Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides
Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides
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DOI：
10.1016/j.bbrc.2013.04.081
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发表时间：
2013-05-31
影响因子：
3.1
通讯作者：
Skjeldal, Lars
中科院分区：
文献类型：
--
作者：
Lindstad, Rune I.;Teigen, Knut;Skjeldal, Lars
已发现山梨醇脱氢酶抑制剂可以预防或减轻糖尿病的各种继发并发症。本研究通过pH 7.4下的稳态动力学研究了核苷和核苷酸对绵羊肝酶催化的山梨醇氧化速率的影响。各种此类化合物，包括 ATP 和 ATP、ADP 和 AMP 的 2'-脱氧类似物，通过形成酶-辅酶-抑制剂三元复合物可逆地抑制酶活性。在每种情况下，使用山梨糖醇或NAD(+)作为不同底物的双倒数图中没有看到线性偏差，并且抑制剂浓度和观察到的抑制效果之间存在线性关系。根据人 SDH-NAD(+) 全酶的结构，将山梨醇对接至绵羊 SDH-NAD(+) 复合物模型中。绵羊 SDH、NAD(+) 和山梨醇的三元复合物（PMDB ID 代码 PM 0078068）的所得结构表明，山梨醇的反应性 C-2 羟基朝向辅酶烟酰胺部分的 4'-位，并且山梨醇的相邻伯羟基与催化锌相互作用。结果表明抑制剂结构的核糖部分是观察到的效果的重要决定因素。具体而言，核糖环的2'位发挥抑制剂效力的作用。 (c) 2013 Elsevier Inc. 保留所有权利。
Sorbitol dehydrogenase inhibitors have been found to prevent, or alleviate, various secondary complications of diabetes mellitus. In the present study, the effects of nucleosides and nucleotides on the rate of sorbitol oxidation catalyzed by the sheep liver enzyme were studied by steady-state kinetics at pH 7.4. Various such compounds, including ATP and the 2'-deoxy-analogues of ATP, ADP and AMP, reversibly inhibit enzyme activity by formation of enzyme-coenzyme-inhibitor ternary complexes. In each case, no deviations from linearity were seen in the double-reciprocal plots using sorbitol or NAD(+) as the varied substrate and there was a linear relationship between inhibitor concentration and the observed inhibitory effects. Sorbitol was docked into a model of the sheep SDH-NAD(+) complex based upon the structure of the human SDH-NAD(+) holoenzyme. The resulting structure of the ternary complex of sheep SDH, NAD(+) and sorbitol (PMDB ID code PM 0078068) shows that the reactive C-2 hydroxyl group of sorbitol is oriented toward the 4'-position of the nicotinamide moiety of the coenzyme, and that the adjacent primary hydroxyl group of sorbitol interacts with the catalytic zinc. The results indicate that the ribose moiety of the inhibitor structures is an important determinant for the observed effects. Specifically, the 2'-position of the ribose ring exerts an effect with respect to inhibitor potency. (c) 2013 Elsevier Inc. All rights reserved.