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Type: Journal article
Title: Structure, activity, and inhibition of the carboxyltransferase β-Subunit of acetyl coenzyme a carboxylase (AccD6) from mycobacterium tuberculosis
Other Titles: Structure, activity, and inhibition of the carboxyltransferase beta-Subunit of acetyl coenzyme a carboxylase (AccD6) from mycobacterium tuberculosis
Author: Reddy, M.
Breda, A.
Bruning, J.
Sherekar, M.
Valluru, S.
Thurman, C.
Ehrenfeld, H.
Sacchettini, J.
Citation: Antimicrobial Agents and Chemotherapy, 2014; 58(10):6122-6132
Publisher: American Society for Microbiolgy
Issue Date: 2014
ISSN: 0066-4804
Statement of
Manchi C. M. Reddy, Ardala Breda, John B. Bruning,* Mukul Sherekar, Spandana Valluru, Cory Thurman, Hannah Ehrenfeld, James C. Sacchettini
Abstract: In Mycobacterium tuberculosis, the carboxylation of acetyl coenzyme A (acetyl-CoA) to produce malonyl-CoA, a building block in long-chain fatty acid biosynthesis, is catalyzed by two enzymes working sequentially: a biotin carboxylase (AccA) and a carboxyltransferase (AccD). While the exact roles of the three different biotin carboxylases (AccA1 to -3) and the six carboxyltransferases (AccD1 to -6) in M. tuberculosis are still not clear, AccD6 in complex with AccA3 can synthesize malonyl-CoA from acetyl-CoA. A series of 10 herbicides that target plant acetyl-CoA carboxylases (ACC) were tested for inhibition of AccD6 and for whole-cell activity against M. tuberculosis. From the tested herbicides, haloxyfop, an arylophenoxypropionate, showed in vitro inhibition of M. tuberculosis AccD6, with a 50% inhibitory concentration (IC50) of 21.4 ± 1 μM. Here, we report the crystal structures of M. tuberculosis AccD6 in the apo form (3.0 Å) and in complex with haloxyfop-R (2.3 Å). The structure of M. tuberculosis AccD6 in complex with haloxyfop-R shows two molecules of the inhibitor bound on each AccD6 subunit. These results indicate the potential for developing novel therapeutics for tuberculosis based on herbicides with low human toxicity.
Keywords: Mycobacterium tuberculosis
Acetyl-CoA Carboxylase
Carboxyl and Carbamoyl Transferases
Bacterial Proteins
Crystallography, X-Ray
Enzyme Activation
Protein Binding
Models, Theoretical
Rights: Copyright © 2014, American Society for Microbiology. All Rights Reserved.
DOI: 10.1128/AAC.02574-13
Published version:
Appears in Collections:Aurora harvest 3
Molecular and Biomedical Science publications

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