Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors

Zhiyin Yu, Jian-Ping Huang, Jing Yang, Chongxi Liu, Yijun Yan, Li Wang, Junwei Zhao, Yin Chen, Wensheng Xiang () and Sheng-Xiong Huang ()
Additional contact information
Zhiyin Yu: Chengdu University of Traditional Chinese Medicine
Jian-Ping Huang: Chengdu University of Traditional Chinese Medicine
Jing Yang: Chinese Academy of Sciences
Chongxi Liu: Northeast Agricultural University
Yijun Yan: Chinese Academy of Sciences
Li Wang: Chengdu University of Traditional Chinese Medicine
Junwei Zhao: Northeast Agricultural University
Yin Chen: Chinese Academy of Sciences
Wensheng Xiang: Northeast Agricultural University
Sheng-Xiong Huang: Chengdu University of Traditional Chinese Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Angiotensin-converting enzyme inhibitors are widely used for treatment of hypertension and related diseases. Here, six karnamicins E1-E6 (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 μM, suggesting their potential use for the treatment of hypertension and related diseases.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-35829-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35829-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-35829-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().