洛伐他汀生物合成中转录后聚酮烯酰还原酶 LovC 的晶体结构和生化研究。
Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis.
机构信息
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
出版信息
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11144-9. doi: 10.1073/pnas.1113029109. Epub 2012 Jun 25.
Abstract
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 trans-acting 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-Å 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.
摘要
洛伐他汀是一种重要的他汀类药物，用于治疗和预防心血管疾病。洛伐他汀的生物合成使用了一种迭代的 I 型聚酮合酶（PKS）。LovC 是一种反式作用的烯酰还原酶（ER），在洛伐他汀生物合成过程中，它专门还原八种可能的聚酮中间产物中的三种。这种反式作用的 ER 已经在其他各种真菌 PKS 酶中被报道，是自然界中使聚酮多样化的一种策略。LovC 如何实现这种特异性尚不清楚。LovC 的 1.9 Å 结构揭示了它具有一个独特的单体组装的中链脱氢酶/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，并确定活性位点残基。序列比对表明，真菌 PKS 的反式作用 ER 具有普遍适用性，以及它们在指导生物合成方面的潜在应用。
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