Investigation of carbonyl amidation and O-methylation during biosynthesis of the pharmacophore pyridyl of antitumor piericidins  

作　　者：Wanlu Li Wenyu Zhang Yijia Cheng Yaoyao Shen Jianzhao Qi Hou-Wen Lin Yongjun Zhou 

机构地区：[1]Research Center for Marine Drugs,State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacy,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,200127,China [2]Shaanxi Key Laboratory of Natural Products&Chemical Biology,College of Chemistry&Pharmacy,Northwest A&F University,Yangling,712100,Shaanxi,China

出　　处：《Synthetic and Systems Biotechnology》2022年第3期880-886,共7页合成和系统生物技术（英文）

基　　金：support from the National Natural Science Foundation of China(Nos.32070070,31929001,and 31800031);the Innovative Research Team of High-Level Local Universities in Shanghai。

摘　　要：Piericidins are a large family of bacterialα-pyridone antibiotics with antitumor activities such as their anti-renal carcinoma activity exhibited recently in nude mice.The backbones of piericidins are derived fromβ,δ-diketo carboxylic acids,which are offloaded from a modular polyketide synthase(PKS)and putatively undergo a carbonyl amidation beforeα-pyridone ring formation.The tailoring modifications to theα-pyridone structure mainly include the verified hydroxylation and O-methylation of the C-4′position and an unidentified C-5′O-methylation.Here,we describe a piericidin producer,terrestrial Streptomyces conglobatus,which contains a piericidin biosynthetic gene cluster in two different loci.Deletion of the amidotransferase gene pieD resulted in the accumulation of two fatty acids that should be degraded from the nascent carboxylic acid released by the PKS,supporting the carbonyl amidation function of PieD duringα-pyridone ring formation.Deletion of the O-methyltransferase gene pieB1 led to the production of three piericidin analogues lacking C-5′O-methylation,therefore confirming that PieB1 specifically catalyses the tailoring modification.Moreover,bioactivity analysis of the mutant-derived products provided clues regarding the structure-function relationship for antitumor activity.The work addresses two previously unidentified steps involved in pyridyl pharmacophore formation during piericidin biosynthesis,facilitating the rational bioengineering of the biosynthetic pathway towards valuable antitumor agents.

关 键 词：POLYKETIDE Pyridine Polyketide synthase(PKS) Natural product biosynthesis 

分 类 号：O62[理学—有机化学]