title: Trypanosoma brucei: inhibition of acetyl-CoA carboxylase by haloxyfop.
abstract: Trypanosoma brucei, a eukaryotic pathogen that causes African sleeping sickness in humans and nagana in cattle, depends on the enzyme acetyl-CoA carboxylase (ACC) for full virulence in mice. ACC produces malonyl-CoA, the two carbon donor for fatty acid synthesis. We assessed the effect of haloxyfop, an aryloxyphenoxypropionate herbicide inhibitor of plastid ACCs in many plants as well as Toxoplasma gondii, on T. brucei ACC activity and growth in culture. Haloxyfop inhibited TbACC in cell lysate (EC(50) 67 μM), despite the presence of an amino acid motif typically associated with resistance. Haloxyfop also reduced growth of bloodstream and procyclic form parasites (EC(50) of 0.8 and 1.2 mM). However, the effect on growth was likely due to off-target effects because haloxyfop treatment had no effect on fatty acid elongation or incorporation into complex lipids in vivo.
authors: Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA. pvigueir@dom.wustl.edu
authors: Patrick A
authors: PA
authors: Vigueira
authors: Kimberly S
authors: KS
authors: Paul
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D003512:Cyclohexanones / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D016415:Sequence Alignment; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
chemical_list: D003512:Cyclohexanones; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011422:Propionates; D011725:Pyridines; D011810:Quinoxalines; C049437:sethoxydim; C477202:quizalofop; C054176:haloxyfop; C050582:fluazifop; D000103:Acetyl-CoA Carboxylase