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复杂天然产物的生物合成和组合生物合成研究:Characterization of the azinomycin B biosynthetic gene cluster ...

  • 关键字: azinomycin B biosynthetic gene cluster 发布者:Qunfei Zhao , Gongli Tang and Wen Liu 发布时间:2009-03-02 18:03:32 点击数: 6261次

Chem. & Biol. 2008, 15, 693-705.
 
Characterization of the azinomycin B biosynthetic gene cluster revealing a different iterative type I polyketide synthase for naphthoate biosynthesis
 
Qunfei Zhao1, Qingli He1, Wei Ding1, 2, Mancheng Tang1, Qianjin Kang1, 3, Yi Yu1, 3, Wei Deng1, Qi Zhang1, Jie Fang1, Gongli Tang1 and Wen Liu1, 3,
 
1 State Key Laboratory of Bioorganic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. 2School of Life Science, Lanzhou University, Lanzhou 730000, China. 3 Laboratory of Microbial Metabolism and School of Life Science & Biotechnology, Shanghai Jiaotong University, Shanghai 200030, China
 
Abstract: Azinomycin B is a complex natural product containing densely assembled functionalities with potent antitumor activity. Cloning and sequence analysis of the azi gene cluster revealed an iterative type I polyketide synthase (PKS) gene, five nonribosomal peptide synthetases (NRPSs) genes and numerous genes encoding the biosynthesis of unusual building blocks and tailoring steps for azinomycin B production. Characterization of AziB as a 5-methyl-naphthoic acid (NPA) synthase showed a distinct selective reduction pattern in aromatic polyketide biosynthesis governed by bacterial iterative type I PKSs. Heterologous expression established the PKS-post modification route from 5-methyl-NPA to reach the first building block 3-methoxy-5-methyl-NPA. This proposed azinomycin B biosynthetic pathway sets the stage to investigate the enzymatic mechanisms for building structurally unique and pharmaceutically important groups, including the unprecedented azabicyclic ring system and highly active epoxide moiety.