KIB OpenIR
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 PublicationNATURE COMMUNICATIONS
ISSN2041-1723
Volume14Issue:1Pages:209
AbstractAngiotensin-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.
KeywordHYPERTENSION PREDICTION FLAVIN MECHANISM PATHWAY OXIDASE COMPLEX DOMAIN SOIL
Subject AreaScience & Technology - Other Topics
DOI10.1038/s41467-023-35829-1
WOS IDWOS:000955813400006
Citation statistics
Document Type期刊论文
Identifierhttp://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.
Files in This Item: Download All
File Name/Size DocType Version Access License
10.1038_s41467-023-3(1819KB)期刊论文出版稿开放获取CC BY-NC-SAView Download
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Yu,Zhiyin]'s Articles
[Huang,Jian-Ping]'s Articles
[Yang,Jing]'s Articles
Baidu academic
Similar articles in Baidu academic
[Yu,Zhiyin]'s Articles
[Huang,Jian-Ping]'s Articles
[Yang,Jing]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Yu,Zhiyin]'s Articles
[Huang,Jian-Ping]'s Articles
[Yang,Jing]'s Articles
Terms of Use
No data!
Social Bookmark/Share
File name: 10.1038_s41467-023-35829-1.pdf
Format: Adobe PDF
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.