Direct tests of cytochrome c and c 1 functions in the electron transport chain of malaria parasites

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Abstract
The mitochondrial electron transport chain (ETC) of Plasmodium malaria parasites is a major antimalarial drug target, but critical cytochrome (cyt) functions remain unstudied and enigmatic. Parasites express two distinct cyt c homologs ( c and c -2) with unusually sparse sequence identity and uncertain fitness contributions. P. falciparum cyt c -2 is the most divergent eukaryotic cyt c homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt c homologs and the related cyt c 1 for inducible knockdown. Translational repression of cyt c and cyt c 1 was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt c -2 knockdown or knockout had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt c for ETC function. Biochemical and structural studies revealed that both cyt c and c -2 are hemylated by holocytochrome c synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt c -2 has an unusually open active site in which heme is stably coordinated by only a single axial amino acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent Plasmodium cytochrome c with molecular adaptations that defy a conserved role in eukaryotic evolution.
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Funding Information
  • HHS | NIH | National Institute of General Medical Sciences (R35GM133764)
  • HHS | NIH | National Institute of General Medical Sciences (R01GM089778)
  • HHS | NIH | National Institute of General Medical Sciences (R35GM133764-04S1)
  • Burroughs Wellcome Fund (1011969)
  • Pew Charitable Trusts (32099)
  • HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (U54DK110858)
  • HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (T32DK007115)
  • HHS | NIH | NHLBI | NHLBI Division of Intramural Research (R25HL108828)
  • National Science Foundation (MRI-0722849)

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