S33
Approaching synthetic microbiology to harness the metabolic power for novel and improved nucleoside antibiotics
Wednesday, January 14, 2015: 10:10 AM
California Ballroom AB
Zixin Deng, State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China, Dr. Wenqing Chen, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan, China, Dr. Yan Li, State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, Mr. Lipeng Zhai, State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, Mr. Jianzhao Qi, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan and Prof. Jiahai Zhou, State Key Laboratory of Bioorganic and Natural Products Chemistry,, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,, Shanghai
Polyoxins, a group of structurally-related peptidyl nucleoside antibiotics elaborated by
Streptomyces cacaoi var.
asoensis and Streptomyces aureochromogenes, were extensively used to control phytopathogenic fungi. Systematic investigation of polyoxin gene cluster revealed distinctive enzymatic reactions involved in the biosynthesis of its buiding blocks, nucleoside skeleton and peptidyl moeities; wherein PolB, a homolog of the distinctive Thymidylate synthase (ThyX) in bacteria, was demonstrated to be a unique UMP/dUMP bifunctional methylase capable of independently catalyzing UMP and dUMP to generate 5-methyl UMP and dTMP
in vitro; Structural analysis of PolB indicated that two loops function as gatekeeper for recognition and selection of the prime substrates for catalysis. Moreover, polyoxin biosynthetic pathway was demonstrated to show distinctive “crosstalks” with primary metabolic networks.
The manipulation of the polyoxin gene cluster in industrial producer strain Streptomyces aureochromogenes resulted in the successful engineering of the industrial polyoxin producer as cell factories for components optimization and combinatorial biosynthesis. Interestingly, making mutations and introducing heterologous genes from other nucleoside antibiotics producer into an industrial S. aureochromogenes polyoxin producer resulted in the production of seven polyoxin-nikkomycin designer hybrid antibiotics (designated as nikkoxin A-G). Some of them were significantly more potent against some human or plant fungal pathogens.
Apparently, elucidation of the molecular mechanism for uridyl polyoxin biosynthesis not only provides a solid foundation for rational designing and generation of natural artificial molecules with enhanced/selective bioactivity, but also set the stage for the biosynthesis-based genome mining and biomanufacturing for successful nucleoside drug discovery.
