Aldose reductase is the first enzyme of the polyol pathway in which glucose is converted to fructose via sorbitol. The understanding of this key enzyme is important as it has been linked to some diabetes mellitus complications. The mechanism of the enzyme was investigated using a hybrid quantum mechanics/molecular mechanics (QM/MM) method. It was found that depending on the protonation state of His110 the mechanism can be concerted or stepwise and the proton donor can be either Tyr48 or His110. These findings are different from the previous theoretical studies based on QM/MM calculations using either AM1 or HF/4-31G, in which the reduction is, respectively, a stepwise or one-step process. The QM/MM energy barriers for the reduction of d-glyceraldehyde were evaluated at a B3LYP/6-31G* level for both HIP and HIE protonation states of His110. These were, respectively, 6.5 ± 2.2 and 16.7 ± 1.0 kcal/mol, which makes only the HIE protonation state consistent with the experimental value of 14.8 kcal/mol derived from kinetics experiments and makes Tyr48 the most probable proton donor.

中文翻译：

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醛糖还原酶催化机理的新见解：一项QM / MM研究

醛糖还原酶是多元醇途径中的第一个酶，其中葡萄糖通过山梨糖醇转化为果糖。对这种关键酶的理解很重要，因为它已与某些糖尿病并发症相关。使用混合量子力学/分子力学（QM / MM）方法研究了酶的机制。已经发现，取决于His110的质子化状态，该机理可以是协调的或逐步的，并且质子供体可以是Tyr48或His110。这些发现与先前基于使用AM1或HF / 4-31G进行QM / MM计算的理论研究不同，在先前的理论研究中，减少量分别是逐步或一步法。减少d的QM / MM能垒在His110的HIP和HIE质子化状态均以B3LYP / 6-31G *水平评估了β-甘油醛。它们分别为6.5±2.2和16.7±1.0 kcal / mol，这仅使HIE质子化状态与动力学实验得出的实验值14.8 kcal / mol一致，并使Tyr48成为最可能的质子供体。