Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (HGPRT)

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a critical metabolic enzyme that facilitates the purine salvage pathway by recycling hypoxanthine and guanine into IMP and GMP, respectively (UniProt P00492). By utilizing 5-phospho-D-ribosyl-1-pyrophosphate (PRPP) as a ribose donor, the enzyme maintains cellular nucleotide pools and prevents the overproduction of uric acid. In humans, mutations in the HPRT1 gene lead to varying degrees of deficiency; a complete loss of activity results in Lesch-Nyhan syndrome, a severe neurogenetic disorder characterized by hyperuricemia, dystonia, and compulsive self-mutilation (StatPearls: Lesch-Nyhan Syndrome). HGPRT is also a vital target in oncology, as it is the primary enzyme required to activate thiopurine prodrugs like 6-mercaptopurine used in the treatment of acute lymphoblastic leukemia. Furthermore, because many protozoan parasites, such as Plasmodium falciparum, lack de novo purine synthesis pathways and rely entirely on salvage, parasitic HGPRT is a major target for the development of selective antimalarial and antiprotozoal drugs (PubMed: 19450131). The enzyme's dual role as a cause of metabolic disease and a gateway for chemotherapy makes it a significant focus of biochemical and clinical research.

Other names

HPRTHPRT1HGPRTaseHypoxanthine phosphoribosyltransferaseGuanine phosphoribosyltransferaseIMP pyrophosphorylaseTransphosphoribosylase

HGPRT catalyzes the conversion of hypoxanthine and guanine to their respective monophosphates, IMP and GMP, using 5-phosphoribosyl-1-pyrophosphate (PRPP) as a co-substrate (PubMed: 19450131). In the context of pharmacology, HGPRT is responsible for the metabolic activation of thiopurine prodrugs like 6-mercaptopurine and 6-thioguanine into cytotoxic thioguanine nucleotides (TGNs). These active metabolites are subsequently incorporated into DNA and RNA, leading to the inhibition of nucleic acid synthesis and the induction of cell cycle arrest or apoptosis in rapidly dividing cells, such as leukemic blasts (PubChem CID 667490).