A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones.
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 achieved. 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-alpha-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.
Vetting
Matthew W
MW
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA.
Magnet
Sophie
S
Nieves
Edward
E
Roderick
Steven L
SL
Blanchard
John S
JS
D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D051548:Histone Acetyltransferases; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D019779:Salmonella enterica / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006657:Histones; D000123:Acetyltransferases; D051548:Histone Acetyltransferases