4FB8: Crystal Structure of apo Acyl-CoA Carboxylase

Citation:
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 muM. Here, we report the crystal structures of M. tuberculosis AccD6 in the apo form (3.0 A) and in complex with haloxyfop-R (2.3 A). 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.
PDB ID: 4FB8Download
MMDB ID: 117610
PDB Deposition Date: 2012/5/22
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 3  Å
Source Organism:
Similar Structures:
Biological Unit for 4FB8: dimeric; determined by author and by software (PISA)
Molecular Components in 4FB8
Label Count Molecule
Proteins (2 molecules)
2
Probable Propionyl-coa Carboxylase Beta Chain 6
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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