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What regulates the catalytic activities in AGE catalysis? An answer from quantum mechanics/molecular mechanics simulations
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2017-11-10 00:00:00 , DOI: 10.1039/c7cp07079a Yulai Zhang 1, 2, 3, 4, 5 , Hongxing Zhang 1, 2, 3, 4, 5 , Qingchuan Zheng 1, 2, 3, 4, 5
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2017-11-10 00:00:00 , DOI: 10.1039/c7cp07079a Yulai Zhang 1, 2, 3, 4, 5 , Hongxing Zhang 1, 2, 3, 4, 5 , Qingchuan Zheng 1, 2, 3, 4, 5
Affiliation
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The AGE superfamily (AGEs) is made up of kinds of isomerase which are very important both physiologically and industrially. One of the most intriguing aspects of AGEs has to do with the mechanism that regulates their activities in single conserved active pocket. In order to clarify the relationship among single conserved active pocket and two activities in AGEs, results for the epimerization activity catalyzed by RaCE and the isomerization activity catalyzed by SeYihS were obtained by using QM/MM umbrella sampling simulations and 2D-FES calculations. Our results show that both of them have similar enzyme-substrate combination mode for inner pyranose ring in single conserved active pocket even though they have different substrate specificity. This means that the pathways of ring opening catalyzed by them are similar. However, one non-conserved residue (Leu183 in RaCE, Met175 in SeYihS) in the active site, which has different steric hindrance, causes a small but effective change in the direction of ring opening in stage 1. And then this change will induce a fundamentally different catalytic activity for RaCE and SeYihS in stage 2. Our results give a novel viewpoint about the regulatory mechanism between CE and YihS in AGEs, and may be helpful for further experiments of rational enzyme design based on the (α/α)6-barrel basic scaffold.
中文翻译：
什么调节AGE催化中的催化活性？量子力学/分子力学模拟的答案
AGE超家族（AGEs）由各种异构酶组成，这些异构酶在生理和工业上都非常重要。AGEs最吸引人的方面之一与调节单个保守活性口袋中其活动的机制有关。为了阐明AGEs中单个保守活性口袋与两个活性之间的关系，Ra CE催化的差向异构活性和Se催化的异构化活性得到了结果。YihS是通过使用QM / MM伞形采样模拟和2D-FES计算获得的。我们的结果表明，尽管它们具有不同的底物特异性，但它们在单个保守的活性口袋中都具有相似的内吡喃糖环的酶-底物组合模式。这意味着由它们催化的开环途径是相似的。但是，活性位点中的一个非保守残基（Ra CE中的Leu183，Se YihS中的Met175）具有不同的空间位阻，会导致第1阶段开环方向的微小但有效的变化，然后这种变化将诱导Ra CE和Se的根本不同的催化活性YihS进入第2阶段。我们的研究结果为CE和YihS在AGEs之间的调控机制提供了新观点，并可能有助于进一步研究基于（α/α）6桶碱性支架的合理酶设计。
更新日期：2017-11-23
中文翻译：
什么调节AGE催化中的催化活性？量子力学/分子力学模拟的答案
AGE超家族（AGEs）由各种异构酶组成，这些异构酶在生理和工业上都非常重要。AGEs最吸引人的方面之一与调节单个保守活性口袋中其活动的机制有关。为了阐明AGEs中单个保守活性口袋与两个活性之间的关系，Ra CE催化的差向异构活性和Se催化的异构化活性得到了结果。YihS是通过使用QM / MM伞形采样模拟和2D-FES计算获得的。我们的结果表明，尽管它们具有不同的底物特异性，但它们在单个保守的活性口袋中都具有相似的内吡喃糖环的酶-底物组合模式。这意味着由它们催化的开环途径是相似的。但是，活性位点中的一个非保守残基（Ra CE中的Leu183，Se YihS中的Met175）具有不同的空间位阻，会导致第1阶段开环方向的微小但有效的变化，然后这种变化将诱导Ra CE和Se的根本不同的催化活性YihS进入第2阶段。我们的研究结果为CE和YihS在AGEs之间的调控机制提供了新观点，并可能有助于进一步研究基于（α/α）6桶碱性支架的合理酶设计。
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