Hypoxanthine-guanine phosphoribosyltransferase: Difference between revisions

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{{Infobox_gene}}
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'''Hypoxanthine-guanine phosphoribosyltransferase''' ('''HGPRT''') is an [[enzyme]] encoded in humans by the ''HPRT1'' [[gene]].<ref name="Entrez">{{cite web |url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=3251&rn=1 |title=Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)}}</ref><ref name="pmid12175903">{{cite journal | vauthors = Finette BA, Kendall H, Vacek PM | title = Mutational spectral analysis at the HPRT locus in healthy children | journal = Mutation Research | volume = 505 | issue = 1–2 | pages = 27–41 | date = Aug 2002 | pmid = 12175903 | doi = 10.1016/S0027-5107(02)00119-7 }}</ref>
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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|5-phosphoribosyl 1-pyrophosphate]] (PRPP) to the purine. HGPRT plays a central role in the generation of [[purine]] [[nucleotide]]s through the [[nucleotide salvage|purine salvage pathway]].
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== Function ==
| update_citations = yes
{{enzyme|align=left
}}
| Name = hypoxanthine phosphoribosyltransferase
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
| EC_number = 2.4.2.8
{{GNF_Protein_box
| CAS_number = 9016-12-0
| image = Hypoxanthine-guanine phosphoribosyltransferase 1BZY.png
| IUBMB_EC_number = 2/4/2/8
| image_source = Ribbon diagram of a human HPRT [[tetramer]]. [[Magnesium]] [[ion]]s visible in green. From {{PDB|1BZY}}.
| GO_code = 0004422
| PDB = {{PDB2|1bzy}}, {{PDB2|1d6n}}, {{PDB2|1hmp}}, {{PDB2|1z7g}}
| image =
| Name = Hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)
| width =  
| HGNCid = 5157
| caption =  
| Symbol = HPRT1
| AltSymbols =; HGPRT; HPRT
| OMIM = 308000
| ECnumber = 
| Homologene = 56590
| MGIid = 96217
| GeneAtlas_image1 = PBB_GE_HPRT1_202854_at_tn.png
| Function = {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0004422 |text = hypoxanthine phosphoribosyltransferase activity}} {{GNF_GO|id=GO:0016757 |text = transferase activity, transferring glycosyl groups}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0001975 |text = response to amphetamine}} {{GNF_GO|id=GO:0006164 |text = purine nucleotide biosynthetic process}} {{GNF_GO|id=GO:0006166 |text = purine ribonucleoside salvage}} {{GNF_GO|id=GO:0006168 |text = adenine salvage}} {{GNF_GO|id=GO:0006178 |text = guanine salvage}} {{GNF_GO|id=GO:0007625 |text = grooming behavior}} {{GNF_GO|id=GO:0009116 |text = nucleoside metabolic process}} {{GNF_GO|id=GO:0019835 |text = cytolysis}} {{GNF_GO|id=GO:0021756 |text = striatum development}} {{GNF_GO|id=GO:0021895 |text = cerebral cortex neuron differentiation}} {{GNF_GO|id=GO:0021954 |text = central nervous system neuron development}} {{GNF_GO|id=GO:0042417 |text = dopamine metabolic process}} {{GNF_GO|id=GO:0045964 |text = positive regulation of dopamine metabolic process}} {{GNF_GO|id=GO:0046100 |text = hypoxanthine metabolic process}} {{GNF_GO|id=GO:0046651 |text = lymphocyte proliferation}} {{GNF_GO|id=GO:0048813 |text = dendrite morphogenesis}} {{GNF_GO|id=GO:0051289 |text = protein homotetramerization}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3251
    | Hs_Ensembl = ENSG00000165704
    | Hs_RefseqProtein = NP_000185
    | Hs_RefseqmRNA = NM_000194
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = X
    | Hs_GenLoc_start = 133421849
    | Hs_GenLoc_end = 133462364
    | Hs_Uniprot = P00492
    | Mm_EntrezGene = 15452
    | Mm_Ensembl = ENSMUSG00000025630
    | Mm_RefseqmRNA = NM_013556
    | Mm_RefseqProtein = NP_038584
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = X
    | Mm_GenLoc_start = 49232760
    | Mm_GenLoc_end = 49266287
    | Mm_Uniprot = Q6TDG6
  }}
}}
'''Hypoxanthine-guanine phosphoribosyltransferase''' ('''HPRT'''<ref name=Entrez>{{cite web |url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=3251&rn=1 |title=Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)}}</ref>) is an [[enzyme]] in [[purine metabolism]].<!--
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HGPRT catalyzes the following reactions:


==Functions==
{| class="wikitable" style="text-align: center;"
It 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.
|}


{| class="wikitable"
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 [[Guanosine monophosphate|GMP]], or between [[hypoxanthine]] and [[phosphoribosyl pyrophosphate]] (PRPP) to form [[inosine monophosphate]].
| '''Substrate''' || '''Product''' || '''Notes'''
{{clear left}}
|-
| [[hypoxanthine]] || [[inosine monophosphate]] || -
|-
| [[guanine]] || [[guanine monophosphate]] || often renamed as HGPRT. Only performs this function in some species.
|-
| [[xanthine]] || [[xanthine monophosphate]] || Only certain HPRTs.
|}


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 [[Guanosine monophosphate|GMP]].
== Substrates and inhibitors ==


