title: Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a β-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 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 structures and catalytic mechanisms. It is likely that a mechanistic imperative has led to convergent evolution of these enzyme active sites, of a β-lactam-recognizing enzyme and a N-terminal protease belonging to different amidohydrolase superfamilies.
authors.affiliation: Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Adediran
authors.forename: G
authors.initials: G
authors.lastname: Lin
authors.forename: R B
authors.initials: RB
authors.lastname: Pelto
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019143:Evolution, Molecular; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D046988:Proteasome Endopeptidase Complex; D000581:Amidohydrolases; C438834:N-terminal nucleophile hydrolase; D001618:beta-Lactamases