Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HXGPRT) (HXGPRT)

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HXGPRT) is a pivotal enzyme in the purine salvage pathway of Leishmania parasites, which are the causative agents of leishmaniasis (UniProt: P43152). Because these protozoan parasites lack the metabolic machinery for de novo purine synthesis, they are entirely dependent on salvaging purine bases from their host to produce the nucleotides required for DNA and RNA replication (Boitz et al., 2012, PubMed: 22541201). HXGPRT specifically catalyzes the transfer of a phosphoribosyl group from phosphoribosyl pyrophosphate (PRPP) to hypoxanthine, guanine, or xanthine, forming IMP, GMP, or XMP, respectively (Guddat et al., 2005, PubMed: 15653341). This enzyme is a highly attractive therapeutic target due to its unique ability to utilize xanthine as a substrate, a capability absent in the human ortholog, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Drugs such as allopurinol exploit this pathway by acting as alternative substrates, leading to the synthesis of abnormal nucleotides that disrupt parasite protein synthesis and growth (PubMed: 12114521). Furthermore, novel inhibitors like acyclic nucleoside phosphonates are being developed to selectively target the parasite enzyme's active site, offering a potential route for new anti-leishmanial therapies with reduced host toxicity (Hocková et al., 2015, PubMed: 25668265). Targeting HXGPRT offers a strategy to selectively starve the parasite of purines or poison its metabolic pathways while minimizing toxicity to the host.

Other names

HGXPRTHXGPRTaseLeishmania hypoxanthine-xanthine-guanosine phosphoribosyltransferaseHypoxanthine-guanine phosphoribosyltransferaseXanthine phosphoribosyltransferase

Competitive inhibition of the purine salvage pathway and metabolic activation of prodrugs into cytotoxic nucleotide analogs.