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首页> 外文期刊>Biochemistry >ALDOSE REDUCTASE AS A TARGET FOR DRUG DESIGN - MOLECULAR MODELING CALCULATIONS ON THE BINDING OF ACYCLIC SUGAR SUBSTRATES TO THE ENZYME
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ALDOSE REDUCTASE AS A TARGET FOR DRUG DESIGN - MOLECULAR MODELING CALCULATIONS ON THE BINDING OF ACYCLIC SUGAR SUBSTRATES TO THE ENZYME

机译：ALDOSE还原酶作为药物设计的目标-非糖基糖基与酶结合的分子建模计算

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In an attempt to obtain a picture of the binding conformation of aldehyde substrates to human aldose reductase (hAR), modeling calculations have been performed on the binding of three substrate, D-xylose, L-xylose, and D-lyxose, to wild-type human aldose reductase and two of its site-directed mutants, It was found that the average geometry of D-xylose in the active site of wild-type aldose reductase is characterized by strong hydrogen bonds involving the reactive carbonyl oxygen of the substrate and both Tyr48 and His110. The calculations also suggest the importance of Trp111 in the binding of 2'-hydroxyl-containing aldehyde substrates. A good correlation between calculated interaction enthalpies and experimental log(K-m) or log(k(cat)/K-m) values was obtained when His110 was modeled with its N epsilon 2 atom protonated and N delta 1 unprotonated. No correlation was found for the other two configurations of His110. On the basis of comparisons of the calculated substrate binding conformations for the three possible His110 configurations, and on the correlations between measured log(K-m) or log(k(cat)/K-m) and calculated parameters, it is proposed that His110 is neutral and protonated at N epsilon 2 when an aldehyde substrate is bound to the hAR/NADPH complex. A chain of three hydrogen-bonded water molecules has been identified in all available crystal structures and is located in an enzyme channel which links the N delta 1 atom of His110 to the solvent-accessible surface of the enzyme. A possible role of this channel in the mechanism of catalysis of aldose reductase is suggested. [References: 33]
机译：为了获得有关醛底物与人醛糖还原酶（hAR）结合构象的图片，已对三种底物D-木糖，L-木糖和D-lyxose与野生型结合进行了建模计算。型人醛糖还原酶及其两个定点突变体，发现野生型醛糖还原酶活性位点中D-木糖的平均几何特征是强氢键，涉及底物的活性羰基氧Tyr48和His110。该计算还暗示了Trp111在结合含2'-羟基的醛底物中的重要性。当His110的N epsilon 2原子为质子化且N delta 1为非质子化时，在计算的相互作用焓与log（K-m）或log（k（cat）/ K-m）值之间具有良好的相关性。未发现His110的其他两种配置之间的相关性。根据对三种可能的His110构型计算的底物结合构象的比较，并根据测得的log（Km）或log（k（cat）/ Km）与计算参数之间的相关性，提出His110为中性且当醛底物结合到hAR / NADPH络合物上时，在N epsilon 2质子化。已在所有可用的晶体结构中鉴定出三个氢键水分子链，它们位于一条酶通道中，该通道将His110的N delta 1原子与酶的溶剂可及表面相连。建议该通道在醛糖还原酶催化机理中的可能作用。 [参考：33]

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