Aminoglycoside antibiotic phosphotransferases are also serine protein kinases
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amino Acid Sequence; Aminoglycosides; Animals; Anti-Bacterial Agents; Catalytic Domain; Cattle; Humans; In Vitro Techniques; Kanamycin Kinase; Models, Molecular; Molecular Sequence Data; Phosphorylation; Protein Conformation; Protein-Serine-Threonine Kinases; Sequence Homology, Amino Acid
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
BACKGROUND: Bacterial resistance to aminoglycoside antibiotics occurs primarily through the expression of modifying enzymes that covalently alter the drugs by O-phosphorylation, O-adenylation or N-acetylation. Aminoglycoside phosphotransferases (APHs) catalyze the ATP-dependent phosphorylation of these antibiotics. Two particular enzymes in this class, APH(3')-IIIa and AAC(6')-APH(2"), are produced in gram-positive cocci and have been shown to phosphorylate aminoglycosides on their 3' and 2" hydroxyl groups, respectively. The three-dimensional structure of APH (3')-IIIa is strikingly similar to those of eukaryotic protein kinases (EPKs), and the observation, reported previously, that APH(3')-IIIa and AAC(6')-APH(2") are effectively inhibited by EPK inhibitors suggested the possibility that these aminoglycoside kinases might phosphorylate EPK substrates.
RESULTS: Our data demonstrate unequivocally that APHs can phosphorylate several EPK substrates and that this phosphorylation occurs exclusively on serine residues. Phosphorylation of Ser/Thr protein kinase substrates by APHs was considerably slower than phosphorylation of aminoglycosides under identical assay conditions, which is consistent with the primary biological roles of the enzymes.
CONCLUSIONS: These results demonstrate a functional relationship between aminoglycoside and protein kinases, expanding on our previous observations of similarities in protein structure, enzyme mechanism and sensitivity to inhibitors, and suggest an evolutionary link between APHs and EPKs.
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Citation: Chem Biol. 1999 Jan;6(1):11-8. Link to article on publisher's site
aminoglycoside, antibiotic, protein kinase, resistance
Daigle, D. M.; McKay, G. A.; Thompson, Paul R.; and Wright, G. D., "Aminoglycoside antibiotic phosphotransferases are also serine protein kinases" (1999). Thompson Lab Publications. 93.