes,
|
|
and <i>Buchnera</i>, which do not encode most purine biosynthesis
|
|
enzymes (<a class="figpopup" href="/books/NBK20266/figure/A431/?report=objectonly" target="object" rid-figpopup="figA431" rid-ob="figobA431">Figure 7.5</a>).</p></div><div id="A433"><h3>Amidophosphoribosyltransferase (EC 2.4.2.14)</h3><p>Glutamine phosphoribosylpyrophosphate amidotransferase (PurF) belongs to the
|
|
N-terminal nucleophile (Ntn) family of glutamine amidotransferases [<a href="/books/n/sef/A727/?report=reader#A1664">936</a>]. This enzyme is encoded in every
|
|
sequenced bacterial genome, with the exception of some obligate parasites, such
|
|
as rickettsiae, chlamydiae, spirochetes, mycoplasmas, and <i>H.
|
|
pylori,</i> and in every archaeal genome except for <i>A.
|
|
pernix</i>. The same phyletic pattern is seen for the majority of
|
|
purine biosynthesis enzymes.</p></div><div id="A434"><h3>Phosphoribosylamine-glycine ligase (EC 6.3.4.13)</h3><p>Phosphoribosylglycinamide synthetase PurD, an ATP-grasp superfamily (<a href="/books/n/sef/A55/?report=reader#A100">Table 3.2</a>) enzyme, has the same phyletic
|
|
pattern as amidophosphoribosyltransferase and many other enzymes of this
|
|
pathway.</p></div><div id="A435"><h3>Phosphoribosylglycinamide formyltransferase (EC 2.1.2.2)</h3><p>5′-Phosphoribosyl-N-formylglycinamide synthase (GAR transformylase)
|
|
exists in two different forms, formate-dependent (PurN) and folate-dependent
|
|
(PurT), which are unrelated to each other and catalyze entirely different
|
|
reactions. The folate-dependent form functions as a transferase, catalyzing
|
|
transfer of the formyl group from formyltetrahydrofolate to
|
|
phosphoribosylglycinamide. This enzyme is found in many bacteria and eukaryotes
|
|
but only in a few archaea, such as <i>Halobacterium</i> sp. and
|
|
<i>Thermoplasma</i> spp. The formate-dependent form of the enzyme
|
|
belongs to the ATP-grasp superfamily (see <a href="/books/n/sef/A55/?report=reader#A100">Table 3.2</a>) and catalyzes an ATP-dependent ligation of
|
|
phosphoribosylglycinamide with formic acid. This is the only form of GAR
|
|
transformylase in methanogens and pyrococci. Surprisingly, neither form of the
|
|
enzyme is encoded in the <i>A. fulgidus</i> genome. With the exception
|
|
of <i>A. fulgidus</i>, the combined phyletic pattern of the two forms
|
|
of GAR transformylase coincides with the patterns for
|
|
amidophosphoribosyltransferase and phosphoribosylamine-glycine ligase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e8.jpg" alt="Image ch7e8.jpg" /></div></div><div id="A436"><h3>Phosphoribosylformylglycinamidine synthase (EC 6.3.5.3)</h3><p>Like many other amidotransferases, phosphoribosylformylglycinamidine (FGAM)
|
|
synthase PurL consists of two subunits, a glutamine amidotransferase of the
|
|
Triad family [<a href="/books/n/sef/A727/?report=reader#A1664">936</a>] and a synthetase.
|
|
The phyletic pattern of both FGAM synthase subunits is the same as that of PurF
|
|
and PurD. In <i>E. coli</i> and many other γ-proteobacteria,
|
|
as well as in yeast and other eukaryotes, these two subunits are fused in one
|
|
polypeptide chain, whereas in most other bacteria and in archaea they are
|
|
encoded by separate genes. In this latter case, FGAM synthase apparently
|
|
requires an additional 80-aa subunit, referred to as PurS [<a href="/books/n/sef/A727/?report=reader#A1475">747</a>].</p></div><div id="A437"><h3>Phosphoribosylaminoimidazol synthetase (EC 6.3.3.1)</h3><p>Phosphoribosylformylglycinamidine cycloligase (AIR synthetase) PurM has the same
|
|
phyletic pattern as PurF, PurD, and PurL.</p></div><div id="A438"><h3>Phosphoribosylaminoimidazole carboxylase (EC 4.1.1.21)</h3><p>Phosphoribosylaminoimidazole (AIR) carboxylase (NCAIR synthetase) PurK is, like
|
|
PurD, an ATP-grasp superfamily enzyme (<a href="/books/n/sef/A55/?report=reader#A100">Table
|
|
3.2</a>), which catalyzes ATP-dependent carboxylation of AIR. Unlike
|
|
other enzymes of purine biosynthesis, PurK is not encoded in the genomes of
|
|
<i>A. fulgidus</i>, <i>C. jejuni</i>, methanogens, and
|
|
pyrococci (<a class="figpopup" href="/books/NBK20266/figure/A431/?report=objectonly" target="object" rid-figpopup="figA431" rid-ob="figobA431">Figure 7.5</a>), so that the
|
|
mechanism of AIR carboxylation in these organisms remains unknown. This reaction
|
|
can occur spontaneously at elevated temperatures in a CO<sub>2</sub>-rich
|
|
atmosphere, which could explain the absence of this enzyme in hyperthermophilic
|
|
archaea. This explanation does not seem to work, however, for <i>C.
|
|
jejuni</i>, suggesting the existence of a still unidentified
|
|
alternative version of PurK (see [<a href="/books/n/sef/A727/?report=reader#A998">270</a>,<a href="/books/n/sef/A727/?report=reader#A1295">567</a>] for
|
|
discussion).</p></div><div id="A439"><h3>Phosphoribosylcarboxyaminoimidazole mutase</h3><p>Phosphoribosylcarboxyaminoimidazole (NCAIR) mutase, previously thought to be a
|
|
subunit of NCAIR synthetase but recently identified as an individual enzyme
|
|
[<a href="/books/n/sef/A727/?report=reader#A1295">567</a>,<a href="/books/n/sef/A727/?report=reader#A1311">583</a>], has the typical phyletic pattern of purine
|
|
biosynthesis enzymes, identical to the phyletic patterns PurF, PurD, and
|
|
PurL.</p></div><div id="A440"><h3>Phosphoribosylaminoimidazolesuccinocarboxamide synthase (EC 4.3.3.2)</h3><p>Phosphoribosylaminoimidazolesuccinocarboxamide (SAICAR) synthase (PurC) contains
|
|
a distinct version of the ATP-grasp domain. In addition to the standard set of
|
|
organisms that are capable of purine biosynthesis, SAICAR synthase is encoded in
|
|
the genome of <i>R. prowazekii</i>. It is hard to imagine what might
|
|
be the function of this enzyme in an intracellular parasite, which lacks all
|
|
other enzymes of purine biosynthesis. The sequence of <i>R.
|
|
prowazekii</i> PurC is closely related to the enzymes from other
|
|
α-proteobacteria but has at least three substitutions of amino acid
|
|
residues that are otherwise conserved in SAICAR synthases (E.V.K., unpublished
|
|
observations). This suggests that rickettsial SAICAR synthase might have lost
|
|
its enzymatic activity and acquired another, perhaps regulatory function.</p></div><div id="A441"><h3>Adenylosuccinate lyase (EC 4.3.2.2)</h3><p>Adenylosuccinate lyase (PurB) has the typical phyletic pattern of purine
|
|
biosynthesis enzymes, with the addition of <i>H. pylori</i>. This is
|
|
most likely due to the involvement of PurB in the conversion of IMP into AMP,
|
|
the reaction that appears to occur in <i>H. pylori</i>.</p></div><div id="A442"><h3>AICAR transformylase (EC 2.1.2.3)</h3><p>Phosphoribosylaminoimidazolecarboxamide (AICAR) formyltransferase (PurH)
|
|
catalyzes the transfer of the formyl group from formyltetrahydrofolate to AICAR.
|
|
In every organism studied to date, this protein is fused to the IMP
|
|
cyclohydrolase in a bifunctional enzyme. AICAR transformylase comprises the
|
|
C-terminal 300-aa portion of the PurH protein, whereas IMP cyclohydrolase
|
|
comprises the N-terminal 200-aa region [<a href="/books/n/sef/A727/?report=reader#A1421">693</a>]. AICAR transformylase is encoded in almost the same set of
|
|
organisms as all other purine biosynthesis enzymes, with the exception of
|
|
<i>A. fulgidus</i>, which encodes only the IMP cyclohydrolase
|
|
portion of PurH, and methanogens and pyrococci that do not encode either of
|
|
these enzymes.</p></div><div id="A443"><h3>IMP cyclohydrolase (EC 3.5.4.10)</h3><p>IMP cyclohydrolase, which catalyzes the last step of purine biosynthesis, is
|
|
fused to AICAR transformylase in every organism, except for <i>A.
|
|
fulgidus</i>, which does not have an AICAR transformylase at all, and
|
|
<i>Halobacterium</i> sp., in which the AICAR transformylase domain
|
|
is fused to PurN, a different folate-dependent GAR transformylase (see above).
|
|
As noted above, methanogens and pyrococci do not encode a recognizable IMP
|
|
cyclohydrolase.</p></div><div id="A444"><h3>Adenylosuccinate synthase (EC 6.3.4.4)</h3><p>Conversion of IMP into AMP can occur in one step, which is catalyzed by the
|
|
eukaryote-specific enzyme AMP deaminase (EC 3.5.4.6), or in two steps, as in
|
|
most bacteria and archaea. First, IMP is converted into adenylosuccinate by
|
|
adenylosuccinate synthase PurA. In addition to the entire set of organisms that
|
|
encode enzymes of IMP biosynthesis, PurA is also encoded in <i>H.
|
|
pylori</i>. The second step, the conversion of adenylosuccinate into
|
|
AMP, is catalyzed by adenylosuccinate lyase PurB (see above), which has the same
|
|
phyletic pattern as PurA.</p></div><div id="A445"><h3>IMP dehydrogenase (EC 1.1.1.205)</h3><p>Although the reverse reaction, catalyzed by GMP reductase (EC 1.6.6.8), occurs in
|
|
one step, conversion of IMP into GMP takes two steps. First, IMP is oxidized
|
|
into XMP by IMP dehydrogenase GuaB, a close paralog of GMP reductase, which,
|
|
however, contains an ~120-amino acid insert comprising two CBS domains involved
|
|
in allosteric regulation of the enzyme activity [<a href="/books/n/sef/A727/?report=reader#A807">79</a>,<a href="/books/n/sef/A727/?report=reader#A1669">941</a>]. Because
|
|
CBS is a “promiscuous” domain, which is found in association
|
|
with various proteins [<a href="/books/n/sef/A727/?report=reader#A754">26</a>], it has
|
|
caused numerous errors in automated genome annotation (see <a href="/books/n/sef/A264/?report=reader#A278">5.2.2</a>) [<a href="/books/n/sef/A727/?report=reader#A992">264</a>].
|
|
Thus, at least twelve <i>A. fulgidus</i> proteins have been annotated
|
|
as IMP dehydrogenases or “IMP dehydrogenase-related”
|
|
proteins [<a href="/books/n/sef/A727/?report=reader#A1172">444</a>], whereas, ironically,
|
|
the real IMP dehydrogenase appears not to be encoded in the <i>A.
|
|
fulgidus</i> genome. With the exception of this archaeon, IMP
|
|
dehydrogenase is present in almost every bacterial and archaeal genome sequenced
|
|
to date, including <i>A. pernix</i>, <i>C. pneumoniae</i>,
|
|
and <i>B. burgdorferi</i>, which do not encode any enzymes of IMP
|
|
biosynthesis and apparently have to import this nucleotide.</p></div><div id="A446"><h3>GMP synthase (EC 6.3.5.2)</h3><p>GMP synthase is another amidotransferase that consists of two subunits, a
|
|
glutamine amidotransferase of Triad family [<a href="/books/n/sef/A727/?report=reader#A1664">936</a>] and a synthetase subunit, which belongs to the PP-loop
|
|
superfamily of ATP pyrophosphatases [<a href="/books/n/sef/A727/?report=reader#A830">102</a>]. The phylogenetic pattern of both GMP synthase subunits is the same
|
|
as that of IMP dehydrogenase, with the addition of <i>A. fulgidus</i>,
|
|
i.e. this enzyme is also found in <i>A. pernix</i>, <i>C.
