1. An unprecedented dual antagonist and agonist of human Transglutaminase 2.
- Author
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Yi MC, Palanski BA, Quintero SA, Plugis NM, and Khosla C
- Subjects
- 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, Enzyme Inhibitors pharmacology, GTP-Binding Proteins agonists, GTP-Binding Proteins antagonists & inhibitors, Transglutaminases antagonists & inhibitors
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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