AAC(6')-Iy from Salmonella enterica

A Bacterial Acetyltransferase Capable of Regioselective N-Acetylation of Antibiotics and Histones Chemistry and Biology 2004 Apr;11(4):565-73 Principle Investigator: John Blanchard Research: Matt Vetting Collaborators: Sophie Magnet Edward Nieves Steven Roderick PDB DATABASE IDENTIFIERS 1S3Z, 1S5K, 1S60

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The Salmonella enterica chromosomally-encoded AAC(6’)-Iy has been shown to confer broad aminoglycoside resistance in strains in which a chromosomal deletion leads to the structural gene’s expression. The three-dimensional structures that we report 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. Comparison of this structure with the M. tuberculosis AAC(2’)-CoA-ribostamycin complex allows us to detail the interactions that control the regioselectivity of acetylation in these two structurally-related aminoglycoside N-acetyltransferases. The AAC(6’)-Iy dimer is most structurally similar to the Saccharomyces cerevisiae Hpa2-encoded histone acetyltransferase. We have demonstrated that AAC(6’)-Iy catalyzes both acetyl-CoA-dependent self alpha-N-acetylation, acetylation of eucaryotic histone proteins and acetylation of the human histone H3 N-terminal 20 residue 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 eucaryotic histone acetyltransferases.