Plasmodium falciparum hypoxanthine–guanine–xanthine phosphoribosyltransferase (PfHGXPRT)

Plasmodium falciparum hypoxanthine–guanine–xanthine phosphoribosyltransferase (PfHGXPRT) is a critical enzyme in the purine salvage pathway of the malaria-causing parasite. Unlike its human host, Plasmodium falciparum is a purine auxotroph, meaning it lacks the metabolic machinery for de novo purine synthesis and must rely entirely on salvaging purine bases from the host environment to produce the nucleotides required for DNA and RNA replication. PfHGXPRT specifically catalyzes the conversion of hypoxanthine, guanine, and xanthine into their respective monophosphate nucleotides (IMP, GMP, and XMP) using phosphoribosyl pyrophosphate (PRPP) as a co-substrate. Due to its essential role in parasite survival and its broader substrate specificity compared to the human ortholog (which does not efficiently utilize xanthine), PfHGXPRT is a high-priority target for the development of novel antimalarials. Research has focused on transition state analogues and acyclic nucleoside phosphonates that potently inhibit the enzyme, effectively starving the parasite of essential genetic building blocks. A significant challenge in drug development is ensuring high selectivity for the parasite enzyme over human HGPRT to avoid potential side effects related to host purine metabolism. Many current leads are being developed as prodrugs to overcome the poor membrane permeability typically associated with potent phosphonate-based inhibitors.

Other names

HGXPRTHypoxanthine-guanine-xanthine phosphoribosyltransferasePfHGPRTHypoxanthine-guanine phosphoribosyltransferase

Inhibition of the purine salvage pathway by competing with purine bases for the enzyme's active site, thereby depleting the parasite's purine nucleotide pool and halting DNA and RNA synthesis.