Duax W L, Ghosh D, Pletnev V
Hauptman-Woodward Medical Research Institute, Inc., Buffalo, New York 14203, USA.
Vitam Horm. 2000;58:121-48. doi: 10.1016/s0083-6729(00)58023-6.
Steroid dehydrogenase enzymes influence mammalian reproduction, hypertension, neoplasia, and digestion. The three-dimensional structures of steroid dehydrogenase enzymes reveal the position of the catalytic triad, a possible mechanism of keto-hydroxyl interconversion, a molecular mechanism of inhibition, and the basis for selectivity. Glycyrrhizic acid, the active ingredient in licorice, and its metabolite carbenoxolone are potent inhibitors of human 11 beta-hydroxysteroid dehydrogenase and bacterial 3 alpha, 20 beta-hydroxysteroid dehydrogenase (3 alpha, 20 beta-HSD). The three-dimensional structure of the 3 alpha, 20 beta-HSD carbenoxolone complex unequivocally verifies the postulated active site of the enzyme, shows that inhibition is a result of direct competition with the substrate for binding, and provides a plausible model for the mechanism of inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone. The structure of the ternary complex of human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD) with the cofactor NADP+ and the antiestrogen equilin reveals the details of binding of an inhibitor in the active site of the enzyme and the possible roles of various amino acids in the catalytic cleft. The short-chain dehydrogenase reductase (SDR) family includes these steroid dehydrogenase enzymes and more than 60 other proteins from human, mammalian, insect, and bacterial sources. Most members of the family contain the tyrosine and lysine of the catalytic triad in a YxxxK sequence. X-ray crystal structures of 13 members of the family have been completed. When the alpha-carbon backbone of the cofactor binding domains of the structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket.
类固醇脱氢酶影响哺乳动物的生殖、高血压、肿瘤形成和消化。类固醇脱氢酶的三维结构揭示了催化三联体的位置、酮-羟基相互转化的可能机制、抑制的分子机制以及选择性的基础。甘草中的活性成分甘草酸及其代谢产物甘珀酸是人类11β-羟基类固醇脱氢酶和细菌3α,20β-羟基类固醇脱氢酶（3α,20β-HSD）的有效抑制剂。3α,20β-HSD与甘珀酸复合物的三维结构明确验证了该酶假定的活性位点，表明抑制是与底物直接竞争结合的结果，并为甘珀酸抑制11β-羟基类固醇脱氢酶的机制提供了一个合理的模型。人类1型17β-羟基类固醇脱氢酶（17β-HSD）与辅因子NADP+和抗雌激素马萘雌酮的三元复合物结构揭示了抑制剂在酶活性位点的结合细节以及催化裂隙中各种氨基酸的可能作用。短链脱氢酶还原酶（SDR）家族包括这些类固醇脱氢酶以及来自人类、哺乳动物、昆虫和细菌来源的60多种其他蛋白质。该家族的大多数成员在YxxxK序列中含有催化三联体的酪氨酸和赖氨酸。该家族13个成员的X射线晶体结构已完成。当这些结构的辅因子结合域的α-碳骨架叠加时，保守残基位于结构的核心和辅因子结合域中，但不在底物结合口袋中。
