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Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a ?-lactamase and a N-terminal nucleophile hydrolase.

ABSTRACT: O-Aryloxycarbonyl hydroxamates and 1,3,4-oxathiazol-2-ones have been identified as covalent inhibitors of ?-lactamases and proteasomes, respectively. The products of these inhibition reactions are remarkably similar, involving carbonyl cross-linking of the active sites. We have cross-checked these inhibitors, showing that the former inhibit proteasomes and the latter ?-lactamases, to form the same inactive carbonyl adducts. These results are discussed in terms of similarities of the active site structures and catalytic mechanisms. It is likely that a mechanistic imperative has led to convergent evolution of these enzyme active sites, of a ?-lactam-recognizing enzyme and a N-terminal protease belonging to different amidohydrolase superfamilies.

SUBMITTER: Adediran SA

PROVIDER: S-EPMC3505995 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a β-lactamase and a N-terminal nucleophile hydrolase.

Adediran S A SA Lin G G Pelto R B RB Pratt R F RF

FEBS letters 20121023 23

O-Aryloxycarbonyl hydroxamates and 1,3,4-oxathiazol-2-ones have been identified as covalent inhibitors of β-lactamases and proteasomes, respectively. The products of these inhibition reactions are remarkably similar, involving carbonyl cross-linking of the active sites. We have cross-checked these inhibitors, showing that the former inhibit proteasomes and the latter β-lactamases, to form the same inactive carbonyl adducts. These results are discussed in terms of similarities of the active site ...[more]

PMID: 23098756

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