|
|
pneumoniae</i>, and <i>B. burgdorferi</i>, which lack many
|
|
other purine biosynthesis enzymes. In bacteria, yeast, and other eukaryotes, and
|
|
in <i>A. pernix</i>, these two subunits are fused together in the same
|
|
polypeptide, whereas in other archaea, they are encoded by separate genes.</p><div id="A447"><h4>General notes on purine biosynthesis evolution</h4><p>The phyletic distribution of purine biosynthesis enzymes shows some of the
|
|
trends noted above for other pathways, i.e. non-orthologous gene
|
|
displacement and increased loss of enzymes for upstream steps of the pathway
|
|
as compared to the downstream steps. With the exception of several obligate
|
|
parasites with very small genomes and <i>Buchnera</i> sp., most
|
|
bacteria encode the entire set of purine biosynthesis enzymes; there is
|
|
little doubt that they are all capable of IMP formation. Based on their gene
|
|
content, bacteria <i>H. pylori</i>, <i>C.
|
|
pneumoniae</i>, and <i>B. burgdorferi</i> and the archaeon
|
|
<i>A. pernix</i> are only capable of converting IMP into GMP;
|
|
AMP formation in these organisms probably occurs through the activity of
|
|
adenine phosphoribosyltransferase or some other mechanism. While
|
|
<i>Halobacterium</i> sp. and <i>Thermoplasma</i>
|
|
spp. encode all the enzymes of purine biosynthesis, other archaea appear to
|
|
miss at least two <i>pur</i> genes. Methanogens and pyrococci lack
|
|
<i>purK</i> and <i>purH</i> genes, and <i>A.
|
|
fulgidus</i> additionally lacks
|
|
<i>purN</i>/<i>purT</i> and <i>guaB</i>,
|
|
making it hard to judge whether the purine biosynthesis pathway is
|
|
functional in this organism. Purine biosynthesis is much more likely to
|
|
occur in methanogens and pyrococci, which would then need to harbor
|
|
alternative versions of AICAR transformylase and IMP cyclohydrolase and,
|
|
potentially, an alternative version of AIR carboxylase. Thus far, no obvious
|
|
candidates for these activities have been identified by comparative genome
|
|
analysis of these organisms. It is amazing that, although purine
|
|
biosynthesis has been intensely studied for over 50 years, comparative
|
|
genomics reveals unsuspected gaps in our understanding of this pathway and
|
|
may eventually lead to the discovery of novel enzymes.</p></div></div></div><div id="A448"><h2 id="_A448_">7.4. Amino Acid Biosynthesis</h2><div id="A449"><h3>7.4.1. Aromatic amino acids</h3><div id="A450"><h4>7.4.1.1. Common steps of the pathway</h4><p>The biosynthetic pathways for phenylalanine, tyrosine, and tryptophan in
|
|
bacteria and eukaryotes share common steps leading from phosphoenolpyruvate
|
|
and erythrose-4-phosphate to chorismate. Enzymes for most of these steps are
|
|
encoded also in archaeal genomes.</p><div id="A451"><h5>2-Dehydro-3-deoxy-D-arabino-heptonate 7-phosphate synthase (EC
|
|
4.1.2.15)</h5><p>Although 2-dehydro-3-deoxy-D-arabino-heptonate 7-phosphate (DAHP)
|
|
synthase is found in <i>E. coli</i> in three different
|
|
versions, AroF, AroG, and AroH, all of these enzymes are close paralogs
|
|
and represent the so-called microbial form of DAHP synthase. A different
|
|
form of this enzyme was originally described in potato and
|
|
<i>Arabidopsis</i> and designated the plant form.
|
|
Subsequently, this form has been discovered also in bacteria [<a href="/books/n/sef/A727/?report=reader#A933">205</a>,<a href="/books/n/sef/A727/?report=reader#A1026">298</a>,<a href="/books/n/sef/A727/?report=reader#A1161">433</a>,<a href="/books/n/sef/A727/?report=reader#A1607">879</a>]. This form
|
|
is encoded in many complete genomes and is the only DAHP synthase in
|
|
<i>M. tuberculosis</i>, <i>M. leprae</i>,
|
|
<i>H. pylori</i>, and <i>C. jejuni</i> (<a class="figpopup" href="/books/NBK20266/figure/A452/?report=objectonly" target="object" rid-figpopup="figA452" rid-ob="figobA452">Figure 7.6</a>). <i>B.
|
|
subtilis</i> and several other Gram-positive bacteria encode a
|
|
third form of DAHP synthase, referred to as AroA(G), which is homologous
|
|
to 3-deoxy-D-manno-octulosonate 8-phosphate synthase of <i>E.
|
|
coli</i> [<a href="/books/n/sef/A727/?report=reader#A824">96</a>].
|
|
Remarkably, this third form is also found in <i>T.
|
|
maritima</i> and in several archaea, such as <i>P.
|
|
abyssi</i>, <i>A. pernix</i>, and
|
|
<i>Thermoplasma</i> spp. Other archaea, such as <i>A.
|
|
fulgidus</i>, <i>M. jannaschii</i>, and <i>M.
|
|
thermoautotrophicum</i>, as well as the bacterium <i>A.
|
|
aeolicus</i>, encode neither of these three DAHP synthases and
|
|
appear to synthesize 3-dehydroquinate via a different mechanism that
|
|
does not include DAHP as an intermediate (see below).
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA452" co-legend-rid="figlgndA452"><a href="/books/NBK20266/figure/A452/?report=objectonly" target="object" title="Figure 7.6" class="img_link icnblk_img figpopup" rid-figpopup="figA452" rid-ob="figobA452"><img class="small-thumb" src="/books/NBK20266/bin/ch7f6.gif" src-large="/books/NBK20266/bin/ch7f6.jpg" alt="Figure 7.6. Distribution of tryptophan biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA452"><h4 id="A452"><a href="/books/NBK20266/figure/A452/?report=objectonly" target="object" rid-ob="figobA452">Figure 7.6</a></h4><p class="float-caption no_bottom_margin">Distribution of tryptophan biosynthesis enzymes in
|
|
organisms with completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A453"><h5>3-Dehydroquinate synthase (EC 4.6.1.3)</h5><p>3-Dehydroquinate synthase is found in many bacteria and in some archaea.
|
|
Remarkably, the phyletic pattern of this enzyme exactly corresponds to
|
|
the overlap of the phyletic patterns for the three forms of DAHP
|
|
synthase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e9.jpg" alt="Image ch7e9.jpg" /></div><p>This correlation suggests that a single form of 3-dehydroquinate synthase
|
|
can account for the conversion of DAHP into 3-dehydroquinate in all the
|
|
organisms with completely sequenced genomes and probably represents the
|
|
only form of this enzyme.</p></div><div id="A454"><h5>3-Dehydroquinate dehydratase (EC 4.2.1.10)</h5><p>Two forms of 3-dehydroquinate dehydratase have been characterized and
|
|
designated class I (encoded by <i>aroD</i> gene) and class II
|
|
(encoded by <i>aroQ</i> or QUTE genes), respectively. Taken
|
|
together, these two enzymes completely cover the phyletic diversity of
|
|
the organisms that encode 3-dehydroquinate synthase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e10.jpg" alt="Image ch7e10.jpg" /></div><p>Notably, dehydroquinate dehydratase (as well as most of the other enzymes
|
|
of tryptophan biosynthesis) is found in several genomes that do not
|
|
encode dehydroquinate synthase, indicating the existence of an
|
|
alternative, still uncharacterized pathway of dehydroquinate formation
|
|
in <i>Halobacterium</i> sp., <i>A. fulgidus</i>,
|
|
<i>M. jannaschii</i>, and <i>M.
|
|
thermoautotrophicum</i>, and <i>A. aeolicus.</i>
|
|
</p></div><div id="A455"><h5>Shikimate 5-dehydrogenase (EC 1.1.1.25)</h5><p>The last enzyme in the shikimate-producing part of the pathway, shikimate
|
|
5-dehydrogenase, is encoded in most of the completely sequenced
|
|
bacterial (with the exception of rickettsiae, spirochetes, and
|
|
mycoplasmas) and archaeal (with the exception of <i>P.
|
|
horikoshii</i>) genomes. The phyletic pattern for shikimate
|
|
5-dehydrogenase coincides with the combined pattern of the two forms of
|
|
3-dehydroquinate synthase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e11.jpg" alt="Image ch7e11.jpg" /></div></div><div id="A456"><h5>Shikimate kinase (EC 2.7.1.71)</h5><p>The typical form of shikimate kinase, found in bacteria and eukaryotes,
|
|
is not encoded in any archaeal genome sequenced so far. Recently, a
|
|
shikimate kinase of the GHMP superfamily has been identified and
|
|
experimentally studied in <i>M. jannaschii</i> [<a href="/books/n/sef/A727/?report=reader#A899">171</a>]. This enzyme is encoded in
|
|
each archaeal genome, except for <i>P. horikoshii</i>.
|
|
Together, these two forms of shikimate kinase have the same phyletic
|
|
pattern as the combination of the two forms of 3-dehydroquinate
|
|
dehydratase or shikimate dehydrogenase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e12.jpg" alt="Image ch7e12.jpg" /></div></div><div id="A457"><h5>5-Enolpyruvylshikimate 3-phosphate synthase (EC 2.5.1.19)</h5><p>Like shikimate dehydrogenase, 5-enolpyruvylshikimate 3-phosphate synthase
|
|
(AroA) is found in only one form with the same phyletic pattern as the
|
|
preceding enzyme.</p></div><div id="A458"><h5>Chorismate synthase (EC 4.6.1.4)</h5><p>The only known chorismate synthase (AroC) has the same phyletic pattern
|
|
as shikimate dehydrogenase and 5-enolpyruvylshikimate 3-phosphate
|
|
synthase.</p></div></div><div id="A459"><h4>7.4.1.2. Tryptophan biosynthesis</h4><p>After chorismate, the tryptophan biosynthetic pathway deviates from the
|
|
pathways leading to phenylalanine and tyrosine. In the tryptophan branch,
|
|
all the remaining enzymes have very similar phyletic patterns.</p><div id="A460"><h5>Anthranilate synthase (EC 4.1.3.27)</h5><p>Anthranilate synthase and the closely related para-aminobenzoate synthase
|
|
consist of two components, the synthetase subunit and the glutamine
|
|
amidotransferase subunit, which, in most organisms, are encoded by
|
|
separate genes <i>trpG</i> (or <i>pabA</i>) and
|
|
<i>trpE</i> (or <i>pabB</i>). In <i>E.
