bims-meprid 2023-04-23 papers

Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2210929120

The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.

Sethu C Nair, Justin T Munro, Alexis Mann, Manuel Llinás, Sean T Prigge.

Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite-labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that the mitochondrion is required for cellular acetyl-CoA biosynthesis and identify a synthetic lethal relationship between the two main ketoacid dehydrogenase enzymes. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is required for cellular acetyl-CoA metabolism and protein acetylation essential for parasite survival.

Keywords: acetyl-CoA; acetylation; lipoic acid; malaria parasites; mitochondrion

DOI: https://doi.org/10.1073/pnas.2210929120

Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2302152120

The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching.

Victoria M Schneider, Joseph E Visone, Chantal T Harris, Francesca Florini, Evi Hadjimichael, Xu Zhang, Mackensie R Gross, Kyu Y Rhee, Choukri Ben Mamoun, Björn F C Kafsack, Kirk W Deitsch.

The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var, and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P. falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.

Keywords: gene expression; immune evasion; metabolism; methylation; var genes

DOI: https://doi.org/10.1073/pnas.2302152120

BBA Adv. 2023 ;3 100075

Discovery and functional characterisation of protein CoAlation and the antioxidant function of coenzyme A.

Valeriy Filonenko, Ivan Gout.

Coenzyme A (CoA) is an essential cofactor in all living cells which plays critical role in cellular metabolism, the regulation of gene expression and the biosynthesis of major cellular constituents. Recently, CoA was found to function as a major antioxidant in both prokaryotic and eukaryotic cells. This unconventional function of CoA is mediated by a novel post-translational modification, termed protein CoAlation. This review will highlight the history of this discovery, current knowledge, and future directions on studying molecular mechanisms of protein CoAlation and whether the antioxidant function of CoA is associated with pathologies, such as neurodegeneration and cancer.

Keywords: Antioxidant function; Coenzyme A; Post-translational modification; Protein protein CoAlation; Reactive oxygen species; Redox regulation

DOI: https://doi.org/10.1016/j.bbadva.2023.100075