Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis
Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis
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DOI：
10.1073/pnas.1113029109
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发表时间：
2012-07-10
影响因子：
11.1
通讯作者：
Tsai, Shiou-Chuan
中科院分区：
文献类型：
--
作者：
Ames, Brian D.;Chi Nguyen;Tsai, Shiou-Chuan
洛伐他汀是治疗和预防心血管疾病的重要他汀类药物。洛伐他汀的生物合成使用迭代的I型聚酮合成酶(PKS)。LOVC是一种交易型烯醇还原酶(ER)，在洛伐他汀的生物合成过程中，它能特异性地还原8种可能的聚酮中间产物中的3种。据报道，这种反式作用的内质网存在于其他各种真菌PKS酶中，本质上是一种使多酮多样化的策略。洛夫克是如何做到这种专一性的还不得而知。LOVC的1.9埃结构揭示了LOVC具有一个具有独特单体组装的中链脱氢/还原酶(MDR)折叠。两个LOVC共晶结构和酶学研究有助于阐明LOVC特异性的分子基础，定义立体化学，并确定活性部位残基。序列比对表明，真菌PKS的反式作用ERs具有普遍的适用性，以及它们在指导生物合成方面的潜在应用。
Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a transacting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-angstrom structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.