Abstract
Coenzyme A (CoA) is an essential universal cofactor for all prokaryotic and eukaryotic cells. In nearly all non-photosynthetic cells, CoA biosynthesis depends on the uptake and phosphorylation of vitamin B5 (pantothenic acid or pantothenate). Recently, putative pantothenate transporter (PAT) and pantothenate kinases (PanKs) were functionally characterized in P. yoelii. PAT and PanKs were shown to be dispensable for blood stage development, but they were essential for mosquito stages development. Yet, little is known about the cellular functions of the other enzymes of the CoA biosynthesis pathway in malaria parasite life cycle stages. All enzymes of this pathway were targeted for deletion or deletion/complementation analyses by knockout/knock-in plasmid constructs to reveal their essential roles in P. yoelii life cycle stages. The intermediate enzymes PPCS (Phosphopantothenylcysteine Synthase), PPCDC (Phosphopantothenylcysteine Decarboxylase) were shown to be dispensable for asexual and sexual blood stage development, but they were essential for oocyst development and the production of sporozoites. However, the last two enzymes of this pathway, PPAT (Phosphopantetheine Adenylyltransferase) and DPCK (Dephospho-CoA Kinase), were essential for blood stage development. These results indicate alternative first substrate requirement for the malaria parasite, other than the canonical pantothenate, for the synthesis of CoA in the blood but not inside the mosquito midgut. Collectively, our data shows that CoA de novo biosynthesis is essential for both blood and mosquito stages, and thus validates the enzymes of this pathway as potential antimalarial targets.
Highlights
Coenzyme A (CoA) is an essential cofactor for all prokaryotes and eukaryotes to support a large number of metabolic processes including fatty acid biosynthesis and oxidation, as well as carbohydrate and amino acid metabolism (Lipmann et al, 1947a,b; Leonardi et al, 2005)
CoA biosynthesis inhibition has been studied in Plasmodium, the genes encoding this pathway have not been biochemically characterized in any malaria parasite species
We explored the cellular roles of the putative enzymes that are implicated in CoA biosynthesis, first with pantothenate transporter (PAT) and with PanK1 and PanK2 (Hart et al, 2014, 2016a)
Summary
CoA is an essential cofactor for all prokaryotes and eukaryotes to support a large number of metabolic processes including fatty acid biosynthesis and oxidation, as well as carbohydrate and amino acid metabolism (Lipmann et al, 1947a,b; Leonardi et al, 2005). It was shown that some pathogenic bacterial species, Caenorhabditis elegans, Drosophila melanogaster, and even human cells in culture rely on the uptake of pantetheine inside cells and use the PanK to generate 4′ phosphopantetheine (Jackowski and Rock, 1984; Leonardi et al, 2005, 2010; Zhang et al, 2007; Spry et al, 2008; Sibon and Strauss, 2016) In this case, 4′ phosphopantetheine is further processed by PPAT and DPCK to produce CoA without the intermediate canonical cysteine addition and cysteine decarboxylation steps
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