Fig. 1

Schematic showing hypoxanthine salvage in Plasmodium falciparum. Hypoxanthine in the cytosol of a red blood cell (RBC) can be formed by catabolism of adenosine triphosphate (ATP) or imported through hypoxanthine transporters from the environment, where it is present at 2–8 µM in human serum. The parasite takes up hypoxanthine from the RBC cytosol and uses it to make purine-based nucleic acids, whereas it synthesizes pyrimidine-based nucleic acids de novo. The parasite can produce hypoxanthine from methylthioinosine (MTI) and methylthioadenosine (MTA), which are produced during polyamine synthesis. The parasite can also produce hypoxanthine from adenosine, which it either takes up from the RBC’s cytosol or by directly cleaving S-adenosylhomocysteine (SAH). SAH is synthesized from methionine (MET), which the parasite acquires through hemoglobin digestion in the food vacuole (FV) or via plasma membrane transporters. Black dots on the RBC membrane indicate hypoxanthine and MET transporters. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; ASA, adenylosuccinic acid; GMP, guanine monophosphate; HCS, homocysteine; IMP, inosine monophosphate; SAM, S-adenosylmethionine; XMP, xanthine monophosphate