A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis
A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis
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DOI：
10.1038/s41929-018-0183-5
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发表时间：
2018-12-01
期刊：
影响因子：
37.8
通讯作者：
Willis, Christine L.
中科院分区：
文献类型：
--
作者：
Wang, Luoyi;Parnell, Alice;Willis, Christine L.
氧杂环-特别是四氢吡喃（THP）和四氢呋喃-是许多具有生物活性的聚酮化合物天然产物的共同结构特征。莫匹罗星是从荧光假单胞菌中分离的临床上重要的抗生素，并且组装在THP环上，这对生物活性至关重要。然而，该部分的生物合成仍然难以捉摸。在这里，我们展示了一个氧化酶催化的级联反应，产生莫匹罗星的THP环。Rieske非血红素加氧酶（MupW）催化的复杂无环前体中的C8-C16单键的选择性氧化与环氧化物水解酶（MupZ）组合以催化随后的区域选择性成环以得到羟基化的THP。在没有MupZ的情况下，分离出五元四氢呋喃环，并且模型研究与通过环氧化物中间体发生的环化一致。MupZ的高分辨率X射线晶体学研究、分子建模和诱变实验提供了通过抗Baldwin 6-endo-tet环化进行THP环形成的见解。
Oxygen heterocycles-in particular, tetrahydropyrans (THPs) and tetrahydrofurans-are common structural features of many biologically active polyketide natural products. Mupirocin is a clinically important antibiotic isolated from Pseudomonas fluorescens and is assembled on a THP ring, which is essential for bioactivity. However, the biosynthesis of this moiety has remained elusive. Here, we show an oxidative enzyme-catalysed cascade that generates the THP ring of mupirocin. Rieske non-haem oxygenase (MupW)-catalysed selective oxidation of the C8-C16 single bond in a complex acyclic precursor is combined with an epoxide hydrolase (MupZ) to catalyse the subsequent regioselective ring formation to give the hydroxylated THP. In the absence of MupZ, a five-membered tetrahydrofuran ring is isolated, and model studies are consistent with cyclization occurring via an epoxide intermediate. High-resolution X-ray crystallographic studies, molecular modelling and mutagenesis experiments of MupZ provide insights into THP ring formation proceeding via an anti-Baldwin 6-endo-tet cyclization.