Biology:Hypoxanthine-guanine phosphoribosyltransferase
Generic protein structure example |
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
hypoxanthine phosphoribosyltransferase | |||||||||
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Identifiers | |||||||||
EC number | 2.4.2.8 | ||||||||
CAS number | 9016-12-0 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
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 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.
References
- ↑ "Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)". https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=3251&rn=1.
- ↑ "Mutational spectral analysis at the HPRT locus in healthy children". Mutation Research 505 (1–2): 27–41. Aug 2002. doi:10.1016/S0027-5107(02)00119-7. PMID 12175903.
- ↑ "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. doi:10.1016/j.ijbiomac.2012.01.010. PMID 22327112.
- ↑ "Establishment of Correlation between In-Silico &In-Vitro Test Analysis against Leishmania HGPRT to inhibitors". International Journal of Biological Macromolecules 83: 78–96. Nov 2015. doi:10.1016/j.ijbiomac.2015.11.051. PMID 26616453.
- ↑ "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports 9 (1): 18577. December 2019. doi:10.1038/s41598-019-54976-4. PMID 31819097. Bibcode: 2019NatSR...918577S.
- ↑ "Kelley-Seegmiller syndrome: a case report and review of the literature". British Journal of Rheumatology 37 (5): 580–1. May 1998. doi:10.1093/rheumatology/37.5.580c. PMID 9651092.
- ↑ "Variable expression of HPRT deficiency in 5 members of a family with the same mutation". Archives of Neurology 65 (9): 1240–3. Sep 2008. doi:10.1001/archneur.65.9.1240. PMID 18779430.
- ↑ "HIF-1α in the heart: Remodeling nucleotide metabolism". Journal of Molecular and Cellular Cardiology 82: 194–200. Feb 2015. doi:10.1016/j.yjmcc.2015.01.014. PMID 25681585.
Further reading
- "A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". Human Genetics 90 (3): 195–207. Nov 1992. doi:10.1007/bf00220062. PMID 1487231.
- "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. doi:10.1016/j.ijbiomac.2012.01.010. PMID 22327112.
- "Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency". American Journal of Human Genetics 48 (5): 951–8. May 1991. PMID 2018042.
- "HPRT: gene structure, expression, and mutation". Annual Review of Genetics 19: 127–48. 1986. doi:10.1146/annurev.ge.19.120185.001015. PMID 3909940.
- "Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency". Human Molecular Genetics 1 (6): 427–32. Sep 1992. doi:10.1093/hmg/1.6.427. PMID 1301916.
- "The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction". Human Genetics 88 (6): 695–6. Mar 1992. doi:10.1007/BF02265300. PMID 1551676.
- "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. 309B. 1992. pp. 121–4. doi:10.1007/978-1-4615-7703-4_27. ISBN 978-1-4615-7705-8.
- "Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification". Human Genetics 87 (6): 688–92. Oct 1991. doi:10.1007/BF00201727. PMID 1937471.
- "Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects". Genomics 10 (2): 499–501. Jun 1991. doi:10.1016/0888-7543(91)90341-B. PMID 2071157. https://deepblue.lib.umich.edu/bitstream/2027.42/29310/1/0000374.pdf.
- "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. doi:10.1007/BF01799570. PMID 2246854.
- "Automated DNA sequencing of the human HPRT locus". Genomics 6 (4): 593–608. Apr 1990. doi:10.1016/0888-7543(90)90493-E. PMID 2341149.
- "Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families". Genomics 7 (2): 235–44. Jun 1990. doi:10.1016/0888-7543(90)90545-6. PMID 2347587.
- "Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures". Human Genetics 85 (1): 111–6. Jun 1990. doi:10.1007/BF00276334. PMID 2358296.
- "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. doi:10.1172/JCI114160. PMID 2738157.
- "Molecular analysis of a female Lesch-Nyhan patient". The Journal of Clinical Investigation 84 (3): 1024–7. Sep 1989. doi:10.1172/JCI114224. PMID 2760209.
- "Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement". Somatic Cell and Molecular Genetics 14 (3): 293–303. May 1988. doi:10.1007/BF01534590. PMID 2835825.
- "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. doi:10.1007/BF00291707. PMID 2896620. https://deepblue.lib.umich.edu/bitstream/2027.42/47622/1/439_2004_Article_BF00291707.pdf.
- "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. doi:10.1016/S0021-9258(17)31289-9. PMID 2909537.
- "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. doi:10.1172/JCI113846. PMID 2910902.
External links
- Hypoxanthine+phosphoribosyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)
- Purine metabolism at genome.jp
- GeneReviews/NCBI/NIH/UW entry on Lesch-Nyhan Syndrome
Original source: https://en.wikipedia.org/wiki/Hypoxanthine-guanine phosphoribosyltransferase.
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