AvmM catalyses macrocyclization through dehydration/Michael-type addition in alchivemycin A biosynthesis

Hong Jie Zhu, Bo Zhang, Wanqing Wei, Shuang He Liu, Lang Xiang, Jiapeng Zhu, Rui Hua Jiao, Yasuhiro Igarashi, Ghader Bashiri, Yong Liang (), Ren Xiang Tan () and Hui Ming Ge ()
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Hong Jie Zhu: Nanjing University
Bo Zhang: Nanjing University
Wanqing Wei: Nanjing University
Shuang He Liu: Nanjing University
Lang Xiang: Nanjing University
Jiapeng Zhu: Nanjing University of Chinese Medicine
Rui Hua Jiao: Nanjing University
Yasuhiro Igarashi: Toyama Prefectural University
Ghader Bashiri: The University of Auckland
Yong Liang: Nanjing University
Ren Xiang Tan: Nanjing University
Hui Ming Ge: Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Macrocyclization is an important process that affords morphed scaffold in biosynthesis of bioactive natural products. Nature has adapted diverse biosynthetic strategies to form macrocycles. In this work, we report the identification and characterization of a small enzyme AvmM that can catalyze the construction of a 16-membered macrocyclic ring in the biosynthesis of alchivemycin A (1). We show through in vivo gene deletion, in vitro biochemical assay and isotope labelling experiments that AvmM catalyzes tandem dehydration and Michael-type addition to generate the core scaffold of 1. Mechanistic studies by crystallography, DFT calculations and MD simulations of AvmM reveal that the reactions are achieved with assistance from the special tenuazonic acid like moiety of substrate. Our results thus uncover an uncharacterized macrocyclization strategy in natural product biosynthesis.

Date: 2022
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DOI: 10.1038/s41467-022-32088-4

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