Structural highlights
Function
[HGXR_PLAFG] Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Works with guanine, hypoxanthine and xanthine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Publication Abstract from PubMed
Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here, we present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.
Acyclic Immucillin Phosphonates: Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase.,Hazleton KZ, Ho MC, Cassera MB, Clinch K, Crump DR, Rosario I Jr, Merino EF, Almo SC, Tyler PC, Schramm VL Chem Biol. 2012 Jun 22;19(6):721-30. PMID:22726686[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hazleton KZ, Ho MC, Cassera MB, Clinch K, Crump DR, Rosario I Jr, Merino EF, Almo SC, Tyler PC, Schramm VL. Acyclic Immucillin Phosphonates: Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase. Chem Biol. 2012 Jun 22;19(6):721-30. PMID:22726686 doi:10.1016/j.chembiol.2012.04.012