|
|
coli</i>, the <i>trpG</i> gene for glutamine
|
|
amidotransferase subunit is fused to the <i>trpD</i> gene that
|
|
encodes anthranilate phosphoribosyltransferase, the enzyme catalyzing
|
|
the next step of the pathway. This sometimes leads to a confusion in
|
|
nomenclature, with the <i>trpG</i> gene being referred to as
|
|
<i>trpD</i> or as
|
|
<i>trpD</i>_<i>1</i>. The phyletic pattern for
|
|
anthranilate synthase is the same as the patterns described above for
|
|
shikimate dehydrogenase, 5-enolpyruvylshikimate 3-phosphate synthase,
|
|
and chorismate synthase, with the exception that anthranilate synthase
|
|
is missing in chlamydiae.</p></div><div id="A461"><h5>Anthranilate phosphoribosyltransferase (EC 2.4.2.18)</h5><p>There is only one form of anthranilate phosphoribosyltransferase that
|
|
shows almost the same phyletic pattern as anthranilate synthase. The
|
|
only diversification in the existing set of genomes is the absence of
|
|
the <i>trpD</i> gene (as well as genes for the remaining steps
|
|
of tryptophan biosynthesis) in <i>S. pyogenes</i>. This
|
|
probably means that genes annotated as <i>trpG</i> and
|
|
<i>trpE</i> in <i>S. pyogenes</i> actually
|
|
encode para-aminobenzoate synthase and have no role in tryptophan
|
|
biosynthesis.</p></div><div id="A462"><h5>N-(5′-Phosphoribosyl)anthranilate isomerase (EC
|
|
5.3.1.24)</h5><p>Phosphoribosylanthranilate isomerase is also represented by only one form
|
|
with essentially the same phyletic pattern as anthranilate
|
|
phosphoribosyltransferase. Here again, the nomenclature is somewhat
|
|
complicated because of a gene fusion in <i>E. coli</i>. The
|
|
phosphoribosylanthranilate isomerase gene that, in most species, is
|
|
referred to as <i>trpF,</i> in <i>E. coli</i> is
|
|
fused to the <i>trpC</i> gene that encodes indole-3-glycerol
|
|
phosphate synthase, the enzyme for the next step of the pathway.
|
|
Therefore, in <i>E. coli,</i> the <i>trpF</i> gene
|
|
is sometimes also referred to as <i>trpC</i>, which can lead
|
|
to confusion. The phyletic pattern of phosphoribosylanthranilate
|
|
isomerase is essentially the same as that of other enzymes of tryptophan
|
|
biosynthesis, with the most notable difference being the apparent
|
|
absence of <i>trpF</i> in <i>M. tuberculosis</i> and
|
|
<i>M. leprae</i>. Another peculiarity is the unusual
|
|
distribution of phosphoribosylanthranilate isomerase in different
|
|
chlamydial species: while <i>C. trachomatis</i> and <i>C.
|
|
muridarum</i> both have the <i>trpF</i> gene,
|
|
<i>C. pneumoniae</i> does not. This probably reflects the
|
|
ongoing gene loss in the evolution of chlamydiae.</p></div><div id="A463"><h5>Indole-3-glycerol phosphate synthase (EC 4.1.1.48)</h5><p>Indole-3-glycerol phosphate synthase exists in a single form with the
|
|
same phyletic pattern as anthranilate phosphoribosyltransferase.</p></div><div id="A464"><h5>Tryptophan synthase (EC 4.2.1.20)</h5><p>Tryptophan synthase consists of two subunits, which are encoded by
|
|
<i>trpA</i> and <i>trpB</i> genes. Their
|
|
phyletic patterns are similar to that of anthranilate
|
|
phosphoribosyltransferase, with the exception that, as seen above for
|
|
<i>trpC</i>, <i>trpA</i>, and
|
|
<i>trpB</i> genes are found in <i>C.
|
|
trachomatis</i> and <i>C. muridarum</i> but not in
|
|
<i>C. pneumoniae</i>. </p></div></div><div id="A465"><h4>7.4.1.3. Phenylalanine and tyrosine biosynthesis</h4><div id="A466"><h5>Chorismate mutase (EC 5.4.99.5)</h5><p>Chorismate mutase is involved in both phenylalanine and tyrosine
|
|
biosynthesis. The best-known version of this enzyme is found in
|
|
<i>E. coli</i> in two paralogous forms fused with
|
|
prephenate dehydratase in PheA and prephenate dehydrogenase in TyrA. In
|
|
addition to these two forms, there is (i) a distantly related form of
|
|
chorismate mutase encoded in yeast, fungi, and in plant cells and (ii)
|
|
an unrelated monofunctional form found in <i>B. subtilis</i>,
|
|
<i>Synechocystis</i> sp., and many other Gram-positive
|
|
bacteria and cyanobacteria.</p><p>Although these three forms of chorismate mutase show almost no sequence
|
|
similarity to each other, structural comparisons indicate that the
|
|
<i>E. coli</i> and yeast enzymes are related to each other
|
|
and are unrelated to the form found in <i>B. subtilis</i> and
|
|
<i>Th. thermophilus</i>. A comparison of the combined
|
|
phyletic pattern of all these forms of chorismate mutase with that of
|
|
chorismate synthase shows that, with the exception of <i>P.
|
|
abyssi</i> and in <i>Chlamydia</i> spp., all
|
|
organisms that produce chorismate are capable of converting it to
|
|
prephenate.</p></div><div id="A467"><h5>Prephenate dehydrogenase (EC 1.3.1.12)</h5><p>Prephenate dehydrogenase TyrA, an enzyme of the tyrosine biosynthesis
|
|
branch of the pathway, is found in a single form with almost the same
|
|
phyletic pattern as chorismate mutase (<a class="figpopup" href="/books/NBK20266/figure/A468/?report=objectonly" target="object" rid-figpopup="figA468" rid-ob="figobA468">Figure 7.7</a>). The only exception is <i>S.
|
|
pyogenes</i> that appears not to encode prephenate
|
|
dehydrogenase.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA468" co-legend-rid="figlgndA468"><a href="/books/NBK20266/figure/A468/?report=objectonly" target="object" title="Figure 7.7" class="img_link icnblk_img figpopup" rid-figpopup="figA468" rid-ob="figobA468"><img class="small-thumb" src="/books/NBK20266/bin/ch7f7.gif" src-large="/books/NBK20266/bin/ch7f7.jpg" alt="Figure 7.7. Distribution of phenylalanine and tyrosine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA468"><h4 id="A468"><a href="/books/NBK20266/figure/A468/?report=objectonly" target="object" rid-ob="figobA468">Figure 7.7</a></h4><p class="float-caption no_bottom_margin">Distribution of phenylalanine and tyrosine biosynthesis
|
|
enzymes in organisms with completely sequenced
|
|
genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A469"><h5>Prephenate dehydratase (EC 4.2.1.51)</h5><p>Prephenate dehydratase, an enzyme of the phenylalanine biosynthesis
|
|
branch of the pathway, is also represented by a single form in all known
|
|
organisms. However, its phyletic pattern shows the absence of this
|
|
enzyme in <i>S. pyogenes</i>, <i>H. pylori</i>, and
|
|
<i>A. pernix</i>, which are all capable of producing
|
|
prephenate, suggesting that these organisms either lack phenylalanine
|
|
biosynthesis or have an alternative form of prephenate dehydratase.</p></div><div id="A470"><h5>Aromatic aminotransferase (EC 2.6.1.1, 2.6.1.5, 2.6.1.9,
|
|
2.6.1.57)</h5><p>There are several families of pyridoxal-phosphate-dependent
|
|
aminotransferases that are capable of producing tyrosine and
|
|
phenylalanine from, respectively, 4-hydroxyphenylpyruvate and
|
|
phenylpyruvate. Although the best-studied tyrosine aminotransferase,
|
|
<i>E. coli</i> TyrB, has a relatively narrow phyletic
|
|
distribution, homologs of histidinol phosphate aminotransferase and
|
|
aspartate aminotransferase are encoded in every bacterial and archaeal
|
|
genome except for spirochetes and mycoplasmas. Thus, once phenylpyruvate
|
|
and 4-hydroxyphenylpyruvate are synthesized, their transamination into,
|
|
respectively, phenylalanine and tyrosine can be performed by all
|
|
organisms whose genome sequences are currently available.</p><div id="A471"><h5>A summary on aromatic amino acid biosynthesis</h5><p>Because aromatic amino acid biosynthesis shares common steps with
|
|
biosynthesis of ubiquinone, this pathway displays a stunning variety
|
|
of alternative enzymes catalyzing the same reaction. This makes
|
|
analysis of their phyletic patterns rather complicated, but, at the
|
|
same time, allows one to draw some interesting conclusions. Most
|
|
bacteria and archaea retain the complete set of genes for tryptophan
|
|
biosynthesis. The exceptions are the obligate archaeal heterotroph
|
|
<i>P. horikoshii</i> and some obligate bacterial
|
|
parasites, such as <i>S. pyogenes</i>, rickettsiae,
|
|
chlamydiae, spirochetes, and mycoplasmas, which apparently obtain
|
|
tryptophan, just like many other nutrients, from other microbes and
|
|
from the host, respectively.</p><p>Enzymes of the tyrosine biosynthesis pathway are encoded in almost as
|
|
many complete genomes, with the conspicuous exception of <i>P.
|
|
abyssi</i>. One could speculate that, while tryptophan is
|
|
rapidly degraded at 105ºC (the optimal growth temperature
|
|
of this organism), tyrosine is not, which alleviates the requirement
|
|
for <i>de novo</i> synthesis. These considerations could
|
|
also explain the absence of phenylalanine biosynthesis in <i>P.
|
|
abyssi</i> and <i>A. pernix</i>.</p><p>The consistency of the phyletic patterns of the enzymes for the
|
|
downstream stages of aromatic amino acid biosynthesis underscores
|
|
the remaining problem with the early stages. Indeed, <i>A.
|
|
aeolicus</i> and four archaeal species encode
|
|
3-dehydroquinate dehydratase and all the downstream enzymes but do
|
|
not encode either DAHP synthase or 3-dehydroquinate synthase:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e13.jpg" alt="Image ch7e13.jpg" /></div><p>It appears that these organisms produce 3-dehydroquinate via a
|
|
different mechanism, which does not include DAHP as an intermediate.
|
|
Using the COG phyletic pattern search tool, one could search for
|
|
orthologous protein sets that are represented in those five genomes
|
|
but are missing in thermoplasmas, pyrococci, <i>A.
|
|
pernix</i>, and <i>T. maritima</i>, all of which
|
|
encode a DAHP synthase and a 3-dehydroquinate synthase. Such a
|
|
search identified just four COGs, only one of which, COG1465,
|
|
consisted of uncharacterized proteins. These proteins, orthologs of
|
|
<i>M. jannaschii</i> MJ1249, can be predicted to
|
|
function as an alternative 3-dehydroquinate synthases (M.Y.G.,
|
|
unpublished). This prediction seems to be further supported by the
|
|
adjacency of the genes encoding COG1465 members AF0229 and VNG0310C
|
|
to the <i>aroC</i> gene in the genomes of <i>A.
|
|
fulgidus</i> and <i>Halobacterium</i> sp.,
|
|
respectively. However, even if this prediction is correct, the exact
|
|
nature of the precursor for 3-dehydroquinate and the mechanism of
|
|
its biosynthesis in these organisms need to be elucidated
|
|
experimentally.</p></div></div></div></div><div id="A472"><h3>7.4.2. Arginine biosynthesis</h3><div id="A473"><h4>N-Acetylglutamate synthase (EC 2.3.1.1, 2.3.1.35)</h4><p>The first step in arginine biosynthesis from glutamate is its acetylation,
|
|
with either acetyl-CoA or acetylornithine utilized as donors of the acetyl
|
|
group (<a class="figpopup" href="/books/NBK20266/figure/A474/?report=objectonly" target="object" rid-figpopup="figA474" rid-ob="figobA474">Figure 7.8</a>). In <i>E.
|
|
coli</i> and several other organisms, this reaction is catalyzed by
|
|
the acetyltransferase ArgA, which employs acetyl-CoA as the acetyl donor. In
|
|
all proteobacteria that encode this enzyme, the <i>argA</i> gene
|
|
is fused to the gene for N-acetylglutamate kinase, which catalyzes the next
|
|
step of the pathway. Like in other domain fusion cases, confusion
|
|
occasionally emerges during genome annotation, especially because the
|
|
N-terminal kinase domain, which consists of ~300 amino acid residues, can
|
|
make the C-terminal acetyltransferase domain almost invisible in BLAST
|
|
outputs (see <a href="/books/n/sef/A166/?report=reader#A224">4.4.4</a>).
