Lee Y S, Hodoscek M, Brooks B R, Kador P F
National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Biophys Chem. 1998 Mar 9;70(3):203-16. doi: 10.1016/s0301-4622(97)00115-4.
The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described.
利用量子力学（QM）和分子力学（MM）的联合势能，研究了醛糖还原酶将D-甘油醛催化还原为甘油的过程，以解决在催化过程中Tyr48或His110是否作为质子供体的问题。定点诱变研究倾向于Tyr48作为质子供体，而存在一条将His110的Nδ1与大量溶剂相连的水通道则表明His110是质子供体。利用QM和MM的联合势能，通过优化醛糖还原酶活性位点处的Asp43、Lys77、Tyr48、His110和NADPH的局部几何结构，研究了底物D-甘油醛的结合模式。然后通过将Tyr48和His110都作为质子供体，构建了将D-甘油醛还原为甘油的反应途径。从反应途径获得的能量学比较表明His110是质子供体。基于这些发现，描述了D-甘油醛还原为甘油的机制。
