Congratulations to graduate student Tanya Espino-Sanchez and the lab of Dr. Paul Sigala in the Department of Biochemistry at the University of Utah School of Medicine for their recent publication in PNAS!! “Direct tests of cytochrome c and c1 functions in the electron transport chain of malaria parasites”. Proc Natl Acad Sci U S A 2023 May 9;120(19):e2301047120. doi: 10.1073/pnas.2301047120. Epub 2023 May 1.PMID: 37126705 PMCID: PMC10175771 https://pubmed.ncbi.nlm.nih.gov/37126705/
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 c1 for inducible knockdown. Translational repression of cyt c and cyt c1 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.
This work was supported by a University of Utah CIHD P&F award DK110858 to PAS .