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Bioorg Med Chem Lett ; 25(21): 4922-4926, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26004580

ABSTRACT

Transglutaminase 2 (TG2) is a ubiquitously expressed, Ca(2+)-activated extracellular enzyme in mammals that is maintained in a catalytically dormant state by multiple mechanisms. Although its precise physiological role in the extracellular matrix remains unclear, aberrantly up-regulated TG2 activity is a hallmark of several maladies, including celiac disease. Previously, we reported the discovery of a class of acylideneoxoindoles as potent, reversible inhibitors of human TG2. Detailed analysis of one of those inhibitors (CK-IV-55) led to an unprecedented and striking observation. Whereas this compound was a non-competitive inhibitor (3.3±0.9 µM) of human TG2 at saturating Ca(2+) concentrations, it activated TG2 in the presence of sub-saturating but physiologically relevant Ca(2+) concentrations (0.5-0.7 mM). This finding was validated in a cellular model of TG2 activation and inhibition. Mutant TG2 analysis suggested that CK-IV-55 and its analogs bound to a low-affinity Ca(2+) binding site on the catalytic core of TG2. A mechanistic model for the dual agonistic/antagonistic action of CK-IV-55 on TG2 is presented, and the pathophysiological implications of basal activation of intestinal TG2 by small molecules are discussed.


Subject(s)
Enzyme Inhibitors/pharmacology , GTP-Binding Proteins/agonists , GTP-Binding Proteins/antagonists & inhibitors , Transglutaminases/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fibroblasts/drug effects , Fibroblasts/enzymology , GTP-Binding Proteins/metabolism , Humans , Molecular Structure , Protein Glutamine gamma Glutamyltransferase 2 , Structure-Activity Relationship , Transglutaminases/metabolism
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