title: Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B.
abstract: The dramatic increase in the prevalence of antibiotic-resistant bacteria has necessitated a search for new antibacterial agents against novel targets. Moiramide B is a natural product, broad-spectrum antibiotic that inhibits the carboxyltransferase component of acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis. Herein, we report the 2.6 Å resolution crystal structure of moiramide B bound to carboxyltransferase. An unanticipated but significant finding was that moiramide B bound as the enol/enolate. Crystallographic studies demonstrate that the (4S)-methyl succinimide moiety interacts with the oxyanion holes of the enzyme, supporting the notion that an anionic enolate is the active form of the antibacterial agent. Structure-activity studies demonstrate that the unsaturated fatty acid tail of moiramide B is needed only for entry into the bacterial cell. These results will allow the design of new antibacterial agents against the bacterial form of carboxyltransferase.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Silvers
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pakhomova
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.|Northeastern Collaborative Access Team, Argonne National Laboratory , Argonne, Illinois 60439, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Neau
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Silvers
authors.forename: Nicholas
authors.initials: N
authors.lastname: Anzalone
authors.forename: Carol M
authors.initials: CM
authors.lastname: Taylor
authors.forename: Grover L
authors.initials: GL
authors.lastname: Waldrop
mesh_terms: D000577:Amides / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D019878:Carboxyl and Carbamoyl Transferases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000201:enzymology*; D013388:Succinimides / Q000378:metabolism*
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D013388:Succinimides; C487819:moiramide B; D019878:Carboxyl and Carbamoyl Transferases