Delineating the Biosynthesis of Gentamicin X2, the Common Precursor of the Gentamicin C Antibiotic Complex

作者：Huang, Chuan; Huang, Fanglu; Moison, Eileen; Guo, Junhong; Jian, Xinyun; Duan, Xiaobo; Deng, Zixin; Leadlay, Peter F.^*; Sun, Yuhui

来源：Chemistry & Biology, 2015, 22(2): 251-261.

DOI：10.1016/j.chembiol.2014.12.012

• STREPTOMYCES-FRADIAE NCIMB-8233
• GENE-CLUSTER
• AMINOGLYCOSIDE BIOSYNTHESIS
• MOLECULAR-CLONING
• ESCHERICHIA-COLI
• NEOMYCIN
• BIOTRANSFORMATION
• KANAMYCIN
• IDENTIFICATION
• FERMENTATION

Gentamicin C complex is a mixture of aminoglycoside antibiotics used worldwide to treat severe Gram-negative bacterial infections. Despite its clinical importance, the enzymology of its biosynthetic pathway has remained obscure. We report here insights into the four enzyme-catalyzed steps that lead fromthe first-formed pseudotrisaccharide gentamicin A2 to gentamicin X2, the last common intermediate for all components of the C complex. We have used both targeted mutations of individual genes and reconstitution of portions of the pathway in vitro to show that the secondary alcohol function at C-3 '' of A2 is first converted to an amine, catalyzed by the tandem operation of oxidoreductase GenD2 and transaminase GenS2. The amine is then specifically methylated by the S-adenosyl-L-methionine (SAM)dependent N-methyltransferase GenN to form gentamicin A. Finally, C-methylation at C-4 '' to form gentamicin X2 is catalyzed by the radical SAM-dependent and cobalamin-dependent enzyme GenD1.

• 出版日期2015-2-19
• 单位武汉大学