| Inhibition of human gamma-glutamyl transpeptidase: development of more potent, physiologically relevant, uncompetitive inhibitors. | |
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MedLine Citation:
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PMID: 23301618 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Gamma-glutamyl transpeptidase (GGT) is an essential enzyme for maintaining cysteine homeostasis, leukotriene synthesis, metabolism of glutathione-conjugates and catabolism of extracellular glutathione. Over expression 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. This 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 catalyzed 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 analogs 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-analogs that have been tested clinically. Development of non-toxic inhibitors is essential for exploiting GGT as a therapeutic target. |
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Authors:
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Stephanie Wickham; Nicholas Regan; Matthew B West; Justin Thai; Paul F Cook; Simon S Terzyan; Pui-Kai Li; Marie H Hanigan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-10 |
Journal Detail:
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Title: The Biochemical journal Volume: - ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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