Aminoglycoside-3'-phosphotransferase (APH(3')), also known as aminoglycoside kinase, is an enzyme that primarily catalyzes the addition of phosphate from ATP to the 3'-hydroxyl group of a 4,6-disubstituted aminoglycoside, such as kanamycin.[2] However, APH(3') has also been found to phosphorylate at the 5'-hydroxyl group in 4,5-disubstituted aminoglycosides, which lack a 3'-hydroxyl group, and to diphosphorylate hydroxyl groups in aminoglycosides that have both 3'- and 5'-hydroxyl groups.[2][3] Primarily positively charged at biological conditions, aminoglycosides bind to the negatively charged backbone of nucleic acids to disrupt protein synthesis, effectively inhibiting bacterial cell growth.[4] APH(3') mediated phosphorylation of aminoglycosides effectively disrupts their mechanism of action, introducing a phosphate group that reduces their binding affinity due to steric hindrances and unfavorable electrostatic interactions.[5] APH(3') is primarily found in certain species of gram-positive bacteria.[6][7][8]
This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor. The systematic name of this enzyme class is ATP:kanamycin 3'-O-phosphotransferase. This enzyme is also called neomycin-kanamycin phosphotransferase.[9]
^Fong DH, Berghuis AM (2002). "Crystal Structure Of 3',5"-Aminoglycoside Phosphotransferase Type IIIa ADP Kanamycin A Complex". World-wide Protein Data Bank. doi:10.2210/pdb1l8t/pdb.
^ abcWright GD, Thompson PR (1999). "Aminoglycoside phosphotransferases: proteins, structure, and mechanism". Front Biosci. 4 (1–3): D9–21. doi:10.2741/wright. PMID 9872733.
^Thompson PR, Hughes DW, Wright GD (1996). "Regiospecificity of aminoglycoside phosphotransferase from Enterococci and Staphylococci (APH(3')-IIIa)". Biochemistry. 35 (26): 8686–95. doi:10.1021/bi960389w. PMID 8679631.
^Cavallo G, Martinetto P (1981). "The mechanism of action of aminoglycosides". G Batteriol Virol Immunol. 74 (7–12): 335–46. PMID 6182050.
^Kotra LP, Haddad J, Mobashery S (2000). "Aminoglycosides: Perspectives on Mechanisms of Action and Resistance and Strategies to Counter Resistance". Antimicrobial Agents and Chemotherapy. 44 (12): 3249–56. doi:10.1128/aac.44.12.3249-3256.2000. PMC 90188. PMID 11083623.
^Fong DH, Berghuis AM (2002). "Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry". The EMBO Journal. 21 (10): 2323–31. doi:10.1093/emboj/21.10.2323. PMC 126009. PMID 12006485.
^Gray GS, Fitch WM (1983). "Evolution of antibiotic resistance genes: the DNA sequence of a kanamycin resistance gene from Staphylococcus aureus". Mol Biol Evol. 1 (1): 57–66. doi:10.1093/oxfordjournals.molbev.a040298. PMID 6100986.
^Thompson PR, Boehr DD, Berghuis AM, Wright GD (2002). "Mechanism of Aminoglycoside Antibiotic Kinase APH(3')-IIIa: Role of the Nucleotide Positioning Loop". Biochemistry. 41 (22): 7001–7. doi:10.1021/bi0256680. PMID 12033933.
^McKay GA, Wright GD (1996). "Catalytic mechanism of enterococcal kanamycin kinase (APH(3')-IIIa): viscosity, thio, and solvent isotope effects support a Theorell-Chance mechanism". Biochemistry. 35 (26): 8680–5. doi:10.1021/bi9603884. PMID 8679630.
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