title: An analysis of why highly similar enzymes evolve differently.
abstract: The TEM-1 and SHV-1 beta-lactamases are important contributors to resistance to beta-lactam antibiotics in gram-negative bacteria. These enzymes share 68% amino acid sequence identity and their atomic structures are nearly superimposable. Extended-spectrum cephalosporins were introduced to avoid the action of these beta-lactamases. The widespread use of antibiotics has led to the evolution of variant TEM and SHV enzymes that can hydrolyze extended-spectrum antibiotics. Despite being highly similar in structure, the TEM and SHV enzymes have evolved differently in response to the selective pressure of antibiotic therapy. Examples of this are at residues Arg164 and Asp179. Among TEM variants, substitutions are found only at position 164, while among SHV variants, substitutions are found only at position 179. To explain this observation, the effects of substitutions at position 164 in both TEM-1 and SHV-1 on antibiotic resistance and on enzyme catalytic efficiency were examined. Competition experiments were performed between mutants to understand why certain substitutions preferentially evolve in response to the selective pressure of antibiotic therapy. The data presented here indicate that substitutions at position Asp179 in SHV-1 and Arg164 in TEM-1 are more beneficial to bacteria because they provide increased fitness relative to either wild type or other mutants.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Fahd K
authors.initials: FK
authors.lastname: Majiduddin
authors.forename: Timothy
authors.initials: T
authors.lastname: Palzkill
mesh_terms: D002442:Ceftazidime / Q000494:pharmacology*; D004798:Enzymes / Q000235:genetics* / Q000502:physiology; D019143:Evolution, Molecular; D007700:Kinetics; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D004798:Enzymes; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime; C054882:beta-lactamase PIT-2; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1