Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors

doi:10.1038/s41467-023-35829-1

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	Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors
	Yu,Zhiyin; Huang,Jian-Ping; Yang,Jing; Liu,Chongxi; Yan,Yijun; Wang,Li; Zhao,Junwei; Chen,Yin; Xiang,Wensheng; Huang,Sheng-Xiong
	2023
Source Publication	NATURE COMMUNICATIONS
ISSN	2041-1723
Volume	14 Issue:1 Pages:209
Abstract	Angiotensin-converting enzyme inhibitors are widely used for treatment of hypertension and related diseases. Here, six karnamicins E-1-E-6 (1-6), which bear fully substituted hydroxypyridine and thiazole moieties are characterized from the rare actinobacterium Lechevalieria rhizosphaerae NEAU-A2. Through a combination of isotopic labeling, genome mining, and enzymatic characterization studies, the programmed assembly of the fully substituted hydroxypyridine moiety in karnamicin is proposed to be due to sequential operation of a hybrid polyketide synthase-nonribosomal peptide synthetase, two regioselective pyridine ring flavoprotein hydroxylases, and a methyltransferase. Based on AlphaFold protein structures predictions, molecular docking, and site-directed mutagenesis, we find that two pyridine hydroxylases deploy active site residues distinct from other flavoprotein monooxygenases to direct the chemo- and regioselective hydroxylation of the pyridine nucleus. Pleasingly, karnamicins show significant angiotensin-converting enzyme inhibitory activity with IC50 values ranging from 0.24 to 5.81 mu M, suggesting their potential use for the treatment of hypertension and related diseases. Treatment of hypertension entails use of angiotensin-converting enzyme inhibitors. Here, the authors show a series of karnamicins with significant inhibitory activity and identify two unusual flavoprotein hydroxylases involved in the assembly of the fully-substituted hydroxypyridine core of karnamicins.
Keyword	HYPERTENSION PREDICTION FLAVIN MECHANISM PATHWAY OXIDASE COMPLEX DOMAIN SOIL
Subject Area	Science & Technology - Other Topics
DOI	10.1038/s41467-023-35829-1
WOS ID	WOS:000955813400006
Citation statistics
Document Type	期刊论文
Identifier	http://ir.kib.ac.cn/handle/151853/74863
Collection	中国科学院昆明植物研究所
Recommended Citation GB/T 7714	Yu,Zhiyin,Huang,Jian-Ping,Yang,Jing,et al. Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors[J]. NATURE COMMUNICATIONS,2023,14(1):209.
APA	Yu,Zhiyin.,Huang,Jian-Ping.,Yang,Jing.,Liu,Chongxi.,Yan,Yijun.,...&Huang,Sheng-Xiong.(2023).Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors.NATURE COMMUNICATIONS,14(1),209.
MLA	Yu,Zhiyin,et al."Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors".NATURE COMMUNICATIONS 14.1(2023):209.

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