Aminoglycoside antibiotic phosphotransferases are also serine protein kinases (original) (raw)

1999, Chemistry & Biology

Background: Elacterial resistance to aminoglycoside antibiotics occurs primarily through the expression of modifying enzymes that covalently alter tl?e drugs by 0-phosphorylation, 0-adenylation or N-acetylation. Aminoglycoside phosphotransferases (APHs) catalyze the ATP-dependent phosphorylation of these antibiotics. Two particular enzymes in this class, APH(3')-llla and AAC(G')-APH(S"), 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')sllla is strikingly similar to those of eukaryotic protein kinases (EPKs), and the observation, reported previously, that APH(3')-llla and AAC(G')-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 proiein structure, enzyme mechanism and sensitivity to inhibitors, and suggest an evolutionary link between APHs and EPKs.

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