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氘同位素对睾丸酮丛毛单胞菌醌血红蛋白醇脱氢酶催化的外消旋2,2-二甲基-4-羟甲基-1,3-二氧戊环(缩苹果醛乙醇)动力学拆分中对映选择性的影响。

Deuterium isotope effect on enantioselectivity in the Comamonas testosteroni quinohemoprotein alcohol dehydrogenase-catalyzed kinetic resolution of rac-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, solketal.

作者信息

Jongejan Aldo, Jongejan Jaap A, Hagen Wilfred R

机构信息

Computational Medicinal Chemistry and Toxicology, Department of Pharmacochemistry, Free University of Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

出版信息

Biochim Biophys Acta. 2003 Apr 11;1647(1-2):297-302. doi: 10.1016/s1570-9639(03)00073-6.

Abstract

Isotopic substitution provides an effective tool to probe the mechanism of enzyme-catalyzed reactions. To our knowledge, kinetic isotope effects on the enantioselectivity of enzymes have not been reported. We investigated the effect of deuterium substitution on the enantiomeric ratio, E, of PQQ-containing quinohemoprotein alcohol dehydrogenase, QH-ADH, from Comamonas testosteroni in the ferricyanide-coupled kinetic resolution of rac-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, solketal. Under otherwise identical conditions, we measured E=30 for solketal and E=6 for rac-2,2-dimethyl-4-[1,1-2H]hydroxymethyl-1,3-[5,5,4-2H]dioxolane, d(5)-solketal. It is proposed that isotopic substitution affects the relative kinetic weights of the initial hydron/deuteron transfer from substrate to cofactor and the subsequent proton/deuteron shift in the cofactor-product complex. The latter step becomes more important in the deuterated complex to the extent that the enantiomer discrimination in the first step is partially overruled.

摘要

同位素取代为探究酶催化反应的机制提供了一种有效工具。据我们所知,尚未有关于动力学同位素效应影响酶对映选择性的报道。我们研究了氘取代对睾丸酮丛毛单胞菌含吡咯喹啉醌的醌血红蛋白醇脱氢酶(QH-ADH)在rac-2,2-二甲基-4-羟甲基-1,3-二氧戊环(缩酮)的铁氰化物偶联动力学拆分中对映体比例E的影响。在其他条件相同的情况下,我们测得缩酮的E = 30,而rac-2,2-二甲基-4-[1,1-2H]羟甲基-1,3-[5,5,4-2H]二氧戊环(d(5)-缩酮)的E = 6。有人提出,同位素取代会影响从底物到辅因子的初始氢/氘转移以及随后在辅因子 - 产物复合物中质子/氘的转移的相对动力学权重。在氘化复合物中,后一步变得更为重要,以至于第一步中的对映体区分被部分推翻。

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