Structural and Biochemical Insight into the Recruitment of Acyl Carrier Protein-Linked Extender Units in Ansamitocin Biosynthesis
Structural and Biochemical Insight into the Recruitment of Acyl Carrier Protein-Linked Extender Units in Ansamitocin Biosynthesis
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安丝菌素生物合成中酰基载体蛋白连接延伸单元招募的结构和生化见解
DOI：
10.1002/cbic.201900628
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发表时间：
2020
期刊：
影响因子：
3.2
通讯作者：
Jianting Zheng
中科院分区：
文献类型：
--
作者：
Fa Zhang;Huining Ji;Imtiaz Ali;Zixin Deng;Linquan Bai;Jianting Zheng
模块化聚酮酶（PKS）的一些酰基转移酶（AT）结构域招募具有不寻常的C2取代基的酰基载体蛋白（ACP）连接的延伸单元，以赋予辅酶A（CoA）连接的延伸单元中不可用的功能。 在这项研究中，对安丝菌素PKS第三模块中的甲氧基丙二酰（Methoxy malonyl，ACP）-ACP特异性AT进行了结构和生化表征。AT在底物结合通道的入口处使用保守的色氨酸残基来区分不同的载体。W275 R突变将其载体特异性从ACP转换为CoA分子。酰基-AT复合物结构清楚地表明，AT接受的β-ACP具有2S而不是相反的2 R立体化学，这是根据来自糖酵解中间体的生物合成衍生物预测的。总之，这些结果揭示了AT在聚酮化合物生物合成中识别ACP连接的延伸单元的结构基础。
A few acyltransferase (AT) domains of modular polyketide synthases (PKSs) recruit acyl carrier protein (ACP)‐linked extender units with unusual C2 substituents to confer functionalities that are not available in coenzyme A (CoA)‐linked ones. In this study, an AT specific for methoxymalonyl (MOM)‐ACP in the third module of the ansamitocin PKS was structurally and biochemically characterized. The AT uses a conserved tryptophan residue at the entrance of the substrate binding tunnel to discriminate between different carriers. A W275R mutation switches its carrier specificity from the ACP to the CoA molecule. The acyl‐AT complex structures clearly show that the MOM‐ACP accepted by the AT has the 2Sinstead of the opposite 2Rstereochemistry that is predicted according to the biosynthetic derivation from ad‐glycolytic intermediate. Together, these results reveal the structural basis of ATs recognizing ACP‐linked extender units in polyketide biosynthesis.