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Transient kinetics of aminoglycoside phosphotransferase(3′)‐IIIa reveals a potential drug target in the antibiotic resistance mechanism
Author(s) -
Lallemand Perrine,
Leban Nadia,
Kunzelmann Simone,
Chaloin Laurent,
Serpersu Engin H.,
Webb Martin R.,
Barman Tom,
Lionne Corinne
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.10.027
Subject(s) - aminoglycoside , kanamycin , enzyme , phosphotransferases , chemistry , phosphotransferase , biochemistry , antibiotics , kinetics , biophysics , biology , physics , quantum mechanics
Aminoglycoside phosphotransferases are bacterial enzymes responsible for the inactivation of aminoglycoside antibiotics by O ‐phosphorylation. It is important to understand the mechanism of enzymes in order to find efficient drugs. Using rapid‐mixing methods, we studied the transient kinetics of aminoglycoside phosphotransferase(3′)‐IIIa. We show that an ADP‐enzyme complex is the main steady state intermediate. This intermediate interacts strongly with kanamycin A to form an abortive complex that traps the enzyme in an inactive state. A good strategy to prevent the inactivation of aminoglycosides would be to develop uncompetitive inhibitors that interact with this key ADP‐enzyme complex.