The Mechanism of Dehydrating Bimodules in trans-Acyltransferase Polyketide Biosynthesis: A Showcase Study on Hepatoprotective Hangtaimycin,Angewandte Chemie International Edition

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The Mechanism of Dehydrating Bimodules in trans-Acyltransferase Polyketide Biosynthesis: A Showcase Study on Hepatoprotective Hangtaimycin
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-07-04 , DOI: 10.1002/anie.202106250
Minghe Luo ₁ , Houchao Xu ₂ , Yulu Dong ₁ , Kun Shen ₁ , Junlei Lu ₁ , Zhiyong Yin ₂ , Miaomiao Qi ₁ , Guo Sun ₁ , Lingjie Tang ₁ , Jin Xiang ₁ , Zixin Deng ₁ , Jeroen S Dickschat ₂ , Yuhui Sun ₁

Affiliation

A bioassay-guided fractionation led to the isolation of hangtaimycin (HTM) from Streptomyces spectabilis CCTCC M2017417 and the discovery of its hepatoprotective properties. Structure elucidation by NMR suggested the need for a structural revision. A putative HTM degradation product was also isolated and its structure was confirmed by total synthesis. The biosynthetic gene cluster was identified and resembles a hybrid trans-AT PKS/NRPS biosynthetic machinery whose first PKS enzyme contains an internal dehydrating bimodule, which is usually found split in other trans-AT PKSs. The mechanisms of such dehydrating bimodules have often been proposed, but have never been deeply investigated. Here we present in vivo mutations and in vitro enzymatic experiments that give first and detailed mechanistic insights into catalysis by dehydrating bimodules.

中文翻译：

转酰基转移酶聚酮化合物生物合成中脱水双模块的机制：保肝汉泰霉素的示范研究

生物测定引导的分级分离导致从壮观链霉菌CCTCC M2017417 中分离出杭泰霉素 (HTM)并发现了其保肝特性。NMR 的结构解析表明需要进行结构修正。还分离了推定的 HTM 降解产物，并通过全合成确认了其结构。生物合成基因簇被鉴定出来，类似于一种杂合反式-AT PKS/NRPS 生物合成机器，其第一个 PKS 酶包含一个内部脱水双模块，通常发现它在其他反式中分裂-AT PKS。这种脱水双模块的机制经常被提出，但从未被深入研究过。在这里，我们介绍了体内突变和体外酶促实验，这些实验通过脱水双模块提供了对催化的初步和详细的机制见解。

更新日期：2021-08-17

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