Patrick A Vigueira

Publications (2)7.13 Total impact

• Article: Trypanosoma brucei: inhibition of acetyl-CoA carboxylase by haloxyfop.

  Patrick A Vigueira, Kimberly S Paul
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  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.
  Experimental Parasitology 11/2011; 130(2):159-65. · 2.12 Impact Factor
• Article: Requirement for acetyl-CoA carboxylase in Trypanosoma brucei is dependent upon the growth environment.

  Patrick A Vigueira, Kimberly S Paul
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  ABSTRACT: Trypanosoma brucei, the causative agent of human African trypanosomiasis, possesses two fatty acid synthesis pathways: a major de novo synthesis pathway in the ER and a mitochondrial pathway. The 2-carbon donor for both pathways is malonyl-CoA, which is synthesized from acetyl-CoA by Acetyl-CoA carboxylase (ACC). Here, we show that T. brucei ACC shares the same enzyme architecture and moderate ∼ 30% identity with yeast and human ACCs. ACC is cytoplasmic and appears to be distributed throughout the cell in numerous puncta distinct from glycosomes and other organelles. ACC is active in both bloodstream and procyclic forms. Reduction of ACC activity by RNA interference (RNAi) resulted in a stage-specific phenotype. In procyclic forms, ACC RNAi resulted in 50-75% reduction in fatty acid elongation and a 64% reduction in growth in low-lipid media. In bloodstream forms, ACC RNAi resulted in a minor 15% decrease in fatty acid elongation and no growth defect in culture, even in low-lipid media. However, ACC RNAi did attenuate virulence in a mouse model of infection. Thus the requirement for ACC in T. brucei is dependent upon the growth environment in two different life cycle stages.
  Molecular Microbiology 02/2011; 80(1):117-32. · 5.01 Impact Factor