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA474" co-legend-rid="figlgndA474"><a href="/books/NBK20266/figure/A474/?report=objectonly" target="object" title="Figure 7.8" class="img_link icnblk_img figpopup" rid-figpopup="figA474" rid-ob="figobA474"><img class="small-thumb" src="/books/NBK20266/bin/ch7f8.gif" src-large="/books/NBK20266/bin/ch7f8.jpg" alt="Figure 7.8. Distribution of arginine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA474"><h4 id="A474"><a href="/books/NBK20266/figure/A474/?report=objectonly" target="object" rid-ob="figobA474">Figure 7.8</a></h4><p class="float-caption no_bottom_margin">Distribution of arginine biosynthesis enzymes in organisms
|
|
with completely sequenced genomes. All details as in Figure
|
|
2.7. </p></div></div><p>A different, unrelated N-acetylglutamate synthase (N-acetylornithine
|
|
transferase, the <i>argJ</i> gene product) is present in
|
|
<i>B. subtilis</i>, yeast, and many other organisms. This
|
|
enzyme couples acetylation of glutamate with deacetylation of
|
|
N-acetylornithine, which is the fifth step in arginine biosynthesis. This
|
|
activity allows recycling of the acetyl group in the arginine biosynthesis
|
|
pathway.</p></div><div id="A475"><h4>N-Acetylglutamate kinase (EC 2.7.2.8)</h4><p>Phosphorylation of N-acetylglutamate is catalyzed by the product of the
|
|
<i>argB</i> gene, a kinase with the carbamate kinase fold.
|
|
This enzyme is found in a wide variety of organisms, such that its phyletic
|
|
pattern is even broader than the combined patterns of both enzymes that
|
|
generate N-acetylglutamate:</p><div class="graphic"><img src="/books/NBK20266/bin/ch7e14.jpg" alt="Image ch7e14.jpg" /></div><p>However, N-acetylglutamate kinase is not encoded in the genomes of many
|
|
parasitic bacteria, such as <i>S. pyogenes</i>, <i>H.
|
|
influenzae</i>, <i>H. pylori</i>, chlamydiae,
|
|
rickettsiae, spirochetes, and mycoplasmas.</p></div><div id="A476"><h4>N-Acetyl-gamma-glutamyl phosphate reductase (EC 1.2.1.38)</h4><p>The enzyme that catalyzes the next step of the pathway, ArgC, has the same
|
|
phyletic pattern as ArgB. In fungi, <i>argB</i> and
|
|
<i>argC</i> genes are fused and encode a single bifunctional
|
|
protein.</p></div><div id="A477"><h4>N-Acetylornithine aminotranferase (EC 2.6.1.11)</h4><p>N-Acetylornithine deacetylase (N-acetylornithinase) belongs to a large family
|
|
of closely related acetyltransferases (deacetylases), which is represented
|
|
by two or more paralogs even in the relatively small genomes of <i>H.
|
|
influenzae</i>, <i>L. lactis</i>, and <i>S.
|
|
pyogenes</i>. Although proper assignment of substrate specificity
|
|
in such a case is difficult, if not impossible, the few organisms that
|
|
produce N-acetylornithine but lack the ArgJ-type N-acetylglutamate synthase
|
|
offer an ample choice of candidates for the function of
|
|
N-acetylornithinase.</p></div><div id="A478"><h4>N-Acetylornithine deacetylase (EC 3.5.1.16)</h4><p>N-Acetylornithinase belongs to a large family of closely related
|
|
acetyltransferases (deacylases), which is represented by two or more
|
|
paralogs even in the relatively small genomes of <i>H.
|
|
influenzae</i>, <i>L. lactis</i>, and <i>S.
|
|
pyogenes</i>. Although proper assignment of substrate specificity
|
|
in such a case is difficult, if not impossible, the few organisms that
|
|
produce N-acetylornithine but lack the ArgJ-type N-acetylglutamate synthase
|
|
offer an ample choice of candidates for the role of N-acetylornithinase.</p></div><div id="A479"><h4>Ornithine carbamoyltransferase (EC 2.1.3.6)</h4><p>Ornithine carbamoyltransferase catalyzes the sixth step of arginine
|
|
biosynthesis, conversion of ornithine into citrulline. Carbamoyl phosphate
|
|
that serves as the second substrate of this reaction is provided by
|
|
carbamoyl phosphate synthetase, which was discussed above (see <a href="#A419">7.2</a>). Ornithine carbamoyltransferase
|
|
has a much wider phyletic distribution than other enzymes of arginine
|
|
biosynthesis. This is probably due to the fact that it also catalyzes the
|
|
reverse reaction, i. e. phosphorolysis of citrulline with the formation of
|
|
ornithine and carbamoyl phosphate, which is part of the urea cycle.
|
|
Accordingly, ornithine carbamoyltransferase is found in humans and other
|
|
higher eukaryotes, which have the urea cycle but are incapable of arginine
|
|
biosynthesis.</p></div><div id="A480"><h4>Argininosuccinate synthase (EC 6.3.4.5)</h4><p>Like ornithine carbamoyltransferase, argininosuccinate synthase participates
|
|
in the urea cycle. As a result, its phyletic distribution is also wider than
|
|
that of the enzymes that catalyze early steps of arginine biosynthesis. This
|
|
enzyme, too, is found in humans and in bacteria, such as <i>H.
|
|
influenzae</i>, which have all the urea cycle enzymes but lack
|
|
several enzymes of arginine biosynthesis.</p></div><div id="A481"><h4>Argininosuccinate lyase (EC 4.3.2.1)</h4><p>Argininosuccinate lyase, the last enzyme of arginine biosynthesis, splits
|
|
argininosuccinate into arginine and fumarate. Like the two preceding
|
|
enzymes, it also participates in the urea cycle, and its phyletic pattern is
|
|
nearly identical to that of argininosuccinate synthetase.</p></div></div><div id="A482"><h3>7.4.3. Histidine biosynthesis</h3><p>In contrast to the pathways of aromatic amino acid and arginine biosynthesis,
|
|
histidine biosynthesis exhibits remarkable consistency of the phyletic patterns
|
|
of all the enzymes involved (<a class="figpopup" href="/books/NBK20266/figure/A483/?report=objectonly" target="object" rid-figpopup="figA483" rid-ob="figobA483">Figure 7.9</a>).
|
|
While the first enzyme of the pathway, phosphoribosylpyrophosphate synthetase
|
|
(EC 2.7.6.1), also participates in the purine biosynthesis pathway (see above),
|
|
nearly all the committed enzymes of histidine biosynthesis have the same
|
|
phyletic pattern, indicating that this pathway is encoded in the great majority
|
|
of complete prokaryotic genomes sequenced to date. The exceptions are the
|
|
heterotrophic archaea <i>Thermoplasma</i> spp.,
|
|
<i>Pyrococcus</i> sp., and <i>A. pernix</i>, and
|
|
parasitic bacteria with small genomes, namely rickettsiae, chlamydiae,
|
|
spirochetes, and mycoplasmas, as well as <i>S. pyogenes</i> and
|
|
<i>H. pylori</i> (despite their larger genomes). Remarkably, the
|
|
aphid symbiont <i>Buchnera</i> sp., which has the second smallest
|
|
genome available to date, encodes the complete set of histidine biosynthesis
|
|
enzymes.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA483" co-legend-rid="figlgndA483"><a href="/books/NBK20266/figure/A483/?report=objectonly" target="object" title="Figure 7.9" class="img_link icnblk_img figpopup" rid-figpopup="figA483" rid-ob="figobA483"><img class="small-thumb" src="/books/NBK20266/bin/ch7f9.gif" src-large="/books/NBK20266/bin/ch7f9.jpg" alt="Figure 7.9. Distribution of histidine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA483"><h4 id="A483"><a href="/books/NBK20266/figure/A483/?report=objectonly" target="object" rid-ob="figobA483">Figure 7.9</a></h4><p class="float-caption no_bottom_margin">Distribution of histidine biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details as in Figure
|
|
2.7. </p></div></div><p>There are several deviations from this common pattern. First, phosphoribosyl-ATP
|
|
pyrophosphatase (EC 3.6.1.31) was not detected in <i>A. fulgidus</i>.
|
|
Since this organism encodes genes for all other enzymes of histidine
|
|
biosynthesis, one should assume that this reaction in <i>A.
|
|
fulgidus</i> is catalyzed by an unrelated pyrophosphatase. Indeed,
|
|
<i>A. fulgidus</i> genome encodes several predicted
|
|
pyrophosphatases of unknown specificity (COG1694) that could be good candidates
|
|
for the role of the missing phosphoribosyl-ATP pyrophosphatase.</p><p>Another deviation from the common pattern is the existence of at least two
|
|
unrelated histidinol phosphatases (<a class="figpopup" href="/books/NBK20266/figure/A483/?report=objectonly" target="object" rid-figpopup="figA483" rid-ob="figobA483">Figure
|
|
7.9</a>), one of which has been experimentally characterized in
|
|
<i>E. coli</i> and the other in yeast and <i>B.
|
|
subtilis</i> [<a href="/books/n/sef/A727/?report=reader#A743">15</a>,<a href="/books/n/sef/A727/?report=reader#A1228">500</a>]. The latter form of this enzyme
|
|
(COG1387) belongs to a large superfamily of PHP-type phosphohydrolases [<a href="/books/n/sef/A727/?report=reader#A769">41</a>], which have common sequence motifs but
|
|
clearly differ in substrate specificity. A closer inspection of COG1387 shows
|
|
that proteins from yeast, <i>B. subtilis</i>, <i>B.
|
|
halodurans</i>, <i>L. lactis</i>, <i>D.
|
|
radiodurans</i>, and <i>T. maritima</i>, comprise a tight
|
|
orthologous set and can be confidently predicted to possess histidinol
|
|
phosphatase activity. Other members of this COG are more distantly related to
|
|
the experimentally characterized histidinol phosphatases from yeast and
|
|
<i>B. subtilis</i> and might have other substrates. In addition,
|
|
both forms of histidinol phosphatase are missing in
|
|
<i>Halobacterium</i> sp. Therefore it appears likely that there is
|
|
yet another, so far unrecognized, form of histidinol phosphatase in
|
|
<i>Halobacterium</i> sp., <i>Thermoplasma</i> spp., and
|
|
other organisms. There are plenty of unassigned predicted hydrolases that could
|
|
potentially have this activity.</p><p>Remarkably, the ortholog of the <i>E. coli</i> histidinol phosphatase
|
|
(HisB, COG0241) is encoded in <i>H. pylori</i>, which lacks all the
|
|
other enzymes of histidine biosynthesis. This protein most likely represents a
|
|
case of enzyme recruitment and functions as a phosphatase that hydrolyzes some
|
|
other phosphoester.</p></div><div id="A484"><h3>7.4.4. Biosynthesis of branched-chain amino acids</h3><p>To those readers who are already tired of numerous instances of non-orthologous
|
|
gene displacement in metabolic pathways, biosynthesis of leucine, isoleucine,
|
|
and valine offers a well-deserved reprieve. In these pathways, the only instance
|
|
of alternative enzymes catalyzing the same reaction is the last step, amination
|
|
of α-ketomethylvaleriate, α-ketoisovaleriate, and
|
|
α-ketoisocaproate. In addition to the branched-chain amino acid
|
|
aminotransferase IlvE, this reaction can be catalyzed by alternative
|
|
aminotransferases (<a class="figpopup" href="/books/NBK20266/figure/A485/?report=objectonly" target="object" rid-figpopup="figA485" rid-ob="figobA485">Figure 7.10</a>)
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA485" co-legend-rid="figlgndA485"><a href="/books/NBK20266/figure/A485/?report=objectonly" target="object" title="Figure 7.10" class="img_link icnblk_img figpopup" rid-figpopup="figA485" rid-ob="figobA485"><img class="small-thumb" src="/books/NBK20266/bin/ch7f10.gif" src-large="/books/NBK20266/bin/ch7f10.jpg" alt="Figure 7.10. Distribution of isoleucine/leucine/valine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA485"><h4 id="A485"><a href="/books/NBK20266/figure/A485/?report=objectonly" target="object" rid-ob="figobA485">Figure 7.10</a></h4><p class="float-caption no_bottom_margin">Distribution of isoleucine/leucine/valine biosynthesis enzymes in
|
|
organisms with completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A486"><h3>7.4.5. Proline biosynthesis</h3><p>The best characterized pathway of proline biosynthesis is a three-step chain of
|
|
reactions (<a class="figpopup" href="/books/NBK20266/figure/A487/?report=objectonly" target="object" rid-figpopup="figA487" rid-ob="figobA487">Figure 7.11</a>) that converts
|
|
glutamate into proline through consecutive action of glutamate kinase (ProB, EC
|
|
2.7.2.11), γ-glutamyl phosphate reductase (ProA, EC 1.2.1.41), and
|
|
Δ-pyrroline-5-carboxylate reductase (ProC, EC 1.5.1.2). This pathway
|
|
is encoded in yeast, <i>E. coli</i>, <i>B. subtilis</i>, and
|
|
in many other bacteria, including <i>C. jejuni</i> (but not <i>H.
