| Autor: |
Reddy, Manchi C. M., Breda, Ardala, Bruning, John B., Sherekar, Mukul, Valluru, Spandana, Thurman, Cory, Ehrenfeld, Hannah, Sacchettini, James C. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; July 2014, Vol. 58 Issue: 10 p6122-6132, 11p |
| Abstrakt: |
ABSTRACTIn 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. tuberculosisare 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 vitroinhibition of M. tuberculosisAccD6, with a 50% inhibitory concentration (IC50) of 21.4 ± 1 μM. Here, we report the crystal structures of M. tuberculosisAccD6 in the apo form (3.0 Å) and in complex with haloxyfop-R(2.3 Å). The structure of M. tuberculosisAccD6 in complex with haloxyfop-Rshows 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. |
| Databáze: |
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