期刊
CHEMISTRY & BIOLOGY
卷 22, 期 2, 页码 251-261出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2014.12.012
关键词
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资金
- Medical Research Council, UK [G1001687]
- 973 program from the Ministry of Science and Technology of China
- 863 program from the Ministry of Science and Technology of China
- National Science Foundation of China
- Translational Medical Research Fund of Wuhan University School of Medicine
- Gates Cambridge Trust
- MRC [MR/M019020/1, G1001687] Funding Source: UKRI
- Medical Research Council [MR/M019020/1, G1001687] Funding Source: researchfish
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.
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