An atypical acyl‐CoA synthetase enables efficient biosynthesis of extender units for engineering a polyketide carbon scaffold
An atypical acyl‐CoA synthetase enables efficient biosynthesis of extender units for engineering a polyketide carbon scaffold
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DOI：
10.1002/anie.202208734
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Xudong Qu
中科院分区：
文献类型：
--
作者：
Mengmeng Zheng;Jun Zhang;Wan Zhang;Lu Yang;Xiaoli Yan;Wenya Tian;Zhihao Liu;Zhi Lin;Zixin Deng;Xudong Qu
Acyl-CoAs are key precursors of primary and secondary metabolism. Their efficient biosynthesis is often impeded by the limited substrate specificity and low in vivo activity of acyl-CoA synthetases (ACSs) due to regulatory acylation of the catalytically important lysine residue in motif A10 (Lys-A10). In this study, we identified an unusual ACS (UkaQ) from the UK-2A biosynthetic pathway that naturally lacks the Lys-A10 residue and exhibits extraordinarily broad substrate specificity. Protein engineering significantly improved its stability and catalytic activity, enabling it to synthesize a large variety of acyl-CoAs with highly robust activity. By combining it with permissive carboxylases, we produced a large array of polyketide extender units and obtained six novel halobenzyl-containing antimycin analogues through an engineered biosynthetic pathway. This study significantly expands the catalytic mode of ACSs and provides a potent tool for the biosynthesis of acyl-CoA-derived natural products.
