Hypoxanthine-guanine phosphoribosyltransferase (HGPRT[1]) is an enzyme in purine metabolism.
Functions
It catalyzes the following reactions:
The enzyme primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP.
B cells contain this enzyme, which enables them to survive when fused to myeloma cells when grown on HAT medium to produce monoclonal antibodies. The antibodies are produced from cells called hybridoma cells. A hybridoma, which can be considered as a hybrid cell, is produced by the injection of a specific antigen into a mouse, procuring the antibody-producing cell from the mouse's spleen and the subsequent fusion of this cell with a cancerous immune cell called a myeloma cell. The hybrid cell, which is thus produced, can be cloned to produce many identical daughter clones. These daughter clones then secrete the immune cell product.
The method of selecting hybridomas is by use of HAT medium, which contain Hypoxanthine, Aminopterin, and Thymidine. The aminopterin inhibits enzyme Dihydrofolate reductase (DHFR), which is necessary in the de novo synthesis of nucleic acids. Thus, the cell is left with no other option but to use the alternate salvage pathway, which utilises HGPRT. In the HAT medium, HGPRT- cell lines will die, as they cannot synthesise nucleic acids through salvage pathway. Only HGPRT+ cells will survive in presence of aminopterin, which are the hybridoma cells and plasma cells. The plasma cells eventually die as they are mortal cell lines, thus only hybridoma cells are left surviving. The hybrid cell, which is thus produced, can be cloned to produce many identical daughter clones. These daughter clones then secrete the monoclonal antibody product.
Role in disease
Mutations in the gene lead to hyperuricemia:
- Lesch-Nyhan syndrome is due to HPRT mutations.[2]
- Some mutations have been linked to gout, the risk of which is increased in hyperuricemia.
See also
References
Further reading
- Sculley DG, Dawson PA, Emmerson BT, Gordon RB (1993). "A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". Hum. Genet. 90 (3): 195–207. PMID 1487231.
- Davidson BL, Tarlé SA, Van Antwerp M, et al. (1991). "Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". Am. J. Hum. Genet. 48 (5): 951–8. PMID 2018042.
- Stout JT, Caskey CT (1986). "HPRT: gene structure, expression, and mutation". Annu. Rev. Genet. 19: 127–48. doi:10.1146/annurev.ge.19.120185.001015. PMID 3909940.
- Sege-Peterson K, Chambers J, Page T, et al. (1993). "Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency". Hum. Mol. Genet. 1 (6): 427–32. doi:10.1093/hmg/1.6.427. PMID 1301916.
- Lightfoot T, Joshi R, Nuki G, Snyder FF (1992). "The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction". Hum. Genet. 88 (6): 695–6. doi:10.1007/BF02265300. PMID 1551676.
- Yamada Y, Goto H, Ogasawara N (1992). "Identification of two independent Japanese mutant HPRT genes using the PCR technique". Adv. Exp. Med. Biol. 309B: 121–4. PMID 1840476.
- Sculley DG, Dawson PA, Beacham IR, et al. (1991). "Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification". Hum. Genet. 87 (6): 688–92. doi:10.1007/BF00201727. PMID 1937471.
- Tarlé SA, Davidson BL, Wu VC, et al. (1991). "Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects". Genomics 10 (2): 499–501. doi:10.1016/0888-7543(91)90341-B. PMID 2071157.
- Gordon RB, Sculley DG, Dawson PA, et al. (1991). "Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE)". J. Inherit. Metab. Dis. 13 (5): 692–700. doi:10.1007/BF01799570. PMID 2246854.
- Edwards A, Voss H, Rice P, et al. (1990). "Automated DNA sequencing of the human HPRT locus". Genomics 6 (4): 593–608. doi:10.1016/0888-7543(90)90493-E. PMID 2341149.
- Gibbs RA, Nguyen PN, Edwards A, et al. (1990). "Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families". Genomics 7 (2): 235–44. doi:10.1016/0888-7543(90)90545-6. PMID 2347587.
- Skopek TR, Recio L, Simpson D, et al. (1990). "Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures". Hum. Genet. 85 (1): 111–6. doi:10.1007/BF00276334. PMID 2358296.
- Davidson BL, Tarlé SA, Palella TD, Kelley WN (1989). "Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts". J. Clin. Invest. 84 (1): 342–6. doi:10.1172/JCI114160. PMID 2738157.
- Ogasawara N, Stout JT, Goto H, et al. (1989). "Molecular analysis of a female Lesch-Nyhan patient". J. Clin. Invest. 84 (3): 1024–7. doi:10.1172/JCI114224. PMID 2760209.
- Yang TP, Stout JT, Konecki DS, et al. (1988). "Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement". Somat. Cell Mol. Genet. 14 (3): 293–303. doi:10.1007/BF01534590. PMID 2835825.
- Fujimori S, Hidaka Y, Davidson BL, et al. (1988). "Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor)". Hum. Genet. 79 (1): 39–43. doi:10.1007/BF00291707. PMID 2896620.
- Davidson BL, Pashmforoush M, Kelley WN, Palella TD (1989). "Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville)". J. Biol. Chem. 264 (1): 520–5. PMID 2909537.
- Fujimori S, Davidson BL, Kelley WN, Palella TD (1989). "Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome". J. Clin. Invest. 83 (1): 11–3. doi:10.1172/JCI113846. PMID 2910902.
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PDB Gallery |
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1bzy: HUMAN HGPRTASE WITH TRANSITION STATE INHIBITOR
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1d6n: TERNARY COMPLEX STRUCTURE OF HUMAN HGPRTASE, PRPP, MG2+, AND THE INHIBITOR HPP REVEALS THE INVOLVEMENT OF THE FLEXIBLE LOOP IN SUBSTRATE BINDING
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1hmp: THE CRYSTAL STRUCTURE OF HUMAN HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH BOUND GMP
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External links
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Transferases: glycosyltransferases (EC 2.4) |
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| 2.4.1: Hexosyltransferases |
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B3GAT1, B3GAT2, B3GAT3
UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10
UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28
Hyaluronan synthase: HAS1 · HAS2 · HAS3
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| 2.4.2: Pentosyltransferases |
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| 2.4.99: Sialyltransferases |
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