4g2r

Publication Abstract from PubMed

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.

Structure, Activity, and Inhibition of the Carboxyltransferase beta-subunit of Acetyl-CoA Carboxylase (AccD6) from Mycobacterium tuberculosis.,Reddy MC, Breda A, Bruning JB, Sherekar M, Valluru S, Thurman C, Ehrenfeld H, Sacchettini JC Antimicrob Agents Chemother. 2014 Aug 4. pii: AAC.02574-13. PMID:25092705^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.