Structure, Activity, and Inhibition of the Carboxyltransferase beta-Subunit of Acetyl Coenzyme A Carboxylase (AccD6) from Mycobacterium tuberculosis | Academic Article individual record
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.

author list (cited authors)
Reddy, M., Breda, A., Bruning, J. B., Sherekar, M., Valluru, S., Thurman, C., Ehrenfeld, H., & Sacchettini, J. C.
publication date
2014
keywords
  • Bacterial Proteins
  • Models, Theoretical
  • Carboxyl And Carbamoyl Transferases
  • Crystallography, X-Ray
  • Mycobacterium Tuberculosis
  • Herbicides
  • Pyridines
  • Acetyl-coa Carboxylase
  • Protein Binding
  • Enzyme Activation
altmetric score

6.0

citation count

11