Source of phosphate in the enzymic reaction as a point of distinction among aminoglycoside 2''-phosphotransferases.
Aminoglycoside 2''-phosphotransferases are clinically important enzymes that cause high levels of resistance to aminoglycoside antibiotics by the organisms that harbor them. These enzymes phosphorylate aminoglycosides, and the modified antibiotics show significant reduction in the binding ability to target the bacterial ribosome. This report presents a detailed characterization of the antibiotic resistance profile and the aminoglycoside and nucleotide triphosphate substrate profiles of four common aminoglycoside 2''-phosphotransferases widely distributed in clinically important Gram-positive microorganisms. Although the antibiotic resistance phenotypes exhibited by these enzymes are similar, their aminoglycoside and nucleotide triphosphate substrate profiles are distinctive. Contrary to the dogma that these enzymes use ATP as the source of phosphate in their reactions, two of the four aminoglycoside 2'-phosphotransferases utilize GTP as the phosphate donor. Of the other two enzymes, one exhibits preference for ATP, and the other can utilize either ATP or GTP as nucleotide triphosphate substrate. A new nomenclature for these enzymes is put forth that takes into account the differences among these enzymes based on their respective substrate preferences. These nucleotide triphosphate preferences should have ramifications for understanding of the evolution, selection, and dissemination of the genes for these important resistance enzymes.
Toth
Marta
M
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Chow
Joseph W
JW
Mobashery
Shahriar
S
Vakulenko
Sergei B
SB
D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000617:Aminoglycosides / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D016983:Enterococcus / Q000201:enzymology* / Q000235:genetics; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D019868:Kanamycin Kinase / Q000235:genetics / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics; D013379:Substrate Specificity / Q000502:physiology
D000617:Aminoglycosides; D001426:Bacterial Proteins; D010710:Phosphates; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D019868:Kanamycin Kinase