|
|
pylori</i>) and <i>T. pallidum</i> (but not <i>B.
|
|
burgdorferi</i>). This pathway, however, is not detectable in archaea,
|
|
except for the two species of <i>Methanosarcina</i>, which, in all
|
|
likelihood, acquired it through HGT. Instead, <i>Halobacterium</i>
|
|
sp., <i>A. fulgidus</i>, <i>M. thermoautotrophicum</i>,
|
|
<i>Thermoplasma</i> spp., and <i>A. pernix</i> encode an
|
|
unusual enzyme, ornithine cyclodeaminase (EC 4.3.1.12), which directly makes
|
|
proline from ornithine. This enzyme, first discovered in tumor-inducing (Ti)
|
|
plasmids of <i>A. tumefaciens</i>, was later found in pseudomonads and
|
|
other bacteria [<a href="/books/n/sef/A727/?report=reader#A911">183</a>,<a href="/books/n/sef/A727/?report=reader#A1526">798</a>]. In plants, expression of this
|
|
interesting enzyme stimulates flowering [<a href="/books/n/sef/A727/?report=reader#A1578">850</a>], whereas the mammalian ortholog of this enzyme is expressed in
|
|
neural tissue, including human retina, and functions as μ-crystallin, a
|
|
major component of the eye lens in marsupials [<a href="/books/n/sef/A727/?report=reader#A1166">438</a>]. Although no such gene was detected in <i>M.
|
|
jannaschii</i>, this archaeon, too, has been reported to possess
|
|
ornithine cyclodeaminase activity [<a href="/books/n/sef/A727/?report=reader#A1037">309</a>].
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA487" co-legend-rid="figlgndA487"><a href="/books/NBK20266/figure/A487/?report=objectonly" target="object" title="Figure 7.11" class="img_link icnblk_img figpopup" rid-figpopup="figA487" rid-ob="figobA487"><img class="small-thumb" src="/books/NBK20266/bin/ch7f11.gif" src-large="/books/NBK20266/bin/ch7f11.jpg" alt="Figure 7.11. Distribution of proline biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA487"><h4 id="A487"><a href="/books/NBK20266/figure/A487/?report=objectonly" target="object" rid-ob="figobA487">Figure 7.11</a></h4><p class="float-caption no_bottom_margin">Distribution of proline biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. </p></div></div><p>An interesting aspect of proline metabolism is that its biosynthesis and
|
|
degradation both proceed through the Δ-pyrroline-5-carboxylate
|
|
intermediate. As a result, the proline biosynthetic pathway is sometimes
|
|
confused with proline catabolism. Another complication in the analysis of
|
|
proline metabolism is that, in <i>E. coli</i> and several other
|
|
bacteria, the genes for proline dehydrogenase (EC 1.5.99.8) and
|
|
γ-glutamate semialdehyde dehydrogenase (EC 1.5.1.12), the first and
|
|
second enzymes of proline catabolism, respectively, are fused, forming the
|
|
bifunctional protein PutA. In the COG database, these two domains of the PutA
|
|
protein belong to two different COGs, COG0506 and COG1012 (<a class="figpopup" href="/books/NBK20266/figure/A487/?report=objectonly" target="object" rid-figpopup="figA487" rid-ob="figobA487">Figure 7.11</a>).</p><p>In conclusion, proline metabolism is tightly interlinked with arginine
|
|
metabolism. Proline biosynthesis from glutamate can be reconstructed in all
|
|
organisms with completely sequenced genomes with the exception of pyrococci,
|
|
<i>H. pylori</i>, <i>B. burgdorferi</i>, chlamydiae, and
|
|
mycoplasmas. The gene encoding ornithine cyclodeaminase in <i>M.
|
|
jannaschii</i> [<a href="/books/n/sef/A727/?report=reader#A1037">309</a>] remains
|
|
to be identified. It can be expected to be a member of a different enzyme
|
|
family, unrelated to the known ornithine cyclodeaminases (COG2423).</p></div></div><div id="A488"><h2 id="_A488_">7.5. Coenzyme Biosynthesis</h2><div id="A489"><h3>7.5.1. Thiamine</h3><p>Biosynthesis of cofactors (coenzymes), particularly thiamine, is a surprisingly
|
|
poorly studied area of biochemistry. Although the first <i>thi</i>
|
|
mutations in <i>E. coli</i> were characterized half a century ago, the
|
|
complete list of thiamine biosynthesis genes has been determined only in the
|
|
1990's [<a href="/books/n/sef/A727/?report=reader#A1596">868</a>], and the functions of
|
|
their products have been characterized only in the last several years [<a href="/books/n/sef/A727/?report=reader#A809">81</a>,<a href="/books/n/sef/A727/?report=reader#A811">83</a>,<a href="/books/n/sef/A727/?report=reader#A1655">927</a>]. The scheme for
|
|
thiamine biosynthesis in <a class="figpopup" href="/books/NBK20266/figure/A490/?report=objectonly" target="object" rid-figpopup="figA490" rid-ob="figobA490">Figure 7.12</a> was
|
|
drawn using the <i>E. coli</i> data. One cannot help noticing that
|
|
every enzyme on this chart has its own distinct phyletic pattern. This indicates
|
|
the abundance of non-orthologous gene displacement cases among thiamine
|
|
biosynthesis enzymes and suggests that different organisms might use different
|
|
compounds as thiamin precursors. The apparent absence of ThiC in thermoplasmas,
|
|
<i>A. pernix</i>, <i>H. influenzae</i>, and <i>H.
|
|
pylori</i>, all of which encode ThiD (<a class="figpopup" href="/books/NBK20266/figure/A490/?report=objectonly" target="object" rid-figpopup="figA490" rid-ob="figobA490">Figure 7.12</a>), is a strong indication that some intermediate other
|
|
than AIR is used as a precursor in these organisms. Thus, although all steps of
|
|
the thiamine biosynthesis pathway have been resolved for <i>E.
|
|
coli</i> [<a href="/books/n/sef/A727/?report=reader#A809">81</a>], there is still
|
|
ample opportunity for new discoveries in other organisms.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA490" co-legend-rid="figlgndA490"><a href="/books/NBK20266/figure/A490/?report=objectonly" target="object" title="Figure 7.12" class="img_link icnblk_img figpopup" rid-figpopup="figA490" rid-ob="figobA490"><img class="small-thumb" src="/books/NBK20266/bin/ch7f12.gif" src-large="/books/NBK20266/bin/ch7f12.jpg" alt="Figure 7.12. Distribution of thiamine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA490"><h4 id="A490"><a href="/books/NBK20266/figure/A490/?report=objectonly" target="object" rid-ob="figobA490">Figure 7.12</a></h4><p class="float-caption no_bottom_margin">Distribution of thiamine biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A491"><h3>7.5.2. Riboflavin</h3><p>The riboflavin biosynthesis pathway is a challenging case, with three of the
|
|
seven <i>rib</i> genes characterized in <i>E. coli</i> and
|
|
<i>B. subtilis</i> having no archaeal orthologs (<a class="figpopup" href="/books/NBK20266/figure/A492/?report=objectonly" target="object" rid-figpopup="figA492" rid-ob="figobA492">Figure 7.13</a>). The archaeal variant of
|
|
riboflavin synthase, the last enzyme of the pathway, has been identified and
|
|
turned out to be unrelated to the bacterial enzyme [<a href="/books/n/sef/A727/?report=reader#A935">207</a>]. In contrast, the archaeal versions of the first two
|
|
enzymes of the pathway, GTP cyclohydrolase II (RibA) and pyrimidine deaminase
|
|
(RibD1), remain unknown, so there is an excellent chance of discovering new
|
|
enzymes of this pathway.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA492" co-legend-rid="figlgndA492"><a href="/books/NBK20266/figure/A492/?report=objectonly" target="object" title="Figure 7.13" class="img_link icnblk_img figpopup" rid-figpopup="figA492" rid-ob="figobA492"><img class="small-thumb" src="/books/NBK20266/bin/ch7f13.gif" src-large="/books/NBK20266/bin/ch7f13.jpg" alt="Figure 7.13. Distribution of riboflavin biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA492"><h4 id="A492"><a href="/books/NBK20266/figure/A492/?report=objectonly" target="object" rid-ob="figobA492">Figure 7.13</a></h4><p class="float-caption no_bottom_margin">Distribution of riboflavin biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A493"><h3>7.5.3. NAD</h3><p>Nicotinate mononucleotide adenylyltransferase, the last missing enzyme of the NAD
|
|
biosynthesis pathway, has been characterized only in 2000, thanks in part to the
|
|
genome context-based methods [<a href="/books/n/sef/A727/?report=reader#A810">82</a>,<a href="/books/n/sef/A727/?report=reader#A1291">563</a>,<a href="/books/n/sef/A727/?report=reader#A1320">592</a>]. It turned out that <i>E. coli</i> has two distantly
|
|
related forms of this enzyme, which shows specificity, respectively, for
|
|
mononucleotides of nicotinic acid (NadR_2) and nicotinamide (NadD) [<a href="/books/n/sef/A727/?report=reader#A1007">279</a>]. Most other organisms encode either
|
|
one or the other form (<a class="figpopup" href="/books/NBK20266/figure/A494/?report=objectonly" target="object" rid-figpopup="figA494" rid-ob="figobA494">Figure 7.14</a>).
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA494" co-legend-rid="figlgndA494"><a href="/books/NBK20266/figure/A494/?report=objectonly" target="object" title="Figure 7.14" class="img_link icnblk_img figpopup" rid-figpopup="figA494" rid-ob="figobA494"><img class="small-thumb" src="/books/NBK20266/bin/ch7f14.gif" src-large="/books/NBK20266/bin/ch7f14.jpg" alt="Figure 7.14. Distribution of NAD biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA494"><h4 id="A494"><a href="/books/NBK20266/figure/A494/?report=objectonly" target="object" rid-ob="figobA494">Figure 7.14</a></h4><p class="float-caption no_bottom_margin">Distribution of NAD biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A495"><h3>7.5.4. Biotin</h3><p>As is the case with many other pathways, the initial steps of biotin biosynthesis
|
|
are poorly understood. The phyletic patterns of the four enzymes that catalyze
|
|
the conversion of pimeloyl-CoA into biotin are relatively consistent (<a class="figpopup" href="/books/NBK20266/figure/A496/?report=objectonly" target="object" rid-figpopup="figA496" rid-ob="figobA496">Figure 7.15</a>), but the mechanisms of the
|
|
formation of pimelate (6-carboxyhexanoate) and pimeloyl-CoA are still largely
|
|
obscure. <i>B. subtilis</i>, <i>A. aeolicus</i>, and
|
|
<i>M. jannaschii</i> encode an enzyme that makes pimeloyl-CoA from
|
|
pimelate and CoA in a reaction that uses the energy of ATP hydrolysis to AMP and
|
|
pyrophosphate [<a href="/books/n/sef/A727/?report=reader#A1403">675</a>]. In contrast,
|
|
pimeloyl-CoA synthetase from <i>Pseudomonas mendocina</i> belongs to
|
|
the family of NDP-forming acyl-CoA synthetases [<a href="/books/n/sef/A727/?report=reader#A819">91</a>,<a href="/books/n/sef/A727/?report=reader#A1466">738</a>]. Neither of these
|
|
two enzyme families is represented in <i>Synechocystis</i> sp.,
|
|
<i>H. influenzae</i>, <i>H. pylori</i>, <i>C.
|
|
jejuni</i>, and several other bacteria, indicating the existence of yet
|
|
another enzyme for the synthesis of pimeloyl-CoA (or an entirely different
|
|
pathway for the formation of 7-keto-8-aminopelargonate).
