title: Antibiotic selection by the promiscuous aminoglycoside acetyltransferase-(3)-IIIb is thermodynamically achieved through the control of solvent rearrangement.
abstract: The results presented here show the first known observation of opposite signs of change in heat capacity (ΔC(p)) of two structurally similar ligands binding to the same protein site. Neomycin and paromomycin are aminoglycoside antibiotics that are substrates for the resistance-conferring enzyme, the aminoglycoside acetyltransferase-(3)-IIIb (AAC). These antibiotics are identical to one another except at the 6' position where neomycin has an amine and paromomycin has a hydroxyl. The opposite trends in ΔC(p) of binding of these two drugs to AAC suggest a differential exposure of nonpolar amino acid side chains. Nuclear magnetic resonance experiments further demonstrate significantly different changes in AAC upon interaction with neomycin and paromomycin. Experiments in H(2)O and D(2)O reveal the first observed temperature dependence of solvent and vibrational contributions to ΔC(p). Coenzyme A significantly influences these effects. Together, the data suggest that AAC exploits solvent properties to facilitate favorable thermodynamic selection of antibiotics.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee 37996, United States.
authors.forename: Adrianne L
authors.initials: AL
authors.lastname: Norris
authors.forename: Engin H
authors.initials: EH
authors.lastname: Serpersu
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D002151:Calorimetry; D003065:Coenzyme A / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology*; D008958:Models, Molecular; D009355:Neomycin / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010303:Paromomycin / Q000378:metabolism*; D012997:Solvents / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D012997:Solvents; D010303:Paromomycin; D000123:Acetyltransferases; C019681:aminoglycoside acetyltransferase; D009355:Neomycin; D003065:Coenzyme A