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Review
. 2012 Jan 2;287(1):11-20.
doi: 10.1074/jbc.R111.257329. Epub 2011 Nov 8.

Divergence and convergence in enzyme evolution: parallel evolution of paraoxonases from quorum-quenching lactonases

Mikael Elias  1 , Dan S Tawfik  2
Affiliations
Review

Divergence and convergence in enzyme evolution: parallel evolution of paraoxonases from quorum-quenching lactonases

Mikael Elias et al. J Biol Chem. .

Abstract

We discuss the basic features of divergent versus convergent evolution and of the common scenario of parallel evolution. The example of quorum-quenching lactonases is subsequently described. Three different quorum-quenching lactonase families are known, and they belong to three different superfamilies. Their key active-site architectures have converged and are strikingly similar. Curiously, a promiscuous organophosphate hydrolase activity is observed in all three families. We describe the structural and mechanistic features that underline this converged promiscuity and how this promiscuity drove the parallel divergence of organophosphate hydrolases within these lactonase families by either natural or laboratory evolution.

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Figures

FIGURE 1.
FIGURE 1.
Definition of key terms and schematic tree representation of protein universe. A, definition of key terms used in this minireview. B, protein families (including certain orthologs and close paralogs) are represented as A, B, etc., and superfamilies, as 1, 2, etc. The routes of divergence of closely related proteins can be readily inferred by sequence resemblance and are represented as continuous lines. However, most families within a given superfamily are so remote in sequence that the routes of divergence remain hypothetical (depicted by dashed lines). The progenitors of many of the contemporary protein superfamilies were present in the LUCA. The LUCA proteins diverged from unknown ancestors and by unknown routes, as indicated by thick dashed lines. Cases of convergent evolution are represented by family A, i.e. enzymes with activity A that appeared in parallel in both superfamilies 1 and 2. If, however, the event could be traced back to the node connecting the LUCA ancestors of these two superfamilies, this would be a case of parallel evolution. In some cases, the same family (e.g. OPH, depicted as F) has diverged in parallel, within two or more superfamilies, from the same ancestral family (QQL, depicted as E).
FIGURE 2.
FIGURE 2.
HSLs, their hydrolysis by QQLs, and promiscuous paraoxonase activity of QQLs. A, structure of HSLs. B, schematic representation of the common catalytic features of the three QQL families described here. The lactone substrate binds to the metal cation via its carbonyl oxygen, thus making the carbonyl carbon more electrophilic. The attacking water molecule is deprotonated either by the active-site metal or by an amino acid side chain acting as a base. The resulting tetrahedral intermediate is subsequently broken (with protonation of the alkoxide leaving group) to give the hydrolyzed product. C, catalytic features of the promiscuous paraoxonase activity of QQLs. Binding of the substrate phosphoryl oxygen and formation and stabilization of the pentacovalent intermediate make use of the same active-site features that mediate the lactonase activity.
FIGURE 3.
FIGURE 3.
Stereo representations of active-site models of representative lactonases from three known QQL families. A, docking model of AiiA (Protein Data Bank code 2A7M), representing the metallo-β-lactamase QQL family, with the tetrahedral reaction intermediate of N-dodecanoylhomoserine lactone. The active-site zinc cations are shown as gray spheres. The carbonyl oxygen interacts with one of the zincs, as well as with the hydroxyl of Tyr-104. The intermediate's hydroxyl interacts with the other zinc cation and with the metal-ligating residue Asp-108, which acts as a base (to generate the attacking hydroxide) and subsequently as an acid (to protonate the alkoxide leaving group). B, same model for SsoPox (Protein Data Bank code 2VC5), representing the PLL family. Tyr-97 and Asp-256 play equivalent roles to Tyr-104 and Asp-108 in AiiA. The spheres represent an iron (orange) and a cobalt (pink) cation, although this enzyme is active with other transition metals. C, active site of PON1 (Protein Data Bank code 1V04), representing the PON family. Shown are the catalytic calcium cation (green sphere) and His-115, which is thought to act as a base in generating the attacking hydroxide. Reasonably accurate docking models of the bound lactone could not be generated because the only available PON structure is without a ligand, at pH 4.5 when the enzyme is inactive, and with an active-site loop missing. D, AiiA and SsoPox active sites are mirror images of one another. The AiiA (green) and SsoPox (blue) active-site models were manually aligned based on their bimetallic centers and their bridging water molecules. Docking models were generated with AutoDock 4.0 (77). The docked ligands were generated using JLigand and DockingServer. A single negative charge was attributed to the intermediate's carbonyl oxygen atom and +2 for the metal cations. The remaining charges for both the intermediate and the enzyme residues were attributed using the Gasteiger method. The docking calculations were performed using a Lamarckian genetic algorithm. The images were generated with PyMOL.
FIGURE 4.
FIGURE 4.
Stereo view of superposition of lactonase and paraoxonase reaction intermediates. Presented are docking models of SsoPox (Protein Data Bank code 2VC5; A) and AiiA (code 2A7M; B) with the reaction intermediates that form upon a nucleophilic attack by hydroxide. The structures of the reaction intermediates for N-acylhomoserine (carbon atoms in pink) and paraoxon (carbon atoms in blue) are aligned. Note that the intermediate for lactone hydrolysis is tetrahedral, and that for paraoxon is bipyramidal.
See this image and copyright information in PMC

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