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA496" co-legend-rid="figlgndA496"><a href="/books/NBK20266/figure/A496/?report=objectonly" target="object" title="Figure 7.15" class="img_link icnblk_img figpopup" rid-figpopup="figA496" rid-ob="figobA496"><img class="small-thumb" src="/books/NBK20266/bin/ch7f15.gif" src-large="/books/NBK20266/bin/ch7f15.jpg" alt="Figure 7.15. Distribution of biotin biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA496"><h4 id="A496"><a href="/books/NBK20266/figure/A496/?report=objectonly" target="object" rid-ob="figobA496">Figure 7.15</a></h4><p class="float-caption no_bottom_margin">Distribution of biotin biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div><p>In spite of the similarity between the phyletic patterns of BioF, BioA, BioD, and
|
|
BioB, one cannot help noticing that <i>Synechocystis</i> sp. lacks the
|
|
<i>bioA</i> gene, suggesting that amination of
|
|
7-keto-8-aminopelargonate is catalyzed by a different aminotransferase. The
|
|
absence of <i>bioD</i> and <i>bioB</i> genes in <i>D.
|
|
radiodurans</i> makes one wonder whether this bacterium can synthesize
|
|
biotin at all.</p><p>The enzyme catalyzing the last reaction in <a class="figpopup" href="/books/NBK20266/figure/A496/?report=objectonly" target="object" rid-figpopup="figA496" rid-ob="figobA496">Figure
|
|
7.15</a>, ligation of biotin to the biotin carboxyl carrier protein (or
|
|
domain), has a much broader phyletic distribution than any of the biotin
|
|
biosynthesis enzymes. This indicates that <i>A. fulgidus</i>,
|
|
<i>Halobacterium</i> sp., <i>Pyrococcus</i> spp.,
|
|
<i>L. lactis</i>, <i>S. pyogenes</i>, and many other
|
|
organisms that do not have a known pathway of biotin synthesis still can utilize
|
|
biotin. Thus, they either have a completely different, unknown biotin synthesis
|
|
pathway or import biotin from the environment (however, a biotin transport
|
|
system so far has not been identified).</p><p>The paucity of data on the enzymes of biotin biosynthesis and a putative biotin
|
|
uptake system should encourage active experimentation in this area. There
|
|
definitely are novel enzymes and transporters yet to be discovered.</p></div><div id="A497"><h3>7.5.5. Heme</h3><p>From the comparative-genomic point of view, the heme biosynthesis pathway is
|
|
characterized by the following trends (<a class="figpopup" href="/books/NBK20266/figure/A498/?report=objectonly" target="object" rid-figpopup="figA498" rid-ob="figobA498">Figure
|
|
7.16</a>): (i) with the single exception of uroporphyrinogen III synthase
|
|
(HemD), the enzymes from <i>R. prowazekii</i> and yeast (mitochondria)
|
|
have identical phyletic patterns; (ii) all archaea, including the aerobes
|
|
<i>A. pernix</i> and <i>Halobacterium</i> sp., produce
|
|
siroheme but not protoheme; (iii) non-orthologous displacement is observed in
|
|
the downstream steps of the pathway, as opposed to the uniformity of all the
|
|
upstream steps down to uroporphirinogen III.
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA498" co-legend-rid="figlgndA498"><a href="/books/NBK20266/figure/A498/?report=objectonly" target="object" title="Figure 7.16" class="img_link icnblk_img figpopup" rid-figpopup="figA498" rid-ob="figobA498"><img class="small-thumb" src="/books/NBK20266/bin/ch7f16.gif" src-large="/books/NBK20266/bin/ch7f16.jpg" alt="Figure 7.16. Distribution of heme biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA498"><h4 id="A498"><a href="/books/NBK20266/figure/A498/?report=objectonly" target="object" rid-ob="figobA498">Figure 7.16</a></h4><p class="float-caption no_bottom_margin">Distribution of heme biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div><div id="A499"><h3>7.5.6. Pyridoxine</h3><p>We conclude our survey of central metabolic pathways with the pyridoxine
|
|
biosynthesis pathway, which, despite recent efforts, is still not completely
|
|
understood. The scheme below is drawn based on the <i>E. coli</i> data
|
|
[<a href="/books/n/sef/A727/?report=reader#A926">198</a>,<a href="/books/n/sef/A727/?report=reader#A1213">485</a>]. In other organisms, the carbon backbone of the
|
|
pyridoxine ring is formed of 4-hydroxythreonine (or its phosphate) and
|
|
1-deoxy-D-xylulose (or its phosphate) with the nitrogen supplied by either
|
|
glutamate (in the PdxAJ-catalyzed reaction), or glutamine (in the
|
|
PDX1,PDX2-catalyzed reaction) [<a href="/books/n/sef/A727/?report=reader#A939">211</a>,<a href="/books/n/sef/A727/?report=reader#A1306">578</a>,<a href="/books/n/sef/A727/?report=reader#A1363">635</a>,<a href="/books/n/sef/A727/?report=reader#A1553">825</a>,<a href="/books/n/sef/A727/?report=reader#A1560">832</a>]. Since 1-deoxy-D-xylulose phosphate
|
|
synthetase (Dxs, COG1154) so far has been identified only in bacteria, it is
|
|
possible that archaea and eukaryotes use a different sugar as a pyridoxine
|
|
precursor. Obviously, new enzymes of this pathway remain to be discovered.</p><p>
|
|
|
|
</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA500" co-legend-rid="figlgndA500"><a href="/books/NBK20266/figure/A500/?report=objectonly" target="object" title="Figure 7.17" class="img_link icnblk_img figpopup" rid-figpopup="figA500" rid-ob="figobA500"><img class="small-thumb" src="/books/NBK20266/bin/ch7f17.gif" src-large="/books/NBK20266/bin/ch7f17.jpg" alt="Figure 7.17. Distribution of pyridoxine biosynthesis enzymes in organisms with completely sequenced genomes." /></a><div class="icnblk_cntnt" id="figlgndA500"><h4 id="A500"><a href="/books/NBK20266/figure/A500/?report=objectonly" target="object" rid-ob="figobA500">Figure 7.17</a></h4><p class="float-caption no_bottom_margin">Distribution of pyridoxine biosynthesis enzymes in organisms with
|
|
completely sequenced genomes. All details are as in Figure
|
|
2.7. </p></div></div></div></div><div id="A501"><h2 id="_A501_">7.6. Microbial Enzymes as Potential Drug Targets</h2><p>One of the major incentives behind the genome sequencing of numerous pathogenic
|
|
bacteria is the desire to better understand their peculiarities and to develop new
|
|
approaches for controlling human diseases caused by these organisms. This task has
|
|
become even more urgent with the rapid evolution of antibiotic resistance in many
|
|
bacterial pathogens, including multidrug-resistant enterococci, pneumococci,
|
|
pseudomonads, staphylococci, and tuberculosis bacilli. Unfortunately, finding new
|
|
antibiotics is an extremely laborious process that includes (i) testing numerous
|
|
compounds for their activity against model organisms (<i>E. coli</i>,
|
|
<i>P. aeruginosa</i>, <i>S. aureus</i>) that are easy to
|
|
maintain in culture; (ii) screening these compounds against mammalian cell cultures
|
|
to eliminate those toxic to humans; (iii) testing the efficacy and safety of each
|
|
chosen drug in animal models; and (iv) pre-clinical and clinical testing, which
|
|
alone takes several years. This process ensures that only highly effective and
|
|
reasonably safe drugs make it to the market. The majority of drug candidates fail
|
|
the tests, usually because in low concentrations they turn out to be safe but
|
|
ineffective, whereas at high doses they are effective but show unfavorable side
|
|
effects.</p><p>In spite of what one might have read in popular press, genomics cannot accelerate
|
|
most steps of the drug development process. What it can do, however, is to increase
|
|
the success rate by helping to choose drug candidates that are most likely to be
|
|
effective (being targeted at essential systems of the bacterial cell) and least
|
|
likely to be toxic (having no targets in the human cell). Indeed, while not all
|
|
currently used antibiotics have well-characterized targets, those targets that have
|
|
been characterized comprise bacterial proteins that (i) are essential for bacterial
|
|
cell metabolism and (ii) are not represented (or represented in a very distinct
|
|
form) in human cells (see <a href="/books/n/sef/A298/?report=reader#A319">Table 6.2</a>).
|
|
Microbial genome sequences provide us with complete lists of the proteins encoded in
|
|
any given pathogen, including all the virulence factors that it could potentially
|
|
produce. This “parts list” offers a wide selection of potential
|
|
drug targets.</p><p>Comparative analysis of microbial genomes based on the notion of a phyletic pattern,
|
|
which is discussed throughout this book, allows the identification of gene products
|
|
that are common to all (or most) pathogenic microorganisms in a chosen group, as
|
|
well as of those specific for a particular organism. The proteins in the former set
|
|
are attractive targets for broad-spectrum antibiotics, whereas the unique proteins
|
|
offer an opportunity to design “magic bullets”, which would
|
|
specifically target a narrow group of bacteria or even one particular pathogen
|
|
[<a href="/books/n/sef/A727/?report=reader#A994">266</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figA506"><a href="/books/NBK20266/table/A506/?report=objectonly" target="object" title="Table 7.1" class="img_link icnblk_img figpopup" rid-figpopup="figA506" rid-ob="figobA506"><img class="small-thumb" src="/books/NBK20266/table/A506/?report=thumb" src-large="/books/NBK20266/table/A506/?report=previmg" alt="Table 7.1. Cellular targets of most commonly used antibiotics." /></a><div class="icnblk_cntnt"><h4 id="A506"><a href="/books/NBK20266/table/A506/?report=objectonly" target="object" rid-ob="figobA506">Table 7.1</a></h4><p class="float-caption no_bottom_margin">Cellular targets of most commonly used antibiotics. </p></div></div><p>In addition to the lists of probable essential genes, search for potential drug
|
|
targets in microbial genomes heavily relies on the understanding of bacterial
|
|
metabolism, which is briefly discussed above.</p><div id="A502"><h3>7.6.1. Potential targets for broad-spectrum drugs</h3><p>The list of probable essential genes that potentially could be used as targets
|
|
for broad-range antibiotics can be derived using more or less the same approach
|
|
as employed for the delineation of the “minimal genome”
|
|
([<a href="/books/n/sef/A727/?report=reader#A1180">452</a>], see <a href="/books/n/sef/A22/?report=reader#A40">2.2.5</a>). Inclusion of certain genes in this list is, of
|
|
course, affected by non-orthologous gene displacement and enzyme
|
|
recruitment.</p><p>It should be noted that compiling the list of the likely essential genes for each
|
|
particular group of bacteria (all bacteria, all Gram-positive bacteria, all
|
|
mycobacteria, and so on) by computational means is only one of several ways to
|
|
accomplish this task, although, arguably, it is the easiest and fastest one. Any
|
|
predictions of essentiality for a given gene still have to be verified
|
|
experimentally by checking the lethality of knockout mutants [<a href="/books/n/sef/A727/?report=reader#A737">9</a>,<a href="/books/n/sef/A727/?report=reader#A1248">520</a>]. As mentioned above (see <a href="/books/n/sef/A55/?report=reader#A117">3.5.1</a>), lists of essential <i>E. coli</i> genes are
|
|
available at <a href="http://www.genome.wisc.edu/resources/essential.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.genome.wisc.edu/resources/essential.htm</a> and <a href="http://www.shigen.nig.ac.jp/ecoli/pec/Analyses.jsp?key0" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.shigen.nig.ac.jp/ecoli/pec/Analyses.jsp?key=0</a>.</p><p>In addition to the genes that encode well-characterized essential proteins, the
|
|
availability of complete genomes allows one to tap into the pool of
|
|
uncharacterized genes whose wide distribution in microbial genomes marks them as
|
|
being most likely essential [<a href="/books/n/sef/A727/?report=reader#A785">57</a>,<a href="/books/n/sef/A727/?report=reader#A1179">451</a>]. Searches for such genes can be
|
|
easily performed using the “phyletic patterns search” tool
|
|
of the COG database. In addition, the COG database contains lists of poorly
|
|
characterized and uncharacterized protein families, which are listed as
|
|
functional groups R and S, respectively. A collection of uncharacterized
|
|
conserved proteins, including those from partially sequenced genomes, is
|
|
available in PROSITE database (<a href="http://www.expasy.org/cgi-bin/lists?upflist.txt" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.expasy.org/cgi-bin/lists?upflist.txt</a>).</p><p>The diversity of microbial metabolic pathways described above offers numerous
|
|
possibilities to look for potential drug targets among the metabolic enzymes.
