RESUMO
A number of benzylalkylketones and benzylalkylcarbinols have been synthesized as non-hydrolizable substrate analogues of penicillin acylase (EC 3.5.1.11), and their affinity to the enzyme has been studied. The compounds with plane trigonal carbonyl group (ketones) were established to has bind to the enzyme 20-40 times more tightly than their tetrahedral counterparts with a hydroxyl function (carbinols). 4-Oxo-5-phenylpentanoic acid was found to be one of the most potent reversible competitive inhibitors of penicillin acylase with Ki-31 microM.
Assuntos
Compostos de Benzil/farmacologia , Escherichia coli/enzimologia , Cetonas/farmacologia , Penicilina Amidase/antagonistas & inibidores , Álcool Feniletílico/análogos & derivados , Alquilação , Hidrólise , Estrutura Molecular , Álcool Feniletílico/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Monoaryl of benzylphosphonic acid have been synthesized and studied as the inhibitors of penicillin acylase. These compounds were found to be effective and selective irreversible inhibitors of the enzyme. The kinetic parameters of enzyme inactivation are determined, and possible mechanism of the inhibition is discussed. These phosphonates should be useful as both penicillin acylase active site titrants and the tools for the enzyme function study. Benzylchloromethyl keton has been also prepared and it is an irreversible inhibitor of penicillin acylase.
Assuntos
Compostos de Benzil/farmacologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Organofosfonatos/farmacologia , Penicilina Amidase/antagonistas & inibidores , Fósforo/análise , Compostos de Benzil/química , Inibidores Enzimáticos/química , Ésteres , Hidrocarbonetos Clorados/farmacologia , Cinética , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Phosphonic analogues of penicillin acylase substrates are found to be selective reversible competitive inhibitors of the enzyme from E. coli (EC 3.5.1.11). The mode of binding of the inhibitors to the enzyme and the influence of the stereoelectronic parameters of the phosphonic inhibitors on their affinity to the enzyme are discussed.
Assuntos
Escherichia coli/enzimologia , Organofosfonatos/farmacologia , Penicilina Amidase/antagonistas & inibidores , Fósforo/análise , Ligação Competitiva/fisiologia , Concentração de Íons de HidrogênioRESUMO
Phosphonate and phosphonoamidate derivatives of benzylphosphonic acids were synthesized as potential inhibitors of penicillin acylase (EC 3.5.1.11) proceeding from the concept of transition-state analogues. The compounds obtained are not the substrates of the enzyme and they are stable under conditions of enzyme activity testing.