The folate metabolic network of Falciparum malaria

The targeting of key enzymes in the folate pathway continues to be an effective chemotherapeutic approach that has earned antifolate drugs a valuable position in the medical pharmacopoeia. The successful therapeutic use of antifolates as antimalarials has been a catalyst for ongoing research into the biochemistry of folate and pterin biosynthesis in malaria parasites. However, our understanding of the parasites folate metabolism remains partial and patchy, especially in relation to the shikimate pathway, the folate cycle, and folate salvage. A sizeable number of potential folate targets remain to be characterised. Recent reports on the parasite specific transport of folate precursors that would normally be present in the human host awaken previous hypotheses on the salvage of folate precursors or by-products. As the parasite progresses through its life-cycle it encounters very contrasting host cell environments that present radically different metabolic milieus and biochemical challenges. It would seem probable that as the parasite encounters differing environments it would need to modify its biochemistry. This would be reflected in the folate homeostasis in Plasmodium. Recent drug screening efforts and insights into folate membrane transport substantiate the argument that folate metabolism may still offer unexplored opportunities for therapeutic attack.

Plasmodium salvage folates at two, thermodynamically, different points. However, the fluctuation of external folate sources may be a selective force to preserve folate de novo synthesis. Figure optionsDownload high-quality image (157 K)Download as PowerPoint slideHighlights
► Using antifolates as antimalarials has motivated biochemical research on Plasmodium.
► Life cycle of Plasmodium parasites modulates their folate homeostasis.
► The molecular aspects of the pterin and pABA synthesis pathways are discussed.
► Awakening of the hypothesis of salvage of folate precursors as pathogenic factors.
► The standard thermodynamics illustrates the advantages of the dual modality of the folate network in malaria.