4G2R: Crystal Structure Of The Carboxyltransferase Subunit Of Acc (accd6) In Complex With Inhibitor Haloxyfop From Mycobacterium Tuberculosis

Citation:
Abstract
In Mycobacterium tuberculosis (Mtb) the carboxylation of 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 (AccA1-3) and the six carboxyltransferases (AccD1-6) in Mtb are still not clear, AccD6 in complex with AccA3 can synthesize malonyl-CoA from acetyl-CoA. A series of ten herbicides that target plant acetyl-CoA carboxylases (ACC) were tested for inhibition of AccD6 and for whole-cell activity against Mtb. From the tested herbicides, haloxyfop, an arylophenoxypropionate, showed in vitro inhibition of Mtb AccD6, with an IC50 = 21.4 +/- 1 muM. Here, we report the crystal structures of Mtb AccD6 in the apo form (3.0 A) and in complex with haloxyfop-R (2.3 A). The structure of Mtb AccD6 in complex with haloxyfop-R shows two molecules of the inhibitor bound on each AccD6 subunit. These results represent the potential for developing novel therapeutics for tuberculosis based on herbicides with low human toxicity.
PDB ID: 4G2RDownload
MMDB ID: 117611
PDB Deposition Date: 2012/7/12
Updated in MMDB: 2014/08
Experimental Method:
x-ray diffraction
Resolution: 2.28  Å
Source Organism:
Similar Structures:
Biological Unit for 4G2R: dimeric; determined by author and by software (PISA)
Molecular Components in 4G2R
Label Count Molecule
Proteins (2 molecules)
2
Accd6, Carboxyltransferase Beta-subunit of Acyl-coa Carboxylase
Molecule annotation
Chemicals (4 molecules)
1
4
* Click molecule labels to explore molecular sequence information.

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