A tylosin ketoreductase reveals how chirality is determined in polyketides
A tylosin ketoreductase reveals how chirality is determined in polyketides
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DOI：
10.1016/j.chembiol.2007.07.009
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发表时间：
2007-08-01
影响因子：
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通讯作者：
Keatinge-Clay, Adrian T.
中科院分区：
文献类型：
--
作者：
Keatinge-Clay, Adrian T.
由于酮还原酶（KR）控制大多数聚酮化合物立体中心，因此它是工程化聚酮化合物还原酶（PKS）的中心靶标。为了阐明立体控制的机制，确定了泰乐菌素PKS的第一个模块的KR的结构。与最近解决的红霉素KR，在同一基板上操作的比较解释了为什么他们的产品具有相反的ocsubstituted手性。该结构揭示了聚酮化合物如何被不同KR类型中的关键残基引导到活性位点。有四种类型的还原酶活性KR，每种都能够固定α-取代基和β-羟基手性的独特组合，以及两种类型的单独控制α-取代基手性的还原酶活性KR。提出了一种基于模块序列分配模块如何增强取代基手性的协议。
Because it controls the majority of polyketide stereocenters, the ketoreductase (KR) is a central target in engineering polyketide synthases (PKSs). To elucidate the mechanisms of stereocontrol, the structure of KR from the first module of the tylosin PKS was determined. A comparison with a recently solved erythromycin KR that operates on the same substrate explains why their products have opposite ocsubstituent chiralities. The structure reveals how polyketides are guided into the active site by key residues in different KR types. There are four types of reductase-competent KRs, each capable of fixing a unique combination of oc-substituent and beta-hydroxyl group chiralities, as well as two types of reductase-incompetent KRs that control alpha-substituent chirality alone. A protocol to assign how a module will enforce substituent chirality based on its sequence is presented.