The structure of a ketoreductase determines the organization of the β-carbon processing enzymes of modular polyketide synthases
The structure of a ketoreductase determines the organization of the β-carbon processing enzymes of modular polyketide synthases
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DOI：
10.1016/j.str.2006.01.009
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发表时间：
2006-04-01
期刊：
影响因子：
5.7
通讯作者：
Stroud, RM
中科院分区：
文献类型：
--
作者：
Keatinge-Clay, AT;Stroud, RM
结合NADPH的红霉素合成酶第一个模块的酮还原酶（KR）的结构被解析到1.79埃的分辨率。51 kDa结构域有两个子结构域，每个子结构域类似于短链脱氢酶/还原酶（SDR）单体。其中一个子结构域具有截断的罗斯曼折叠，并起到稳定另一个子结构域的纯粹结构作用，催化聚酮的-羰基还原，并可能催化α取代基的外映化。该结构使我们能够确定KR，脱水酶（DH）和烯基还原酶（ER）的结构域边界。它还限制了这些域在模块内的三维组织，揭示了KR不会在模块的2倍轴上进行二聚体接触。四元结构阐明了底物如何在聚酮合成酶（pks）以及相关脂肪酸合成酶（FASs）的活性位点之间穿梭，并提示了如何交换结构域以制造产生新型聚酮的杂交合成酶。
The structure of the ketoreductase (KR) from the first module of the erythromycin synthase with NADPH bound was solved to 1.79 angstrom resolution. The 51 kDa domain has two subdomains, each similar to a shortchain dehydrogenase/reductase (SDR) monomer. One subdomain has a truncated Rossmann fold and serves a purely structural role stabilizing the other subdomain, which catalyzes the reduction of the beta-carbonyl of a polyketide and possibly the epimerization of an alpha-substituent. The structure enabled us to define the domain boundaries of KR, the dehydratase (DH), and the enoylreductase (ER). It also constrains the three-dimensional organization of these domains within a module, revealing that KR does not make dimeric contacts across the 2-fold axis of the module. The quaternary structure elucidates how substrates are shuttled between the active sites of polyketide synthases (PKSs), as well as related fatty acid synthases (FASs), and suggests how domains can be swapped to make hybrid synthases that produce novel polyketides.