Biosynthesis of trialkyl-substituted aromatic polyketide NFAT-133 involves unusual P450 monooxygenase-mediating aromatization and a putative metallo-beta-lactamase fold hydrolase  

作　　者：Ming Yang Wanlu Li Lin Zhou Xiao Lin Wenyu Zhang Yaoyao Shen Hai Deng Hou-wen Lin Yongjun Zhou 

机构地区：[1]Research Center for Marine Drugs,Department of Pharmacy,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,200127,China [2]Institute of Marine Drugs,Guangxi Key Laboratory of Marine Drugs,Guangxi University of Chinese Medicine,Nanning,530200,PR China [3]Department of Chemistry,University of Aberdeen,Aberdeen,AB243UE,UK

出　　处：《Synthetic and Systems Biotechnology》2023年第3期349-356,共8页合成和系统生物技术（英文）

基　　金：the National Natural Science Foundation of China(Nos.32070070,32211530074 and 31929001);the innovative research team of high-level local universities in Shanghai.H.D.thanks Royal Society-NSFC international exchange grant(IEC\NSFC\211349).

摘　　要：The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123(1),veramycin A(2),NFAT-133(3)and benwamycin I(4),which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities.Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase(PKS),the PKS assembly line was interpreted inconsistently,and it remains a mystery how the compound 3 was generated.Herein,the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains.Based on gene deletion and complementation,the putative P450 monooxygenase nftE1 and metallo-beta-lactamase(MBL)fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4.The absence of nftE1 led to abolishment of 1-4 and accumulation of new products(5-8).Structural elucidation reveals 5-8 as the non-aromatic analogs of 1,suggesting the NftE1-catalyzed aromatic core formation.Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected.As a rare MBL-fold hydrolase from type I PKSs,NftF1 potentially generates the compound 3 through two strategies:catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.

关 键 词：Thioesterase Metallo hydrolase METALLO-BETA-LACTAMASE Aromatic polyketide Polyketide synthase P450 monooxygenase 

分 类 号：O62[理学—有机化学]