Serendipitous discovery of ?-hydroxyalkyl esters as ?-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 ?-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 ?-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather that hydroxamates are also substrates. Structure-activity experiments showed that the ?-hydroxyl group was required for any substantial substrate activity. Although both d- and l-?-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 ?-hydroxy group might interact with the class C ?-lactamase active site. Incorporation of the ?-hydroxyalkyl moiety into novel inhibitors will be of considerable interest.

SUBMITTER: Pelto RB 

PROVIDER: S-EPMC2999657 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature