Structural and mechanistic studies on the crotonase superfamily (CS) are reviewed with the aim of illustrating how a conserved structural platform can enable catalysis of a very wide range of reactions. Many CS reactions have precedent in the 'carbonyl' chemistry of organic synthesis; they include alkene hydration/isomerization, aryl-halide dehalogenation, (de)carboxylation, CoA ester and peptide hydrolysis, fragmentation of beta-diketones and C-C bond formation, cleavage and oxidation. CS enzymes possess a canonical fold formed from repeated betabetaalpha units that assemble into two approximately perpendicular beta-sheets surrounded by alpha-helices. CS enzymes often, although not exclusively, oligomerize as trimers or dimers of trimers. Two conserved backbone NH groups in CS active sites form an oxyanion 'hole' that can stabilize enolate/oxyanion intermediates. The range and efficiency of known CS-catalyzed reactions coupled to their common structural platforms suggest that CS variants may have widespread utility in biocatalysis.

There are four main subfamilies of clinically used bicyclic ␤-lactam antibiotics comprised of the penicillins, the cephalosporins, the carbapenems, and the oxacephems. Three inhibitors of the serine ␤-lactamases have also found extensive clinical use and although these compounds are themselves bicyclic ␤-lactams, they possess limited antibiotic activity; hence are used in conjunction with a penicillin. With

Enzyme in action: Labeling studies and the finding that carboxymethylproline synthase catalyzes production of deuterated (2S,5S)‐6,6′‐dimethyl‐trans‐carboxymethylproline (3) from dimethylmalonyl‐CoA (1) and labeled l‐pyrroline‐5‐carboxylate (2) limit possible mechanisms of CC bond formation and thioester hydrolysis. A key feature in the catalysis is that intermediates are stabilized by hydrogen bonds in the “oxy‐anion hole” of the enzyme (dark curve in scheme).

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