title: Elucidation of Piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation.
abstract: Piericidins are a class of α-pyridone antibiotics that inhibit mitochondrial respiratory chain and exhibit antimicrobial, antifungal, and antitumor activities. Sequential analysis of Streptomyces piomogeues var. Hangzhouwanensis genome revealed six modular polyketide synthases, an amidotransferase, two methyltransferases, and a monooxygenase for piericidin A1 production. Gene functional analysis and deletion results provide overview of the biosynthesis pathway. Furthermore, in vitro characterization of the terminal polyketide synthase module with the thioesterase domain using β-ketoacyl substrates was performed. That revealed a pathway where the α-pyridone ring formation is dependent on hydrolysis of the product β, δ-diketo carboxylic acid by the C-terminal thioesterase followed by amidation and cyclization. These findings set the stage to investigate unusual enzymatic mechanisms in α-pyridone antibiotics biosynthesis, provide a foundation for genome mining of α-pyridone antibiotics, and produce analogs by molecular engineering.
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Fen
authors.initials: F
authors.lastname: Yao
authors.forename: Yit Heng
authors.initials: YH
authors.lastname: Chooi
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Kang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Yanran
authors.initials: Y
authors.lastname: Li
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Shao
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Shi
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Delin
authors.initials: D
authors.lastname: You
mesh_terms: D019295:Computational Biology; D003500:Cyclization; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011725:Pyridines; D011728:Pyridones; D048630:Polyketide Synthases; C100213:piericidin A; D006899:Mixed Function Oxygenases; D008780:Methyltransferases; D013869:Thiolester Hydrolases