Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin
Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin
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程序化迭代控制抗生素莫匹罗星壬酸侧链的组装
DOI：
10.1002/ange.202212393
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发表时间：
2022
影响因子：
--
通讯作者：
Winter A
中科院分区：
文献类型：
--
作者：
Winter A
莫匹罗星是由荧光假单胞菌NCIMB 10586产生的一种临床上重要的抗生素，由复杂的反式AT聚酮合酶组装。聚酮化合物片段monic acid被9-羟基壬酸（9 HN）侧链酯化，这是生物活性所必需的。酯侧链组装从连接到酰基载体蛋白（ACP）MacpD的3-羟基丙酸酯（3 HP）起始单元初始化，但该物质的命运未知。在这里，我们报告的应用核磁共振光谱，质谱，化学探针和体外测定，以建立9 HN生物合成的其余步骤。这些研究揭示了一个新的迭代或“口吃”KS-AT双域（MmpF），多域模块MmpB和多个ACP之间的复杂相互作用。这项工作对于理解莫匹罗星的后期生物合成步骤具有重要意义，并且对于未来相关trans-AT生物合成途径（例如硫代马利诺）的工程设计非常重要。
Mupirocin is a clinically important antibiotic produced byPseudomonas fluorescensNCIMB 10586 that is assembled by a complextrans‐AT polyketide synthase. The polyketide fragment, monic acid, is esterified by a 9‐hydroxynonanoic acid (9HN) side chain which is essential for biological activity. The ester side chain assembly is initialised from a 3‐hydroxypropionate (3HP) starter unit attached to the acyl carrier protein (ACP) MacpD, but the fate of this species is unknown. Herein we report the application of NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays to establish the remaining steps of 9HN biosynthesis. These investigations reveal a complex interplay between a novel iterative or “stuttering” KS‐AT didomain (MmpF), the multidomain module MmpB and multiple ACPs. This work has important implications for understanding the late‐stage biosynthetic steps of mupirocin and will be important for future engineering of relatedtrans‐AT biosynthetic pathways (e.g. thiomarinol).