Hypoxanthine-guanine phosphoribosyltransferase and de novo purine synthesis enzymes (HGPRT/HPRT)

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme in the purine salvage pathway, responsible for converting free purine bases into their respective nucleotides, IMP and GMP (UniProt P00492). This enzyme is critical for maintaining nucleotide balance, especially in tissues like the brain that have low de novo synthesis capacity. In clinical practice, HGPRT is the essential activator for thiopurine prodrugs, such as 6-mercaptopurine and azathioprine, which are used to treat leukemia and autoimmune diseases. Once activated, these drugs produce metabolites that inhibit several enzymes in the de novo purine synthesis pathway, including amidophosphoribosyltransferase, and incorporate into nucleic acids to disrupt cell division (StatPearls, 2023). Consequently, the interplay between HGPRT and de novo synthesis enzymes is a major focal point for immunosuppressive and antineoplastic therapy. Genetic deficiency of HGPRT leads to Lesch-Nyhan syndrome, a condition marked by hyperuricemia and severe neurological dysfunction. Additionally, the safety of drugs targeting this system is heavily influenced by genetic polymorphisms in enzymes like TPMT and NUDT15, which can cause severe bone marrow toxicity (NCBI, 2022).

Other names

HPRT1HGPRTasePurine phosphoribosyltransferaseDe novo purine biosynthetic pathway

Metabolic activation of thiopurine prodrugs by HGPRT into active nucleotides, which then exert feedback inhibition on de novo purine synthesis enzymes and incorporate into DNA/RNA to induce cytotoxicity (StatPearls, 2023).