title: The structural basis for substrate versatility of chloramphenicol acetyltransferase CATI.
abstract: Novel antibiotics are needed to overcome the challenge of continually evolving bacterial resistance. This has led to a renewed interest in mechanistic studies of once popular antibiotics like chloramphenicol (CAM). Chloramphenicol acetyltransferases (CATs) are enzymes that covalently modify CAM, rendering it inactive against its target, the ribosome, and thereby causing resistance to CAM. Of the three major types of CAT (CAT(I-III)), the CAM-specific CAT(III) has been studied extensively. Much less is known about another clinically important type, CAT(I). In addition to inactivating CAM and unlike CAT(III), CAT(I) confers resistance to a structurally distinct antibiotic, fusidic acid. The origin of the broader substrate specificity of CAT(I) has not been fully elucidated. To understand the substrate binding features of CAT(I), its crystal structures in the unbound (apo) and CAM-bound forms were determined. The analysis of these and previously determined CAT(I)-FA and CAT(III)-CAM structures revealed interactions responsible for CAT(I) binding to its substrates and clarified the broader substrate preference of CAT(I) compared to that of CAT(III).
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Tapan
authors.initials: T
authors.lastname: Biswas
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Houghton
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002701:Chloramphenicol / Q000737:chemistry*; D015500:Chloramphenicol O-Acetyltransferase / Q000737:chemistry*; D003460:Crystallization; D004789:Enzyme Activation; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology*; D005672:Fusidic Acid / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D016415:Sequence Alignment; D013379:Substrate Specificity; D014961:X-Ray Diffraction
chemical_list: D005672:Fusidic Acid; D002701:Chloramphenicol; D015500:Chloramphenicol O-Acetyltransferase