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Publication Abstract from PubMed

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.

Direct tests of cytochrome c and c(1) functions in the electron transport chain of malaria parasites.,Espino-Sanchez TJ, Wienkers H, Marvin RG, Nalder SA, Garcia-Guerrero AE, VanNatta PE, Jami-Alahmadi Y, Mixon Blackwell A, Whitby FG, Wohlschlegel JA, Kieber-Emmons MT, Hill CP, Sigala PA Proc Natl Acad Sci U S A. 2023 May 9;120(19):e2301047120. doi: , 10.1073/pnas.2301047120. Epub 2023 May 1. PMID:37126705^[1]

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