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首页> 外文期刊>Journal of Molecular Biology >SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone
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SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone

机译：SimC7是一种新型的NAD（P）H依赖性酮还原酶，对于DNA促旋酶抑制剂Simocyclinone的抗菌活性必不可少

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Simocyclinone D8 (SD8) is a potent DNA gyrase inhibitor produced by Streptomyces antibioticus Tu6040. The simocyclinone (sim) biosynthetic gene cluster has been sequenced and a hypothetical biosynthetic pathway has been proposed. The tetraene linker in SD8 was suggested to be the product of a modular type I polyketide synthase working in trans with two monofunctional enzymes. One of these monofunctional enzymes, SimC7, was proposed to supply a dehydratase activity missing from two modules of the polyketide synthase. In this study, we report the function of SimC7. We isolated the entire similar to 72-kb sim cluster on a single phage artificial chromosome clone and produced simocyclinone heterologously in a Streptomyces coelicolor strain engineered for improved antibiotic production. Deletion of simC7 resulted in the production of a novel simocyclinone, 7-oxo-SD8, which unexpectedly carried a normal tetraene linker but was altered in the angucyclinone moiety. We demonstrate that SimC7 is an NAD(P)H-dependent ketoreductase that catalyzes the conversion of 7-oxo-SD8 into SD8. 7-oxo-SD8 was essentially inactive as a DNA gyrase inhibitor, and the reduction of the keto group by SimC7 was shown to be crucial for high-affinity binding to the enzyme. Thus, SimC7 is an angucyclinone ketoreductase that is essential for the biological activity of simocyclinone. (C) 2015 The Authors. Published by Elsevier Ltd.
机译：Simocyclinone D8（SD8）是一种有效的DNA旋转酶抑制剂，由抗生素链霉菌Tu6040生产。 simocyclinone（sim）生物合成基因簇已被测序，并提出了一种假设的生物合成途径。 SD8中的四烯接头被认为是与两种单功能酶反式工作的模块化I型聚酮化合物合酶的产物。提出了这些单功能酶之一SimC7来提供聚酮化合物合酶两个模块所缺少的脱水酶活性。在这项研究中，我们报告了SimC7的功能。我们在单个噬菌体人工染色体克隆上分离了整个与72-kb sim簇相似的基因，并在为改进抗生素生产而设计的链霉菌青色链霉菌中异源产生了西莫环素。 simC7的删除导致新的simocyclinone，7-oxo-SD8的产生，它出乎意料地带有一个正常的四烯连接基，但是在angucyclinone部分发生了改变。我们证明SimC7是NAD（P）H依赖的酮还原酶，催化7-氧代-SD8转换为SD8。 7-oxo-SD8作为DNA促旋酶抑制剂基本上没有活性，SimC7的酮基还原作用对于高亲和力结合至该酶至关重要。因此，SimC7是一种环己酮酮还原酶，对simocyclinone的生物学活性至关重要。 （C）2015作者。由Elsevier Ltd.发布

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