Caerulomycin and collismycin antibiotics share a trans-acting flavoprotein-dependent assembly line for 2,2’-bipyridine formation

Bo Pang, Rijing Liao, Zhijun Tang, Shengjie Guo, Zhuhua Wu and Wen Liu ()
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Bo Pang: University of Chinese Academy of Sciences
Rijing Liao: Shanghai Jiao Tong University School of Medicine
Zhijun Tang: University of Chinese Academy of Sciences
Shengjie Guo: University of Chinese Academy of Sciences
Zhuhua Wu: University of Chinese Academy of Sciences
Wen Liu: University of Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Linear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2’-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2’-bipyridine intermediates through differential treatment of the sulfhydryl group arising from l-cysteine incorporation. Subsequent l-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2’-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.

Date: 2021
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DOI: 10.1038/s41467-021-23475-4

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