Delineating the biosynthesis of gentamicin X2, the common precursor of the gentamicin C antibiotic complex

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Abstract

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 from the 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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Huang, C., Huang, F., Moison, E., Guo, J., Jian, X., Duan, X., … Sun, Y. (2015). Delineating the biosynthesis of gentamicin X2, the common precursor of the gentamicin C antibiotic complex. Chemistry and Biology, 22(2), 251–261. https://doi.org/10.1016/j.chembiol.2014.12.012

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