HGPRT

HGPRT, or hypoxanthine-guanine phosphoribosyltransferase, is an enzyme of the purine salvage pathway. In humans, it is encoded by the HPRT1 gene on the X chromosome and is primarily located in the cytosol. The enzyme catalyzes the transfer of the ribose-5-phosphate moiety from phosphoribosyl pyrophosphate (PRPP) to hypoxanthine or guanine, forming inosine monophosphate (IMP) or guanosine monophosphate (GMP) and releasing pyrophosphate. HGPRT also acts on analogs such as 6-thioguanine and 6-mercaptopurine, converting them into nucleotide forms involved in cellular metabolism or drug activation.

Function and significance: HGPRT is a key component of the purine salvage pathway, which recycles purine bases released during nucleic acid turnover to conserve cellular energy and resources. By maintaining pools of IMP and GMP, HGPRT supports nucleotide balance and DNA/RNA synthesis, particularly in cells with limited de novo synthesis.

Clinical significance: Deficiency of HGPRT causes Lesch-Nyhan syndrome, an X-linked disorder presenting in severe cases with neurological impairment, dystonia, self-mutilating behavior, and hyperuricemia due to increased de novo purine synthesis and uric acid production. Partial deficiencies lead to Kelley-Seegmiller syndrome, with milder neurological symptoms. Diagnosis is based on low or absent HPRT enzyme activity in blood cells, often confirmed by genetic testing for HPRT1 mutations. Treatment focuses on symptom management and uric acid control, commonly with allopurinol, and supportive care; there is no cure for the underlying deficiency.

In summary, HGPRT is essential for purine conservation through salvage, and its loss has profound metabolic and neurological consequences.