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首页> 外文期刊>Chemistry: A European journal >Substrate-dependent stereospecificity of Tyl-KR1: An isolated polyketide synthase ketoreductase domain from Streptomyces fradiae
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Substrate-dependent stereospecificity of Tyl-KR1: An isolated polyketide synthase ketoreductase domain from Streptomyces fradiae

机译：Tyl-KR1的底物依赖性立体特异性：来自链霉菌的分离的聚酮化合物合酶酮还原酶结构域

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摘要

The stereospecificity of an enzymatic reaction depends on the way in which a substrate and its enantiomer bind to the active site. These binding modes cannot be easily predicted. We have studied the stereospecificity and stereoselectivity of the ketoreductase domain Tyl-KR1 of the tylactone polyketide synthase from Streptomyces fradiae by analysing the stereochemical outcome of the reduction of five different keto ester substrates. The absolute configuration of the Tyl-KR1 reduction products was determined by using vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. The conversion of only one of the tested substrates, 2-methyl-3-oxovaleric acid N-acetylcysteamine thioester, afforded the expected anti-(2R,3R) configuration of the α-methyl-β-hydroxyl ester product, representing the stereochemistry observed for the physiological polyketide product tylactone. For all other substrates, which were modified with respect to the type of ester and/or the chain length (C_4 instead of C _5), the opposite configuration (anti-(2S,3S)) was obtained with significant enantio- and diastereoselectivity. Inversion of both stereocentres suggests completely different binding modes invoked by only minor modifications of the substrate structure. Substrate dependence: The stereospecificity of an enzymatic reduction depends on the way a substrate binds to the active site. By using vibrational circular dichroism, it was shown that the stereospecificity and stereoselectivity of the ketoreductase Tyl-KR1 from a polyketide synthase complex in Streptomyces fradiae are inverted for different surrogates of polyketide-like substrates (see figure).
机译：酶促反应的立体特异性取决于底物及其对映异构体与活性位点结合的方式。这些绑定模式无法轻易预测。我们已经通过分析五个不同的酮酯底物还原的立体化学结果，研究了Streptomyces fradiae的酪酮聚酮化合物合酶的酮还原酶结构域Tyl-KR1的立体特异性和立体选择性。 Tyl-KR1还原产物的绝对构型是通过使用振动圆二色性（VCD）光谱结合量子化学计算来确定的。仅一种被测底物2-甲基-3-氧代戊酸N-乙酰基半胱胺硫酯的转化提供了预期的α-甲基-β-羟基酯产物的抗（2R，3R）构型，代表了所观察到的立体化学用于生理上的聚酮化合物产品内酯。对于所有其他根据酯的类型和/或链长（C_4代替C_5）进行修饰的底物，都获得了对映体构型（抗-（2S，3S）），具有显着的对映体和非对映体选择性。两个立体中心的倒置表明完全不同的结合模式，仅通过对底物结构的微小修改即可调用。底物依赖性：酶促还原的立体特异性取决于底物与活性位点结合的方式。通过使用振动圆二色性，显示了从链霉菌中的聚酮化合物合酶复合物中来的酮还原酶Tyl-KR1的立体特异性和立体选择性对于聚酮化合物样底物的不同替代物是相反的（见图）。

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