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Delineating the biosynthesis of gentamicin x2, the common precursor of the gentamicin C antibiotic complex.

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.
AuthorsChuan Huang, Fanglu Huang, Eileen Moison, Junhong Guo, Xinyun Jian, Xiaobo Duan, Zixin Deng, Peter F Leadlay, Yuhui Sun
JournalChemistry & biology (Chem Biol) Vol. 22 Issue 2 Pg. 251-61 (Feb 19 2015) ISSN: 1879-1301 [Electronic] United States
PMID25641167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Chemical References
  • Anti-Bacterial Agents
  • Gentamicins
  • Recombinant Proteins
  • gentamicin X(2)
  • gentamicin A
  • Oxidoreductases
  • Methyltransferases
  • Transaminases
Topics
  • Anti-Bacterial Agents (biosynthesis, chemistry)
  • Biocatalysis
  • Escherichia coli (metabolism)
  • Gentamicins (biosynthesis, chemistry, metabolism)
  • Methylation
  • Methyltransferases (genetics, metabolism)
  • Oxidoreductases (genetics, metabolism)
  • Recombinant Proteins (biosynthesis, genetics, isolation & purification)
  • Transaminases (genetics, metabolism)

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