title: Divergent effects of compounds on the hydrolysis and transpeptidation reactions of γ-glutamyl transpeptidase.
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.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Centre, Oklahoma City, OK 73104, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wickham
authors.forename: Nicholas
authors.initials: N
authors.lastname: Regan
authors.forename: Matthew B
authors.initials: MB
authors.lastname: West
authors.forename: Vidya Prasanna
authors.initials: VP
authors.lastname: Kumar
authors.forename: Justin
authors.initials: J
authors.lastname: Thai
authors.forename: Pui Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Paul F
authors.initials: PF
authors.lastname: Cook
authors.forename: Marie H
authors.initials: MH
authors.lastname: Hanigan
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013830:Thiadiazoles; D005723:gamma-Glutamyltransferase; C540802:N-(5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides