Aminoglycoside antibiotic phosphotransferases are also serine protein kinases
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UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
1999-01-01Keywords
Amino Acid SequenceAminoglycosides
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
aminoglycoside
antibiotic
protein kinase
resistance
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
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Show full item recordAbstract
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.Source
Chem Biol. 1999 Jan;6(1):11-8. Link to article on publisher's siteDOI
10.1016/S1074-5521(99)80016-7Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50089Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/S1074-5521(99)80016-7