Hypoxanthine-guanine phosphoribosyltransferase explained

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme encoded in humans by the HPRT1 gene.^{[1] [2]}

HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate (PRPP) to the purine. HGPRT plays a central role in the generation of purine nucleotides through the purine salvage pathway.

Function

Align:	left
hypoxanthine phosphoribosyltransferase
Ec Number:	2.4.2.8
Cas Number:	9016-12-0
Go Code:	0004422

HGPRT catalyzes the following reactions:

Substrate	Product	Notes
		—
		Often called HGPRT. Performs this function only in some species.
		Only certain HPRTs.

HGPRTase functions primarily 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.

Substrates and inhibitors

Comparative homology modelling of this enzyme in L. donovani 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).^[3] The in silico and in-vitro correlation of these compounds were test in Leishmania HGPRT and validates the result.^[4]

Role in disease

Mutations in the gene lead to hyperuricemia. At least 67 disease-causing mutations in this gene have been discovered:^[5]

• 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.^[6]
• Lesch–Nyhan syndrome is due to deficiency of HGPRT caused by HPRT1 mutation.^[7]
• Some mutations have been linked to gout, the risk of which is increased in hypoxanthine-guanine phosphoribosyltransferase deficiency.
• 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.^[8]

Creation of hybridomas

Hybridomas are immortal (immune to cellular senescence), HGPRT⁺ cells that result from fusion of mortal, HGPRT⁺ plasma cells and immortal, HGPRT⁻ myeloma cells. They are created to produce monoclonal antibodies in biotechnology. HAT medium inhibits de novo synthesis of nucleic acids, killing myeloma cells that cannot switch over to the salvage pathway, due to lack of HPRT1. The plasma cells in the culture eventually die from senescence, leaving pure hybridoma cells.

Further reading

• Sculley DG, Dawson PA, Emmerson BT, Gordon RB . A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency . Human Genetics . 90 . 3 . 195–207 . Nov 1992 . 1487231 . 10.1007/bf00220062 . 25118113 .
• Ansari MY, Dikhit MR, Sahoo GC, Das P . Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP . International Journal of Biological Macromolecules . 50 . 3 . 637–49 . Apr 2012 . 22327112 . 10.1016/j.ijbiomac.2012.01.010 .
• Davidson BL, Tarlé SA, Van Antwerp M, Gibbs DA, Watts RW, Kelley WN, Palella TD . Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency . American Journal of Human Genetics . 48 . 5 . 951–8 . May 1991 . 2018042 . 1683055 .
• Stout JT, Caskey CT . HPRT: gene structure, expression, and mutation . Annual Review of Genetics . 19 . 127–48 . 1986 . 3909940 . 10.1146/annurev.ge.19.120185.001015 .
• Walsh MJ, Sanchez-Pozo A, LeLeiko, NS . A regulatory element is characterized by purine-mediated and cell-type-specific gene transcription . Molecular and Cellular Biology . 10 . 4356–64 . Aug 1990 . 8 . 2370869 . 10.1128/mcb.10.8.4356-4364.1990 . 360986 .
• Sege-Peterson K, Chambers J, Page T, Jones OW, Nyhan WL . Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency . Human Molecular Genetics . 1 . 6 . 427–32 . Sep 1992 . 1301916 . 10.1093/hmg/1.6.427 .
• Lightfoot T, Joshi R, Nuki G, Snyder FF . The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction . Human Genetics . 88 . 6 . 695–6 . Mar 1992 . 1551676 . 10.1007/BF02265300 . 30114636 .
• Book: Yamada Y, Goto H, Ogasawara N . Purine and Pyrimidine Metabolism in Man VII . Identification of two independent Japanese mutant HPRT genes using the PCR technique . 309B . 121–4 . 1992 . 1840476 . 10.1007/978-1-4615-7703-4_27 . 978-1-4615-7705-8 . Advances in Experimental Medicine and Biology .
• Sculley DG, Dawson PA, Beacham IR, Emmerson BT, Gordon RB . Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification . Human Genetics . 87 . 6 . 688–92 . Oct 1991 . 1937471 . 10.1007/BF00201727 . 2197550 .
• Tarlé SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD . Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects . Genomics . 10 . 2 . 499–501 . Jun 1991 . 2071157 . 10.1016/0888-7543(91)90341-B . 2027.42/29310 . free .
• Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT . Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE) . Journal of Inherited Metabolic Disease . 13 . 5 . 692–700 . 1991 . 2246854 . 10.1007/BF01799570 . 34183501 .
• Edwards A, Voss H, Rice P, Civitello A, Stegemann J, Schwager C, Zimmermann J, Erfle H, Caskey CT, Ansorge W . Automated DNA sequencing of the human HPRT locus . Genomics . 6 . 4 . 593–608 . Apr 1990 . 2341149 . 10.1016/0888-7543(90)90493-E .
• Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT . Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families . Genomics . 7 . 2 . 235–44 . Jun 1990 . 2347587 . 10.1016/0888-7543(90)90545-6 .
• Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ . Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures . Human Genetics . 85 . 1 . 111–6 . Jun 1990 . 2358296 . 10.1007/BF00276334 . 21412991 .
• Davidson BL, Tarlé SA, Palella TD, Kelley WN . Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts . The Journal of Clinical Investigation . 84 . 1 . 342–6 . Jul 1989 . 2738157 . 303988 . 10.1172/JCI114160 .
• Ogasawara N, Stout JT, Goto H, Sonta S, Matsumoto A, Caskey CT . Molecular analysis of a female Lesch-Nyhan patient . The Journal of Clinical Investigation . 84 . 3 . 1024–7 . Sep 1989 . 2760209 . 329751 . 10.1172/JCI114224 .
• Yang TP, Stout JT, Konecki DS, Patel PI, Alford RL, Caskey CT . Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement . Somatic Cell and Molecular Genetics . 14 . 3 . 293–303 . May 1988 . 2835825 . 10.1007/BF01534590 . 247130 .
• Fujimori S, Hidaka Y, Davidson BL, Palella TD, Kelley WN . Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor) . Human Genetics . 79 . 1 . 39–43 . May 1988 . 2896620 . 10.1007/BF00291707 . 2027.42/47622 . 1288136 . free .
• Davidson BL, Pashmforoush M, Kelley WN, Palella TD . Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville) . The Journal of Biological Chemistry . 264 . 1 . 520–5 . Jan 1989 . 10.1016/S0021-9258(17)31289-9 . 2909537 . free .
• Fujimori S, Davidson BL, Kelley WN, Palella TD . Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome . The Journal of Clinical Investigation . 83 . 1 . 11–3 . Jan 1989 . 2910902 . 303636 . 10.1172/JCI113846 .

