Yi Michael C, Palanski Brad A, Quintero Steven A, Plugis Nicholas M, Khosla Chaitan
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4922-4926. doi: 10.1016/j.bmcl.2015.05.006. Epub 2015 May 15.
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.
转谷氨酰胺酶2（TG2）是一种在哺乳动物中广泛表达的、Ca(2+)激活的细胞外酶，它通过多种机制维持在催化休眠状态。尽管其在细胞外基质中的确切生理作用尚不清楚，但TG2活性异常上调是包括乳糜泻在内的几种疾病的标志。此前，我们报道了一类酰亚胺基氧吲哚作为人TG2的强效、可逆抑制剂的发现。对其中一种抑制剂（CK-IV-55）的详细分析导致了一个前所未有的惊人发现。在饱和Ca(2+)浓度下，该化合物是人TG2的非竞争性抑制剂（3.3±0.9 μM），而在亚饱和但生理相关的Ca(2+)浓度（0.5 - 0.7 mM）存在时，它会激活TG2。这一发现已在TG2激活和抑制的细胞模型中得到验证。突变型TG2分析表明，CK-IV-55及其类似物与TG2催化核心上的一个低亲和力Ca(2+)结合位点结合。本文提出了CK-IV-55对TG2的双重激动/拮抗作用的机制模型，并讨论了小分子对肠道TG2基础激活的病理生理学意义。
