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Title: Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B

Journal Article · · Biochemistry
 [1];  [1];  [2];  [3];  [1];  [1];  [1]
  1. Louisiana State Univ., Baton Rouge, LA (United States)
  2. Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
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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. Furthermore, these results will allow the design of new antibacterial agents against the bacterial form of carboxyltransferase.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health
Grant/Contract Number:
AC02-06CH11357; P41 GM103403; S10 RR029205
OSTI ID:
1314237
Journal Information:
Biochemistry, Vol. 55, Issue 33; ISSN 0006-2960
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 9 works
Citation information provided by
Web of Science

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Cited By (2)

Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights journal January 2017
Regioselective C–C cross-coupling of 1,2,4-thiadiazoles with maleimides through iridium-catalyzed C–H activation journal January 2019

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59 BASIC BIOLOGICAL SCIENCES
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lipids
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