Document Detail

Inhibition of human γ-glutamyl transpeptidase: development of more potent, physiologically relevant, uncompetitive inhibitors.
MedLine Citation:
PMID:  23301618     Owner:  NLM     Status:  MEDLINE    
GGT (γ-glutamyl transpeptidase) is an essential enzyme for maintaining cysteine homoeostasis, leukotriene synthesis, metabolism of glutathione conjugates and catabolism of extracellular glutathione. Overexpression of GGT has been implicated in many pathologies, and clinical inhibitors of GGT are under development for use in the treatment of asthma, cancer and other diseases. Inhibitors are generally characterized using synthetic GGT substrates. The present study of uncompetitive inhibitors of GGT, has revealed that the potency with which compounds inhibit GGT activity in the standard biochemical assay does not correlate with the potency with which they inhibit the physiological reaction catalysed by GGT. Kinetic studies provided insight into the mechanism of inhibition. Modifications to the sulfobenzene or distal benzene ring of the uncompetitive inhibitor OU749 affected activity. One of the most potent inhibitors was identified among a novel group of analogues with an amine group para on the benzosulfonamide ring. New more potent uncompetitive inhibitors of the physiological GGT reaction were found to be less toxic than the glutamine analogues that have been tested clinically. Development of non-toxic inhibitors is essential for exploiting GGT as a therapeutic target.
Stephanie Wickham; Nicholas Regan; Matthew B West; Justin Thai; Paul F Cook; Simon S Terzyan; Pui Kai Li; Marie H Hanigan
Related Documents :
24089528 - The arabidopsis atamy3 is a unique redox-regulated chloroplastic α-amylase.
23178238 - Bag-1 stabilizes mutant f508del-cftr in a ubiquitin-like-domain-dependent manner.
24480108 - Effect of urea and alkylureas on the stability and structural fluctuation of the m80-co...
24913158 - His224 alters the r2 drug binding site and phe218 influences the catalytic efficiency i...
23319598 - The heme chaperone apoccme forms a ternary complex with ccmi and apocytochrome c.
10433118 - Analysis of wheat mitochondrial complex i purified by a one-step immunoaffinity chromat...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  450     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-28     Completed Date:  2013-04-17     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  547-57     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Binding, Competitive / drug effects
Cells, Cultured
Drug Design*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis,  metabolism,  pharmacology*
Glutathione / metabolism
Models, Biological
NIH 3T3 Cells
Protein Binding
Substrate Specificity
Sulfonamides / pharmacology
Thiadiazoles / pharmacology
gamma-Glutamyltransferase / antagonists & inhibitors*,  metabolism*
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/N-(5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide; 0/Sulfonamides; 0/Thiadiazoles; EC; GAN16C9B8O/Glutathione

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  A CLSM method for the dynamic observation of pH change within polymer matrices for oral delivery.
Next Document:  Identification of PDE6D as a Molecular Target of Anecortave Acetate via a Methotrexate-Anchored Yeas...