|
|
One straightforward approach is to select the pathways that are essential for
|
|
certain pathogens but are absent in humans. Such pathways include murein
|
|
biosynthesis, the shikimate pathway of aromatic amino acid biosynthesis (<a class="figpopup" href="/books/NBK20266/figure/A452/?report=objectonly" target="object" rid-figpopup="figA452" rid-ob="figobA452">Figure 7.6</a>), and the deoxyxylulose
|
|
(non-mevalonate) pathway of terpenoid biosynthesis. It is remarkable that
|
|
certain inhibitors of the latter pathway (fosmidomycin, fluoropyruvate,
|
|
FR-900098) have been studied as potential antibiotics long before the
|
|
characterization of their cellular targets [<a href="/books/n/sef/A727/?report=reader#A1128">400</a>,<a href="/books/n/sef/A727/?report=reader#A1246">518</a>].</p></div><div id="A503"><h3>7.6.2. Potential targets for pathogen-specific drugs</h3><p>Although current approaches favor “one-shot” antibacterials
|
|
that can eliminate bacterial infection irrespective of the nature of the
|
|
pathogen, it gradually becomes clear that we will soon need a variety of drugs
|
|
that would be effective against selected groups of organisms or even a single
|
|
pathogen. There is nothing particularly new in this concept: people have been
|
|
using anti-tuberculine and anti-syphilis drugs for almost a century without
|
|
requiring them to also cure common cold or gastrointestinal problems.</p><p>The novelty stemming from the availability of complete genome sequences is that
|
|
now it has become possible to analyze the genome of a pathogen in detail,
|
|
looking for weak spots or unusual enzymes that are likely to be essential for
|
|
this particular organism. In addition to the traditional drug targets, such as
|
|
the cell envelope and the systems for DNA replication, transcription, and
|
|
translation, this brings into play for consideration as potential drug targets
|
|
such proteins as host interaction factors, transporters for essential nutrients,
|
|
enzymes of intermediary metabolism, and many others.</p><p>Host interaction factors can be searched for by using the so-called
|
|
“differential genome display”, first proposed by Peer Bork
|
|
and his colleagues [<a href="/books/n/sef/A727/?report=reader#A1094">366</a>,<a href="/books/n/sef/A727/?report=reader#A1099">371</a>]. This approach looks for the genes
|
|
that are present in the genome of a pathogen but not in the genome of a closely
|
|
related free-living bacterium. Because genomes of parasitic bacteria typically
|
|
code for fewer proteins than the genomes of their free-living cousins, genes
|
|
detected by this approach are likely to be important for pathogenicity. Bork and
|
|
colleagues applied this approach to the identification of potential
|
|
pathogenicity factors in <i>H. influenzae</i> and <i>H.
|
|
pylori</i> through comparison of their genomes against <i>E.
|
|
coli</i> [<a href="/books/n/sef/A727/?report=reader#A1094">366</a>,<a href="/books/n/sef/A727/?report=reader#A1099">371</a>].</p><p>Because many pathogens have reduced biosynthetic capabilities and rely on the
|
|
host for the supply of certain essential nutrients (see <a href="/books/n/sef/A55/?report=reader#A70">3.2</a>), the respective membrane transport systems can be
|
|
valid targets for drug intervention. For example, the still uncharacterized
|
|
biotin transport system appears to be the only means of biotin acquisition for
|
|
several pathogens, such as <i>S. pyogenes</i>, <i>R.
|
|
prowazekii</i>, <i>C. trachomatis</i>, and <i>T.
|
|
pallidum</i> (see <a href="#A495">7.5.4</a>).
|
|
Actually, one could start probing this hypothetical system right away by using
|
|
various biotin analogs. As an added benefit, such a study would eventually lead
|
|
to the identification of the transport system components.</p><p>Using surface proteins of bacteria as drug targets has an obvious advantage
|
|
because drugs interacting with these proteins do not have to cross the
|
|
cytoplasmic membrane, which largely removes the problem of drug efflux-mediated
|
|
resistance [<a href="/books/n/sef/A727/?report=reader#A1251">523</a>,<a href="/books/n/sef/A727/?report=reader#A1252">524</a>]. On the other hand, humans also import biotin,
|
|
therefore at this stage, it cannot be ruled out that an inhibitor of biotin
|
|
uptake might be toxic for humans. This emphasizes the need for identification of
|
|
the genes coding for the bacterial uptake system: once these are known, we will
|
|
be in a better position to assess the likelihoods of toxic side effects of any
|
|
drugs targeting this function.</p><p>Another approach to searching for pathogen-specific drug targets would rely on
|
|
the enzymes that are subject to non-orthologous gene displacement and are found
|
|
in certain pathogens in a different form that is present in humans. The
|
|
rationale for using enzyme inhibitors as antimicrobial drugs comes from the
|
|
successful use of sulfamethoxazole and trimethoprim, inhibitors of two different
|
|
steps of the folate biosynthetic pathway. Indeed, while each of these drugs is
|
|
only moderately effective against most bacterial pathogens, their combination
|
|
proved to be effective and reasonably safe. In several instances, detailed
|
|
analysis of non-orthologous displacement cases has led to suggestions that
|
|
alternative forms of essential enzymes could be used as drug targets ([<a href="/books/n/sef/A727/?report=reader#A994">266</a>,<a href="/books/n/sef/A727/?report=reader#A999">271</a>], see refs. in <a class="figpopup" href="/books/NBK20266/table/A504/?report=objectonly" target="object" rid-figpopup="figA504" rid-ob="figobA504">Table
|
|
7.2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figA504"><a href="/books/NBK20266/table/A504/?report=objectonly" target="object" title="Table 7.2" class="img_link icnblk_img figpopup" rid-figpopup="figA504" rid-ob="figobA504"><img class="small-thumb" src="/books/NBK20266/table/A504/?report=thumb" src-large="/books/NBK20266/table/A504/?report=previmg" alt="Table 7.2. Examples of pathogen-specific drug targets." /></a><div class="icnblk_cntnt"><h4 id="A504"><a href="/books/NBK20266/table/A504/?report=objectonly" target="object" rid-ob="figobA504">Table 7.2</a></h4><p class="float-caption no_bottom_margin">Examples of pathogen-specific drug targets. </p></div></div></div></div><div id="A505"><h2 id="_A505_">7.7. Conclusions and Outlook</h2><p>This chapter shows that central metabolism is the ultimate playground of
|
|
non-orthologous gene displacement, where the logic of phyletic patterns works best.
|
|
Metabolic pathways are so amenable to this type of analysis because, if an organism
|
|
encodes a significant fraction of the enzymes for a particular pathway, it is
|
|
extremely likely that, in reality, is also has the enzymes for the rest of the
|
|
steps. Therefore, candidate enzymes for the missing steps may be sought for and, at
|
|
least in some instances, found among uncharacterized orthologous sets (identified
|
|
through COGs or otherwise) with phyletic patterns that are, at least in part,
|
|
complementary to those for known enzymes for the given step. So far, only very few
|
|
of the computational predictions made by this approach have been tested
|
|
experimentally, but in those studies that have been conducted, the success rate has
|
|
been quite high. Conversely, there are enigmatic cases where most of the enzymes of
|
|
a given pathway are missing in an organism but one or two still stay around (by
|
|
using this language, we imply loss of a pathway, which is indeed largely the case in
|
|
parasites and heterotrophs, including ourselves). Most likely, these are cases of
|
|
exaptation, where an enzyme that is no longer needed in its original metabolic
|
|
capacity has found another job, thus saving itself from extinction. Elucidation of
|
|
these exapted functions seems to be an interesting avenue of research.</p><p>The finding that metabolic pathways are so prone to non-orthologous gene displacement
|
|
seems to indirectly convey a message of general biological significance. We know for
|
|
a fact that enzymes in the same metabolic pathway are connected through reaction
|
|
intermediates, but, on almost all occasions, precious little is known about the
|
|
actual macromolecular organization of these enzymes in the cell. Analysis of
|
|
phyletic patterns shows that many, if not most, metabolic enzymes with different
|
|
structures but the same reaction chemistry are interchangeable in evolution. This
|
|
suggests that, most of the time, the chemistry is, after all, the principal aspect
|
|
of the metabolic functions, whereas the role of co-adaptation of subunits of
|
|
macromolecular complexes is likely to be limited.</p><p>The major contribution of lineage-specific gene loss to the evolution of metabolic
|
|
pathways is beyond doubt. Horizontal gene transfer is harder to demonstrate but,
|
|
realistically, it appears certain that this phenomenon also had a substantial role.
