HEO Y, PARK M, KIM Y, SHIN D, KIM E, YANG C, KIM J, JEON Y, RO S, CHO J, HWANG K, LEE T; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. F-1448.

CrystalGenomics, Inc., Daejon, Republic of Korea.

BACKGROUND: Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in long-chain fatty acid synthesis. In Helicobacter pylori, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyl transferase. ATP-dependent carboxylation of biotin, which is the first step to utilize biotin to carboxylate acetyl CoA to form malonyl CoA by ACC, is catalyzed by biotin carboxylase. METHODS: Here, we provide four X-ray structures of biotin carboxylase. Three structures of them are the snapshots of the three sequential states in the hydrolysis of ATP: before ATP biding, ATP recognition, and ATP hydrolysis step. And the other structure is an inhibitor complex structure with an ATP mimicking irreversible inhibitor. RESULTS: Before ATP binding, biotin carboxylase adapts an open conformation but the major conformational change that occurs upon ATP binding causes the closure of the active site pocket. The closure is triggered by the interaction between the backbone amide groups of glycine rich loop and phosphoryl group of ATP and completed by grasping of Glutamine 250 by torsional adaptation of side chain, resulting in the rearrangement of ATP for hydrolysis. The inhibitor complexed biotin carboxylase structure implicates the catalytic activity of the enzyme may be inhibited by means of suspending the biotin carboxylase at the reaction intermediate state of ATP hydrolysis. CONCLUSIONS: Fatty acid biosynthesis is an emerging target for the development of novel antibacterial chemotherapeutics. The structures described here provide insight into the design of inhibitors of biotin carboxylase in ACC shedding light on the possibility of the new type of antibiotics.

Publication Types:

• Meeting Abstracts

Keywords:

• Acetyl-CoA Carboxylase
• Binding Sites
• Biotin
• Carbon-Nitrogen Ligases
• Carboxyl and Carbamoyl Transferases
• Carrier Proteins
• Catalysis
• Malonyl Coenzyme A
• biotin carboxyl carrier protein
• biotin carboxylase
• metabolism

Other ID:

• GWAIDS0025001

UI: 102264625

From Meeting Abstracts