A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones

Matthew W. Vetting, Sophie Magnet, Edward Nieves, Steven L. Roderick, John S. Blanchard

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


The Salmonella enterica chromosomally encoded AAC(6′)-Iy has been shown to confer broad aminoglycoside resistance in strains in which the structural gene is expressed. The three-dimensional structures reported place the enzyme in the large Gcn5-related N-acetyltransferase (GNAT) superfamily. The structure of the CoA-ribostamycin ternary complex allows us to propose a chemical mechanism for the reaction, and comparison with the Mycobacterium tuberculosis AAC(2′)-CoA-ribostamycin complex allows us to define how regioselectivity of acetylation is acheived. The AAC(6′)-Iy dimer is most structurally similar to the Saccharomyces cerevisiae Hpa2-encoded histone acetyltransferase. We demonstrate that AAC(6′)-Iy catalyzes both acetyl-CoA-dependent self-α-N-acetylation and acetylation of eukaryotic histone proteins and the human histone H3 N-terminal peptide. These structural and catalytic similarities lead us to propose that chromosomally encoded bacterial acetyltransferases, including those functionally identified as aminoglycoside acetyltransferases, are the evolutionary progenitors of the eukaryotic histone acetyltransferases.

Original languageEnglish (US)
Pages (from-to)565-573
Number of pages9
JournalChemistry and Biology
Issue number4
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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