Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors.
Zhiyin YuJian-Ping HuangJing YangChongxi LiuYijun YanLi WangJunwei ZhaoYin ChenWen-Sheng XiangSheng-Xiong HuangPublished in: Nature communications (2023)
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 IC 50 values ranging from 0.24 to 5.81 μM, suggesting their potential use for the treatment of hypertension and related diseases.
Keyphrases
- angiotensin converting enzyme
- molecular docking
- angiotensin ii
- blood pressure
- molecular dynamics simulations
- combination therapy
- small molecule
- crispr cas
- nitric oxide
- gene expression
- high resolution
- squamous cell carcinoma
- hydrogen peroxide
- dna methylation
- mass spectrometry
- drug delivery
- cancer therapy
- smoking cessation
- drug induced
- human health