Structure, activity, and inhibition of the Carboxyltransferase β-subunit of acetyl coenzyme A carboxylase (AccD6) from Mycobacterium tuberculosis

• Published in: Antimicrobial agents and chemotherapy 2014-10, Vol.58 (10), p.6122-6132
• Main Authors: Reddy, Manchi C M, Breda, Ardala, Bruning, John B, Sherekar, Mukul, Valluru, Spandana, Thurman, Cory, Ehrenfeld, Hannah, Sacchettini, James C
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase; Acetyl-CoA Carboxylase - chemistry; Acetyl-CoA Carboxylase - metabolism; Bacterial Proteins; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Carboxyl and Carbamoyl Transferases; Carboxyl and Carbamoyl Transferases - chemistry; Carboxyl and Carbamoyl Transferases - metabolism; Crystallography, X-Ray; Enzyme Activation - drug effects; Herbicides - pharmacology; Models, Theoretical; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Pharmacology; Protein Binding; Pyridines - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02574-13

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.