O-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis

Yuchun Zhao, Xiangyang Liu, Zhihong Xiao, Jie Zhou, Xingyu Song, Xiaozheng Wang, Lijun Hu, Ying Wang, Peng Sun, Wenning Wang, Xinyi He, Shuangjun Lin, Zixin Deng, Lifeng Pan and Ming Jiang ()
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Yuchun Zhao: Shanghai Jiao Tong University
Xiangyang Liu: Shanghai Jiao Tong University
Zhihong Xiao: Shanghai Jiao Tong University
Jie Zhou: Shanghai Jiao Tong University
Xingyu Song: Fudan University
Xiaozheng Wang: Shanghai Jiao Tong University
Lijun Hu: Jinan University
Ying Wang: Jinan University
Peng Sun: Second Military Medical University
Wenning Wang: Fudan University
Xinyi He: Shanghai Jiao Tong University
Shuangjun Lin: Shanghai Jiao Tong University
Zixin Deng: Shanghai Jiao Tong University
Lifeng Pan: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ming Jiang: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Diazo compounds are rare natural products possessing various biological activities. Kinamycin and lomaiviticin, two diazo natural products featured by the diazobenzofluorene core, exhibit exceptional potency as chemotherapeutic agents. Despite the extensive studies on their biosynthetic gene clusters and the assembly of their polyketide scaffolds, the formation of the characteristic diazo group remains elusive. l-Glutamylhydrazine was recently shown to be the hydrazine donor in kinamycin biosynthesis, however, the mechanism for the installation of the hydrazine group onto the kinamycin scaffold is still unclear. Here we describe an O-methyltransferase-like protein, AlpH, which is responsible for the hydrazine incorporation in kinamycin biosynthesis. AlpH catalyses a unique SAM-independent coupling of l-glutamylhydrazine and polyketide intermediate via a rare Mannich reaction in polyketide biosynthesis. Our discovery expands the catalytic diversity of O-methyltransferase-like enzymes and lays a strong foundation for the discovery and development of novel diazo natural products through genome mining and synthetic biology.

Date: 2023
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DOI: 10.1038/s41467-023-41062-7

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