4G2R

Crystal Structure of the carboxyltransferase subunit of ACC (AccD6) in complex with inhibitor haloxyfop from Mycobacterium tuberculosis

Summary for 4G2R

• Entry DOI: 10.2210/pdb4g2r/pdb
• Related: 4FB8
• Descriptor: AccD6, Carboxyltransferase beta-subunit of Acyl-CoA Carboxylase, (2R)-2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (3 entities in total)
• Functional Keywords: structural genomics, tb structural genomics consortium, tbsgc, crotonase super family, carboxyltransferase, transferase-herbicide complex, transferase, transferase-transferase inhibitor complex, psi-2, protein structure initiative, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 101844.67

Authors

Reddy, M.C.M.,Bruning, J.B.,Thurman, C.,Sherekar, M.,Valluru, S.,Ehrenfeld, H.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2012-07-12, release date: 2014-02-19, Last modification date: 2023-09-13)

Primary citation

Reddy, M.C.,Breda, A.,Bruning, J.B.,Sherekar, M.,Valluru, S.,Thurman, C.,Ehrenfeld, H.,Sacchettini, J.C.
Structure, Activity, and Inhibition of the Carboxyltransferase beta-Subunit of Acetyl Coenzyme A Carboxylase (AccD6) from Mycobacterium tuberculosis.
Antimicrob.Agents Chemother., 58:6122-6132, 2014

PubMed 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.

PubMed: 25092705
DOI: 10.1128/AAC.02574-13

Experimental method

X-RAY DIFFRACTION (2.28 Å)