Hypoxanthine-guanine phosphoribosyltransferase
| hypoxanthine phosphoribosyltransferase | |||||||||
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Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme encoded in humans by the HPRT1 gene.[1][2]
HGPRT is a
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
| hypoxanthine phosphoribosyltransferase | |||||||||
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ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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HGPRT catalyzes the following reactions:
| Substrate | Product | Notes |
|---|---|---|
| hypoxanthine | inosine monophosphate |
— |
| guanine | guanosine monophosphate | Often called HGPRT. Performs this function only in some species. |
| xanthine | xanthosine monophosphate | 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
inosine monophosphate
.
Substrates and inhibitors
Comparative homology modelling of this enzyme in acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).[3]
The 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 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 (myocardial ischemia.[8]
Creation of hybridomas
salvage pathway
, due to lack of HPRT1. The plasma cells in the culture eventually die from senescence, leaving pure hybridoma cells.
References
Further reading
- Sculley DG, Dawson PA, Emmerson BT, Gordon RB (Nov 1992). "A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". Human Genetics. 90 (3): 195–207. S2CID 25118113.
- Ansari MY, Dikhit MR, Sahoo GC, Das P (Apr 2012). "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. PMID 22327112.
- Davidson BL, Tarlé SA, Van Antwerp M, Gibbs DA, Watts RW, Kelley WN, Palella TD (May 1991). "Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". American Journal of Human Genetics. 48 (5): 951–8. PMID 2018042.
- Stout JT, Caskey CT (1986). "HPRT: gene structure, expression, and mutation". Annual Review of Genetics. 19: 127–48. PMID 3909940.
- Walsh MJ, Sanchez-Pozo A, LeLeiko, NS (Aug 1990). "A regulatory element is characterized by purine-mediated and cell-type-specific gene transcription". Molecular and Cellular Biology. 10 (8): 4356–64. PMID 2370869.
- Sege-Peterson K, Chambers J, Page T, Jones OW, Nyhan WL (Sep 1992). "Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency". Human Molecular Genetics. 1 (6): 427–32. PMID 1301916.
- Lightfoot T, Joshi R, Nuki G, Snyder FF (Mar 1992). "The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction". Human Genetics. 88 (6): 695–6. S2CID 30114636.
- Yamada Y, Goto H, Ogasawara N (1992). "Identification of two independent Japanese mutant HPRT genes using the PCR technique". Purine and Pyrimidine Metabolism in Man VII. Advances in Experimental Medicine and Biology. Vol. 309B. pp. 121–4. PMID 1840476.
- Sculley DG, Dawson PA, Beacham IR, Emmerson BT, Gordon RB (Oct 1991). "Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification". Human Genetics. 87 (6): 688–92. S2CID 2197550.
- Tarlé SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD (Jun 1991). "Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects" (PDF). Genomics. 10 (2): 499–501. PMID 2071157.
- Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT (1991). "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. S2CID 34183501.
- Edwards A, Voss H, Rice P, Civitello A, Stegemann J, Schwager C, Zimmermann J, Erfle H, Caskey CT, Ansorge W (Apr 1990). "Automated DNA sequencing of the human HPRT locus". Genomics. 6 (4): 593–608. PMID 2341149.
- Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT (Jun 1990). "Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families". Genomics. 7 (2): 235–44. PMID 2347587.
- Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ (Jun 1990). "Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures". Human Genetics. 85 (1): 111–6. S2CID 21412991.
- Davidson BL, Tarlé SA, Palella TD, Kelley WN (Jul 1989). "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. PMID 2738157.
- Ogasawara N, Stout JT, Goto H, Sonta S, Matsumoto A, Caskey CT (Sep 1989). "Molecular analysis of a female Lesch-Nyhan patient". The Journal of Clinical Investigation. 84 (3): 1024–7. PMID 2760209.
- Yang TP, Stout JT, Konecki DS, Patel PI, Alford RL, Caskey CT (May 1988). "Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement". Somatic Cell and Molecular Genetics. 14 (3): 293–303. S2CID 247130.
- Fujimori S, Hidaka Y, Davidson BL, Palella TD, Kelley WN (May 1988). "Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor)" (PDF). Human Genetics. 79 (1): 39–43. S2CID 1288136.
- Davidson BL, Pashmforoush M, Kelley WN, Palella TD (Jan 1989). "Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville)". The Journal of Biological Chemistry. 264 (1): 520–5. PMID 2909537.
- Fujimori S, Davidson BL, Kelley WN, Palella TD (Jan 1989). "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. PMID 2910902.
External links
- Hypoxanthine+phosphoribosyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Purine metabolism at genome.jp Archived 2020-09-21 at the Wayback Machine
- GeneReviews/NCBI/NIH/UW entry on Lesch-Nyhan Syndrome
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