|
|
Indeed, it defies credibility to postulate that LUCA had each one of the alternative
|
|
forms of metabolic enzymes (and the corresponding reaction intermediates), the
|
|
existence of which became apparent through the comparative-genomic studies (as well
|
|
as those, perhaps numerous ones that remain to be discovered). The relative
|
|
contributions of gene loss and horizontal transfer hopefully will be better
|
|
understood through the application of algorithmic methods briefly outlined in <a href="/books/n/sef/A298/?report=reader">Chapter 6</a>.</p><p>Identification of potential targets for antibacterial drugs using phyletic patterns,
|
|
the differential genome display technique and other similar approaches is a natural
|
|
task for comparative genomics and will likely remain one of its most important
|
|
practical applications for years to come.</p></div><div id="A507"><h2 id="_A507_">7.8. Further Reading</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="A509">Romano AH, Conway T. Evolution of carbohydrate metabolic
|
|
pathways. <span><span class="ref-journal">Research in Microbiology. </span>1996;<span class="ref-vol">147</span>:448–455.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9084754" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9084754</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="A510">Galperin MY, Walker DR, Koonin EV. Analogous enzymes: independent inventions in enzyme
|
|
evolution. <span><span class="ref-journal">Genome Research. </span>1998;<span class="ref-vol">8</span>:779–790.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9724324" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9724324</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="A511">Dandekar T, Schuster S, Snel B, Huynen M, Bork P. Pathway alignment: application to the comparative
|
|
analysis of glycolytic enzymes. <span><span class="ref-journal">Biochemical Journal. </span>1999;<span class="ref-vol">343</span>:115–124.</span> [<a href="/pmc/articles/PMC1220531/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1220531</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10493919" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10493919</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="A512">Huynen MA, Dandekar T, Bork P. Variation and evolution of the citric-acid cycle: a
|
|
genomic perspective. <span><span class="ref-journal">Trends in Microbiology. </span>1999;<span class="ref-vol">7</span>:281–291.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10390638" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10390638</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="A513">Cordwell SJ. Microbial genomes and “missing”
|
|
enzymes: redefining biochemical pathways. <span><span class="ref-journal">Archives of Microbiology. </span>1999;<span class="ref-vol">172</span>:269–279.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10550468" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10550468</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="A514">Galperin MY, Koonin EV. 2001. Comparative
|
|
genome analysis. In: <em>Bioinformatics: a practical guide to the
|
|
analysis of genes and proteins</em> (Baxevanis AD and Ouellette
|
|
BFF, eds) pp. 359–392. John Wiley & Sons, New
|
|
York. [<a href="https://pubmed.ncbi.nlm.nih.gov/11449732" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11449732</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="A515">Canback B, Andersson SG, Kurland CG. The global phylogeny of glycolytic
|
|
enzymes. <span><span class="ref-journal">Proceedings of the National Academy of Sciences of the United
|
|
States of America. </span>2002;<span class="ref-vol">99</span>:6097–6102.</span> [<a href="/pmc/articles/PMC122908/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC122908</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11983902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11983902</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="A516">Galperin MY, Koonin EV. Searching for drug targets in microbial
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genomes. <span><span class="ref-journal">Current Opinion in Biotechnology. </span>1999;<span class="ref-vol">10</span>:571–578.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10600691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10600691</span></a>]</div></dd></dl></dl></div><div style="display:none"><div id="figA520"><img alt="Image ch8f1" src-large="/books/n/sef/A517/bin/ch8f1.jpg" /></div><div id="figA35"><img alt="Image ch2f7" src-large="/books/n/sef/A22/bin/ch2f7.jpg" /></div><div id="figA523"><img alt="Image ch8f2" src-large="/books/n/sef/A517/bin/ch8f2.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK20266_pubdet_">Publication Details</h2><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 2003, Kluwer Academic.</div></div><h3>Publisher</h3><p><a href="http://www.springer.com/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">Kluwer Academic</a>, Boston</p><h3>NLM Citation</h3><p>Koonin EV, Galperin MY. Sequence - Evolution - Function: Computational Approaches in Comparative Genomics. Boston: Kluwer Academic; 2003. Chapter 7, Evolution of Central Metabolic Pathways: The Playground of Non-Orthologous Gene Displacement.<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/sef/A298/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/sef/A517/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobA378"><div id="A378" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f1.jpg" alt="Figure 7.1. Distribution of glycolysis (Embden-Meyerhoff-Parnas pathway) enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.1</span><span class="title">Distribution of glycolysis (Embden-Meyerhoff-Parnas pathway)
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enzymes in organisms with completely sequenced genomes</span></h3><div class="caption"><p> Each rounded rectangle shows a glycolytic enzyme, denoted by its
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gene name and the COG number. Alternative enzymes catalyzing the
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|
same reaction are shown side-by-side. Each COG is accompanied by
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its phyletic pattern (see <a href="/books/n/sef/A22/?report=reader#A43">2.2.6</a>). The species abbreviations are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>.</p></div></div></article><article data-type="fig" id="figobA386"><div id="A386" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f2.jpg" alt="Figure 7.2. Distribution of gluconeogenesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.2</span><span class="title">Distribution of gluconeogenesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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|
2.7</a>.</p></div></div></article><article data-type="fig" id="figobA391"><div id="A391" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f3.jpg" alt="Figure 7.3. Distribution of enzymes of the pentose phosphate and Entner-Doudoroff pathways in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.3</span><span class="title">Distribution of enzymes of the pentose phosphate and
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Entner-Doudoroff pathways in organisms with completely sequenced
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genomes</span></h3><div class="caption"><p>Details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA411"><div id="A411" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f4.jpg" alt="Figure 7.4. Distribution of the TCA cycle enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.4</span><span class="title">Distribution of the TCA cycle enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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|
2.7</a>.</p></div></div></article><article data-type="fig" id="figobA431"><div id="A431" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f5.jpg" alt="Figure 7.5. Distribution of purine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.5</span><span class="title">Distribution of purine biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details as in <a href="/books/n/sef/A22/?report=reader#A35">Figure 2.7</a>.</p></div></div></article><article data-type="fig" id="figobA452"><div id="A452" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f6.jpg" alt="Figure 7.6. Distribution of tryptophan biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.6</span><span class="title">Distribution of tryptophan biosynthesis enzymes in
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organisms with completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
|
2.7</a>.</p></div></div></article><article data-type="fig" id="figobA468"><div id="A468" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f7.jpg" alt="Figure 7.7. Distribution of phenylalanine and tyrosine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.7</span><span class="title">Distribution of phenylalanine and tyrosine biosynthesis
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|
enzymes in organisms with completely sequenced
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|
genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
|
2.7</a>.</p></div></div></article><article data-type="fig" id="figobA474"><div id="A474" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f8.jpg" alt="Figure 7.8. Distribution of arginine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.8</span><span class="title">Distribution of arginine biosynthesis enzymes in organisms
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with completely sequenced genomes</span></h3><div class="caption"><p>All details as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA483"><div id="A483" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f9.jpg" alt="Figure 7.9. Distribution of histidine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.9</span><span class="title">Distribution of histidine biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA485"><div id="A485" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f10.jpg" alt="Figure 7.10. Distribution of isoleucine/leucine/valine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.10</span><span class="title">Distribution of isoleucine/leucine/valine biosynthesis enzymes in
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organisms with completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA487"><div id="A487" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f11.jpg" alt="Figure 7.11. Distribution of proline biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.11</span><span class="title">Distribution of proline biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3></div></article><article data-type="fig" id="figobA490"><div id="A490" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f12.jpg" alt="Figure 7.12. Distribution of thiamine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.12</span><span class="title">Distribution of thiamine biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA492"><div id="A492" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f13.jpg" alt="Figure 7.13. Distribution of riboflavin biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.13</span><span class="title">Distribution of riboflavin biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA494"><div id="A494" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f14.jpg" alt="Figure 7.14. Distribution of NAD biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.14</span><span class="title">Distribution of NAD biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA496"><div id="A496" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f15.jpg" alt="Figure 7.15. Distribution of biotin biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.15</span><span class="title">Distribution of biotin biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA498"><div id="A498" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f16.jpg" alt="Figure 7.16. Distribution of heme biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.16</span><span class="title">Distribution of heme biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
|
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2.7</a>.</p></div></div></article><article data-type="fig" id="figobA500"><div id="A500" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK20266/bin/ch7f17.jpg" alt="Figure 7.17. Distribution of pyridoxine biosynthesis enzymes in organisms with completely sequenced genomes." /></div><h3><span class="label">Figure 7.17</span><span class="title">Distribution of pyridoxine biosynthesis enzymes in organisms with
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completely sequenced genomes</span></h3><div class="caption"><p>All details are as in <a href="/books/n/sef/A22/?report=reader#A35">Figure
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2.7</a>.</p></div></div></article><article data-type="table-wrap" id="figobA506"><div id="A506" class="table"><h3><span class="label">Table 7.1</span><span class="title">Cellular targets of most commonly used antibiotics</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK20266/table/A506/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__A506_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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Antibiotic groups, Examples
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</th><th id="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">
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Bacterial target
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</th><th id="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">
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Resistance mechanisms
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</th></tr></thead><tbody><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β<b>-Lactams:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Penicillins, cephalosporins,
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carbapenems, monobactams</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Peptidoglycan transpeptidase, other
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proteins</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hydrolysis by β-lactamase,
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alterations in penicillin-binding proteins</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Glycopeptides:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bacitracin, colistin, dactinomycin,
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teichoplanin, vancomycin, virginiamycin</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Peptidoglycan transpeptidase,
|
|
transglycosylase</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Modification of the UDP-muramyl
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pentapeptide</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Aminoglycosides:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Amikacin, kanamycin, gentamycin,
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hygromycin, neomycin, puromycin, streptomycin, tobramycin</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ribosomal 30S subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Acetylation, adenylation, or
|
|
phosphorylation of the antibiotic by specific modifying
|
|
enzymes</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Tetracyclins:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Doxycycline, methacycline,
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|
minocycline, tetracycline</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ribosomal 30S subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Export by efflux pumps, mutations</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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|
<b>Macrolides:</b>
|
|
</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Azithromycin, dirithromycin,
|
|
clarithromycin, spiramycin, erythromycin, oleandomycin</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ribosomal 50S subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rRNA methylation;
|
|
<i>rrn</i>, <i>rplD</i>, and
|
|
<i>rplV</i> mutations; hydrolysis by esterases,
|
|
export by efflux pumps</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>Quinolones:</b>
|
|
</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nalidixic acid, ciprofloxacin</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DNA gyrase β-subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<i>gyrB</i> mutations</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>Lincosamides:</b>
|
|
</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clindamycin, lincomycin</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23S rRNA</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rRNA methylation, <i>rrn</i>
|
|
mutations, drug adenylation</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>Chloramphenicol</b>
|
|
</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Peptidyl-transferase center on the
|
|
ribosomal 50S subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inactivation by acetylation, export by
|
|
efflux pumps</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>Sulfonamides:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sulfamethoxazole</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dihydropteroate synthase</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>folP</i> mutations</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Trimethoprim</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dihydrofolate reductase</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>folA</i> mutations</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Nitroimidazoles:</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Metronidazole</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chromosomal DNA</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nitroreductase mutations, preventing
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drug activation</td></tr><tr><td headers="hd_h_A506_1_1_1_1 hd_h_A506_1_1_1_2 hd_h_A506_1_1_1_3" colspan="3" rowspan="1" style="vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<b>Rifampin</b>
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</td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_A506_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_A506_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RNA polymerase β-subunit</td><td headers="hd_h_A506_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>rpoB</i> mutations</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobA504"><div id="A504" class="table"><h3><span class="label">Table 7.2</span><span class="title">Examples of pathogen-specific drug targets</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK20266/table/A504/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__A504_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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Enzymes with limited phyletic distribution
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</th><th id="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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Human pathogens that depend on these enzymes
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</th><th id="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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Ref.
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</th></tr></thead><tbody><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATP/ADP translocase, bacterial/plant
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type</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>R. prowazekii, C. trachomatis, C. pneumoniae</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A1623">895</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3-Dehydroquinate dehydratase, class
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II</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>C. jejuni</i>, <i>H. influenzae</i>,
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<i>H. pylori</i>, <i>P. aeruginosa</i>,
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<i>V. cholerae</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A1033">305</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DhnA-type fructose-1,6-bisphosphate
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aldolase</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>C. trachomatis</i>, <i>C. pneumoniae</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A985">257</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lysyl-tRNA synthetase, class I</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>B. burgdorferi, R. prowazekii, T. pallidum,</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A1103">375</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Na-translocating NADH: ubiquinone
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oxidoreductase</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>C. trachomatis, C. pneumoniae, Cl. perfringens, T.
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denticola</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A1062">334</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Na-translocating oxalo-acetate
|
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decarboxylase</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>S. pyogenes, T. pallidum,</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A1062">334</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Orotidine 5′-phosphate
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decarboxylase</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>M. leprae, M. tuberculosis</i>
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A740">12</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pyridoxine biosynthesis enzymes PDX1,
|
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PDX2</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<i>Bacillus anthracis, H. influenzae, L. monocytogenes, M.
|
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leprae, M. tuberculosis, S. pneumoniae</i>
|
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</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A991">263</a>,<a href="/books/n/sef/A727/?report=reader#A1363">635</a>]</td></tr><tr><td headers="hd_h_A504_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cofactor-independent phosphoglycerate
|
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mutase</td><td headers="hd_h_A504_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<i>C. jejuni, H. pylori, M. genitalium, P.
|
|
aeruginosa</i>, <i>V. cholerae</i>
|
|
</td><td headers="hd_h_A504_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<a href="/books/n/sef/A727/?report=reader#A986">258</a>,<a href="/books/n/sef/A727/?report=reader#A989">261</a>]</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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