External links

• • Purine metabolism at genome.jp
• GeneReviews/NCBI/NIH/UW entry on Lesch-Nyhan Syndrome

Notes and References

1. Web site: Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome).
2. Finette BA, Kendall H, Vacek PM . Mutational spectral analysis at the HPRT locus in healthy children . Mutation Research . 505 . 1–2 . 27–41 . Aug 2002 . 12175903 . 10.1016/S0027-5107(02)00119-7 .
3. Ansari MY, Dikhit MR, Sahoo GC, Das P . Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP . International Journal of Biological Macromolecules . 50 . 3 . 637–49 . Apr 2012 . 22327112 . 10.1016/j.ijbiomac.2012.01.010 .
4. Ansari MY, Equbal A, Dikhit MR, Mansuri R, Rana S, Ali V, Sahoo GC, Das P . Establishment of Correlation between In-Silico &In-Vitro Test Analysis against Leishmania HGPRT to inhibitors . International Journal of Biological Macromolecules . Nov 2015 . 26616453 . 10.1016/j.ijbiomac.2015.11.051 . 83 . 78–96. Leishmania .
5. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
6. Khattak FH, Morris IM, Harris K . Kelley-Seegmiller syndrome: a case report and review of the literature . British Journal of Rheumatology . 37 . 5 . 580–1 . May 1998 . 9651092 . 10.1093/rheumatology/37.5.580c . free .
7. Hladnik U, Nyhan WL, Bertelli M . Variable expression of HPRT deficiency in 5 members of a family with the same mutation . Archives of Neurology . 65 . 9 . 1240–3 . Sep 2008 . 18779430 . 10.1001/archneur.65.9.1240 . free .
8. Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, Wright G . HIF-1α in the heart: Remodeling nucleotide metabolism . Journal of Molecular and Cellular Cardiology . Feb 2015 . 25681585 . 10.1016/j.yjmcc.2015.01.014 . 82 . 194–200 . 4405794.