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

Authors :
Espino-Sanchez TJ
Wienkers H
Marvin RG
Nalder SA
García-Guerrero AE
VanNatta PE
Jami-Alahmadi Y
Mixon Blackwell A
Whitby FG
Wohlschlegel JA
Kieber-Emmons MT
Hill CP
Sigala PA
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 09; Vol. 120 (19), pp. e2301047120. Date of Electronic Publication: 2023 May 01.
Publication Year :
2023

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 <subscript>1</subscript> for inducible knockdown. Translational repression of cyt c and cyt c <subscript>1</subscript> 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.

Details

Language :
English
ISSN :
1091-6490
Volume :
120
Issue :
19
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
37126705
Full Text :
https://doi.org/10.1073/pnas.2301047120