Crystal structure of Vat(D): an acetyltransferase that inactivates streptogramin group A antibiotics.
The streptogramin class of antibiotics act to inhibit bacterial protein synthesis, and their semisynthetic derivatives, such as dalfopristin-quinupristin (Synercid), are used to treat serious or life-threatening infections due to multiply antibiotic resistant bacteria. Acquired resistance of the nosocomial pathogen Enterococcus faecium to the group A component of natural and semisynthetic streptogramin mixtures is a prerequisite for the streptogramin resistance phenotype and is mediated by a streptogramin acetyltransferase. The crystal structure of Vat(D), a streptogramin acetyltransferase from a human urinary isolate of E. faecium, has been determined as an apoenzyme and in complex with either acetyl-CoA or virginiamycin M1 and CoA. These structures illustrate the location and arrangement of residues at the active site, and point to His 82 as a residue that may function as a general base. The structural similarity of Vat(D) to the xenobiotic acetyltransferase from Pseudomonas aeruginosa indicates similarities in the catalytic mechanism for these enzymes as well as several shared and distinctive antibiotic binding interactions between these enzymes and their respective substrates. These results reveal the molecular basis for a reaction by which Gram-positive cocci acquire resistance to a last resort antibiotic.
Sugantino
Michele
M
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Roderick
Steven L
SL
D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001051:Apoenzymes / Q000737:chemistry; D001426:Bacterial Proteins; D001665:Binding Sites; D015500:Chloramphenicol O-Acetyltransferase / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D016984:Enterococcus faecium / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D025362:Streptogramin Group A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015262:Xenobiotics / Q000737:chemistry
D001051:Apoenzymes; D001426:Bacterial Proteins; D025362:Streptogramin Group A; D015262:Xenobiotics; D000123:Acetyltransferases; C082449:Vat protein, Bacteria; D015500:Chloramphenicol O-Acetyltransferase