Hypoxanthine-guanine phosphoribosyltransferase and Inosine-5'-monophosphate dehydrogenase (HGPRT; IMPDH)

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an essential enzyme in the purine salvage pathway, catalyzing the conversion of hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP), thus recycling purine bases from degraded nucleic acids. Deficient HGPRT activity causes Lesch-Nyhan syndrome and hyperuricemia-related pathology, but the enzyme also has important roles in pharmacogenetics as it activates certain cytotoxic drugs. Inosine-5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme of de novo guanine nucleotide biosynthesis, converting IMP to xanthosine monophosphate (XMP), the precursor for GMP. There are two main isoforms in humans, IMPDH1 and IMPDH2, both critical to maintaining cellular GTP pools necessary for DNA and RNA synthesis, cell proliferation, and immune function. IMPDH is a major therapeutic target in immunosuppression (e.g. transplant medicine) and cancer, and its inhibition leads to cytostatic effects in rapidly dividing cells.

Other names

Hypoxanthine phosphoribosyltransferaseHPRTHPRT1 (gene)EC 2.4.2.8IMP dehydrogenaseIMPDH1IMPDH2inosine monophosphate dehydrogenaseEC 1.1.1.205

HGPRT is involved in the metabolism of certain prodrugs, such as 6-mercaptopurine, activating them for antileukemic therapy. Drugs targeting IMPDH, such as mycophenolate mofetil and ribavirin, inhibit IMPDH activity, thereby reducing de novo GTP synthesis and suppressing cell proliferation, particularly in rapidly dividing cells (e.g., immune cells, cancer cells). This leads to immunosuppression (via cell cycle arrest and apoptosis induction) and antiviral effects.