Crosstalk between purine nucleotide metabolism and mitochondrial pathways in Plasmodium falciparum

Abstract

Metabolism is known for its intricate adjustments to meet the needs of an organism. Due to demands of adaptation, parasite metabolic pathways are greatly altered from those of their hosts. A key difference in metabolic pathways in Plasmodium spp, during the intra-erythrocytic stages, pertains to energy metabolism with the absence of a major role for the mitochondria in adenosine triphosphate (ATP) generation. In most organisms there exists a tight link between nucleotide and energy metabolism. An important feature of purine nucleotide metabolism in Plasmodium falciparum is the absence of the de novo pathway, with purine requirements being completely met by the salvage pathway. Presence of the enzymes adenylosuccinate lyase, adenylosuccinate synthetase and adenosine monophosphate (AMP) deaminase, involved in AMP metabolism, suggests the existence of a functional purine nucleotide cycle (PNC) in P. falciparum with fumarate, a tricarboxylic acid (TCA) cycle intermediate, and ammonia being the net output from the cycle. In the absence of a conventional TCA cycle, the fate of fumarate generated from PNC merits examination. In this review we cover ATP generation through glycolysis, key features of the TCA cycle, the role of electron transport chain and the link between PNC and the mitochondrion. Recent studies using genetic approaches highlight unexpected features that were hitherto unknown with respect to these pathways and these are also summarized in this review.