HGPRT

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Introductions

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a genetically translated enzyme in the human body HGPRT is a transferase that catalyzes the conversion of hypoxanthine to inosinic acid (IMP) and the reaction of guanine to guanosine monophosphate. Both reactions involve the transfer of nucleoside 5-phosphate from PRPP to purine. HGPRT plays an important role in the nucleotide remediation synthesis pathway.

Figure 1. Structure of HGPRT.

Catalytic reactions

HGPRT functions to salvage purines from degraded DNA to reintroduce into purine synthetic pathways. In this role, it catalyzes the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP, or between hypoxanthine and phosphoribosyl pyrophosphate (PRPP) to form inosine monophosphate. Comparative homology modelling of this enzyme in suggest that among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).

Functions

• HGPRT is a multifunctional and functionally diverse enzyme. It is primarily used to catalyze the transfer of glycosides and glycosylates between hypoxanthine guanine phosphate conjugates and has important physiological functions in a variety of organisms.
• HGPRT functions horizontally by having catalytic activity and regulatory activity and vertically by having important inhibitory effects that inhibit apoptosis and proliferation. Moreover, it also plays an important role in cellular glucose metabolism by inhibiting the synthesis and metabolism of intracellular sugars, thus improving the glycemic content at the cellular level.

As a regulatory factor

• HGPRT is an important regulator of cellular glucose metabolism and is also key in regulating the level of glycans. It inhibits the synthesis and metabolism of intracellular glycans and promotes healthy cellular metabolism, from HGPRT also plays an important role in inflammatory responses and cancer processes. It can inhibit the activity of inflammatory cells, thus suppressing the development of inflammation, preventing the deterioration of lesions and reducing the incidence of cancer.
• HGPRT is a multifunctional and diverse enzyme that plays an important role in sugar metabolism, inflammatory response and cancer processes.

Role in disease

Mutations in the gene lead to hyperuricemia. At least 67 disease-causing mutations in this gene have been discovered:

• Some men have partial (up to 20% less activity of the enzyme) HGPRT deficiency that causes high levels of uric acid in the blood, which leads to the development of gouty arthritis and the formation of uric acid stones in the urinary tract. This condition has been named the Kelley–Seegmiller syndrome.
• HPRT expression on the mRNA and protein level is induced by hypoxia inducible factor 1 (HIF1A). HIF-1 is a transcription factor that directs an array of cellular responses that are used for adaptation during oxygen deprivation. This finding implies that HPRT is a critical pathway that helps preserve the cell's purine nucleotide resources under hypoxic conditions as found in pathology such as myocardial ischemia.
• Some mutations have been linked to gout, the risk of which is increased in hypoxanthine-guanine phosphoribosyltransferase deficiency.

Summary

HGPRT is a cytoplasmic enzyme that is widely present in the body. It is not only involved in the remedial synthesis pathway of purine bases, but related to the metabolism of purine drugs and is a key enzyme in the regulation of pharmacological effects and toxic reactions of these drugs. The actual mutation of its gene can affect the enzyme activity, which may not only lead to the occurrence of metabolic diseases with different clinical manifestations; but also affect the metabolism of purine drugs in vivo. At the same time, HGPRT, as a housekeeping gene, is a target gene for the diagnosis of many diseases.