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Titolo:
Active site labeling of the gentamicin resistance enzyme AAQ6 ')-APH(2 '')by the lipid kinase inhibitor wortmannin
Autore:
Boehr, DD; Lane, WS; Wright, GD;
Indirizzi:
McMaster Univ, Dept Biochem, Antimicrobial Res Ctr, Hamilton, ON L8N 3Z5, Canada McMaster Univ Hamilton ON Canada L8N 3Z5 tr, Hamilton, ON L8N 3Z5, Canada Harvard Univ, Harvard Microchem Facil, Cambridge, MA 02138 USA Harvard Univ Cambridge MA USA 02138 rochem Facil, Cambridge, MA 02138 USA
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 8, volume: 8, anno: 2001,
pagine: 791 - 800
SICI:
1074-5521(200108)8:8<791:ASLOTG>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
GCN5-RELATED N-ACETYLTRANSFERASE; THEORELL-CHANCE MECHANISM; AMINOGLYCOSIDE PHOSPHOTRANSFERASE; SUBSTRATE-SPECIFICITY; PHOSPHATIDYLINOSITOL 3-KINASE; CRYSTAL-STRUCTURE; PROTEIN-KINASES; APH(3')-IIIA; STAPHYLOCOCCI; ENTEROCOCCI;
Keywords:
antibiotic resistance; aminoglycoside; active site label;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Wright, GD McMaster Univ, Dept Biochem, Antimicrobial Res Ctr, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada McMaster Univ 1200 Main St W Hamilton ON Canada L8N 3Z5 Canada
Citazione:
D.D. Boehr et al., "Active site labeling of the gentamicin resistance enzyme AAQ6 ')-APH(2 '')by the lipid kinase inhibitor wortmannin", CHEM BIOL, 8(8), 2001, pp. 791-800

Abstract

Background: Aminoglycoside antibiotic resistance is largely the result of the production of enzymes that covalently modify the drugs including kinases (APHs) with structural and functional similarity to protein and lipid kinases. One of the most important aminoglycoside resistance enzymes is AAC(6 ')-APH(2 "), a bifunctional enzyme with both aminoglycoside acetyltransferase and kinase activities. Knowledge of enzyme active site structure is important in deciphering the molecular mechanism of antibiotic resistance and here we explored active site labeling techniques to study AAC(6 ')-APH(2 ") structure and function. Results: AAC(6 ')-APH(2 ") was irreversibly inactivated by wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, through the covalent modification of a conserved lysine in the ATP binding pocket. 5 '-[p-(Fluorosulfonyl)benzoyl] adeno sine, an electrophilic ATP analogue and known inactivatorof other APH enzymes such as APH(3 ')-IIIa, did not inactivate AAC(6 ')-APH(2 "), and reciprocally, wortmannin did not inactivate APH(3 ')-IIIa. Conclusions: These distinct active site label sensitivities point to important differences in aminoglycoside kinase active site structures and suggest that design of broad range, ATP binding site-directed inhibitors against APHs will be difficult. Nonetheless, given the sensitivity of APH enzymes to both protein and lipid kinase inhibitors, potent lead inhibitors of this important resistance enzyme are likely to be found among the libraries of compounds directed against other pharmacologically important kinases. (C) 2001 Elsevier Science Ltd. All rights reserved.

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Documento generato il 08/07/20 alle ore 07:43:44