Divergent Effects of Compounds on the Hydrolysis and Transpeptidation Reactions of γ-glutamyl Transpeptidase

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2011 Aug 26

PMID 21864033

Citations 7

Authors

Stephanie Wickham

Nicholas Regan

Matthew B West

Vidya Prasanna Kumar

Justin Thai

Pui Kai Li

Paul F Cook

Marie H Hanigan

Affiliations

Soon will be listed here.

Abstract

A novel class of inhibitors of the enzyme γ-glutamyl transpeptidase (GGT) were evaluated. The analog OU749 was shown previously to be an uncompetitive inhibitor of the GGT transpeptidation reaction. The data in this study show that it is an equally potent uncompetitive inhibitor of the hydrolysis reaction, the primary reaction catalyzed by GGT in vivo. A series of structural analogs of OU749 were evaluated. For many of the analogs, the potency of the inhibition differed between the hydrolysis and transpeptidation reactions, providing insight into the malleability of the active site of the enzyme. Analogs with electron withdrawing groups on the benzosulfonamide ring, accelerated the hydrolysis reaction, but inhibited the transpeptidation reaction by competing with a dipeptide acceptor. Several of the OU749 analogs inhibited the transpeptidation reaction by slow onset kinetics, similar to acivicin. Further development of inhibitors of the GGT hydrolysis reaction is necessary to provide new therapeutic compounds.

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