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

Autor: Tanya J. Espino-Sanchez, Henry Wienkers, Rebecca G. Marvin, Shai-anne Nalder, Aldo E. García-Guerrero, Peter E. VanNatta, Yasaman Jami-Alahmadi, Amanda Mixon Blackwell, Frank G. Whitby, James A. Wohlschlegel, Matthew T. Kieber-Emmons, Christopher P. Hill, Paul A. Sigala
Rok vydání: 2023
Předmět:
Zdroj: Proceedings of the National Academy of Sciences. 120
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.2301047120
Popis: 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.
Databáze: OpenAIRE
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