title: Serendipitous discovery of α-hydroxyalkyl esters as β-lactamase substrates.
abstract: O-(1-Carboxy-1-alkyloxycarbonyl) hydroxamates were found to spontaneously decarboxylate in aqueous neutral buffer to form O-(2-hydroxyalkylcarbonyl) hydroxamates. While the former molecules do not react rapidly with serine β-lactamases, the latter are quite good substrates of representative class A and C, but not D, enzymes, and particularly of a class C enzyme. The enzymes catalyze hydrolysis of these compounds to a mixture of the α-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather that hydroxamates are also substrates. Structure-activity experiments showed that the α-hydroxyl group was required for any substantial substrate activity. Although both d- and l-α-hydroxy acid derivatives were substrates, the former were preferred. The response of the class C activity to pH and to alternative nucleophiles (methanol and d-phenylalanine) suggested that the same active site functional groups participated in catalysis as for classical substrates. Molecular modeling was employed to explore how the α-hydroxy group might interact with the class C β-lactamase active site. Incorporation of the α-hydroxyalkyl moiety into novel inhibitors will be of considerable interest.
authors.affiliation: Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459, United States.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Pelto
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
mesh_terms: D000192:Actinomycetales / Q000201:enzymology; D000478:Alkylation / Q000502:physiology; D000480:Alkynes / Q000737:chemistry* / Q000378:metabolism; D001667:Binding, Competitive; D055808:Drug Discovery / Q000379:methods*; D016972:Enterobacter cloacae / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology; D004952:Esters; D006868:Hydrolysis; D008958:Models, Molecular; D013302:Streptomyces / Q000201:enzymology; D013379:Substrate Specificity / Q000502:physiology; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism
chemical_list: D000480:Alkynes; D004952:Esters; D001618:beta-Lactamases