ACETYLCOA SYNTHESIS IN PLASMODIUM FALCIPARUM: AN UPDATE

The most dangerous human malaria parasite Plasmodium falciparum possesses a unique acetyl-CoA synthetase (PfACS) which is the only enzyme that supplies acetylCoA (AcCoA) moieties during the malaria-causing blood stages. For this reason, it is central to many different metabolic pathways and also for epigenetic regulation, interacting with histone acetyltransferases. Due to its structural differences with the human enzyme, PfACS is also an interesting drug target. In previous studies, we discovered that a conditional knockdown of the enzyme was deleterious for parasite growth and influenced the acetylation of histones and gene expression. When the subcellular localization of PfACS was evaluated, we found that the enzyme was present initially in the nucleus briefly after erythrocyte reinvasion and appeared later also in the cytosol of the parasites. To address the question in which compartment PfACS was more important, novel mutant parasite lines were created. These permitted the mislocation of PfACS either to the nucleus or to a secretory compartment. While the targeting PfACS to the nucleus together with a knockdown of its transcript had no significant influence on parasite growth, the knockdown/transfer of the enzyme to a secretory compartment strongly abrogated growth. This indicates a pivotal role of the enzyme in regulatory/nucleus-associated processes and possibly the existence of AcCoA transporters for export of PfACS out of the nucleus while AcCoA import appears not to happen. We are currently analysing by proximity-based biotinylation, which factors interact with PfACS.  

This work was supported by CNPq (CNPq 308479/2023-8) and FAPESP (2021/13727-2 and 2021/02298-3)