[[B cells]] contain this enzyme which enables them to survive when fused to [[myeloma]] cells when grown on [[HAT medium]] to produce [[monoclonal antibodies]].
Comparative homology modelling of this enzyme in ''[[L. donovani]]'' suggest that among all of the computationally screened compounds, [[pentamidine]], 1,3-dinitro[[adamantane]], [[acyclovir]] and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).<ref name="pmid22327112">{{cite journal | vauthors = Ansari MY, Dikhit MR, Sahoo GC, Das P | title = Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP | journal = International Journal of Biological Macromolecules | volume = 50 | issue = 3 | pages = 637–49 | date = Apr 2012 | pmid = 22327112 | doi = 10.1016/j.ijbiomac.2012.01.010 }}</ref>
The [[in silico]] and [[in-vitro]] correlation of these compounds were test in [[Leishmania]] HGPRT and validates the result.<ref name="pmid26616453">{{cite journal | vauthors = Ansari MY, Equbal A, Dikhit MR, Mansuri R, Rana S, Ali V, Sahoo GC, Das P | title = Establishment of Correlation between In-Silico &In-Vitro Test Analysis against [[Leishmania]] HGPRT to inhibitors | journal = International Journal of Biological Macromolecules | date = Nov 2015  | pmid = 26616453 | doi = 10.1016/j.ijbiomac.2015.11.051 | volume=83 | pages=78–96}}
</ref>


==Role in disease==
== Role in disease ==
Mutations in the gene lead to [[hyperuricemia]]:
Mutations in the gene lead to [[hyperuricemia]]:
* [[Lesch-Nyhan syndrome]] is due to HPRT mutations.
* 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]].<ref name="pmid9651092">{{cite journal | vauthors = Khattak FH, Morris IM, Harris K | title = Kelley-Seegmiller syndrome: a case report and review of the literature | journal = British Journal of Rheumatology | volume = 37 | issue = 5 | pages = 580–1 | date = May 1998 | pmid = 9651092 | doi = 10.1093/rheumatology/37.5.580c }}</ref>
* Some mutations have been linked to [[gout]], the risk of which is increased in hyperuricemia.
* [[Lesch-Nyhan syndrome]] is due to deficiency of HGPRT caused by HPRT1 mutation <ref name="pmid18779430">{{cite journal | vauthors = Hladnik U, Nyhan WL, Bertelli M | title = Variable expression of HPRT deficiency in 5 members of a family with the same mutation | journal = Archives of Neurology | volume = 65 | issue = 9 | pages = 1240–3 | date = Sep 2008 | pmid = 18779430 | doi = 10.1001/archneur.65.9.1240 }}</ref>
* 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]].<ref name="pmid25681585">{{cite journal | vauthors = Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, Wright G | title = HIF-1α in the heart: Remodeling nucleotide metabolism | journal = Journal of Molecular and Cellular Cardiology | date = Feb 2015 | pmid = 25681585 | doi = 10.1016/j.yjmcc.2015.01.014 | volume=82 | pages=194–200 | pmc=4405794}}</ref>
 
== Creation of hybridomas ==


==See also==
[[Hybridoma]]s are immortal (immune to [[cellular senescence]]), HGPRT<sup>+</sup> cells that result from fusion of mortal, HGPRT<sup>+</sup> [[plasma cells]] and immortal, HGPRT<sup>−</sup> [[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 HRPT1. The plasma cells in the culture eventually die from senesence, leaving pure hybridoma cells.
 
== See also ==
* [[Nucleotide salvage]]
* [[Nucleotide salvage]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Sculley DG, Dawson PA, Emmerson BT, Gordon RB | title = A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency | journal = Human Genetics | volume = 90 | issue = 3 | pages = 195–207 | date = Nov 1992 | pmid = 1487231 | doi = 10.1007/bf00220062 }}
| citations =
* {{cite journal | vauthors = Ansari MY, Dikhit MR, Sahoo GC, Das P | title = Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP | journal = International Journal of Biological Macromolecules | volume = 50 | issue = 3 | pages = 637–49 | date = Apr 2012 | pmid = 22327112 | doi = 10.1016/j.ijbiomac.2012.01.010 }}
*{{cite journal | author=Sculley DG, Dawson PA, Emmerson BT, Gordon RB |title=A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. |journal=Hum. Genet. |volume=90 |issue= 3 |pages= 195-207 |year= 1993 |pmid= 1487231 |doi= }}
* {{cite journal | vauthors = Davidson BL, Tarlé SA, Van Antwerp M, Gibbs DA, Watts RW, Kelley WN, Palella TD | title = Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency | journal = American Journal of Human Genetics | volume = 48 | issue = 5 | pages = 951–8 | date = May 1991 | pmid = 2018042 | pmc = 1683055 }}
*{{cite journal | author=Davidson BL, Tarlé SA, Van Antwerp M, ''et al.'' |title=Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. |journal=Am. J. Hum. Genet. |volume=48 |issue= 5 |pages= 951-8 |year= 1991 |pmid= 2018042 |doi= }}
* {{cite journal | vauthors = Stout JT, Caskey CT | title = HPRT: gene structure, expression, and mutation | journal = Annual Review of Genetics | volume = 19 | pages = 127–48 | date = 1986 | pmid = 3909940 | doi = 10.1146/annurev.ge.19.120185.001015 }}
*{{cite journal | author=Stout JT, Caskey CT |title=HPRT: gene structure, expression, and mutation. |journal=Annu. Rev. Genet. |volume=19 |issue=  |pages= 127-48 |year= 1986 |pmid= 3909940 |doi= 10.1146/annurev.ge.19.120185.001015 }}
* {{cite journal | vauthors = Sege-Peterson K, Chambers J, Page T, Jones OW, Nyhan WL | title = Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency | journal = Human Molecular Genetics | volume = 1 | issue = 6 | pages = 427–32 | date = Sep 1992 | pmid = 1301916 | doi = 10.1093/hmg/1.6.427 }}
*{{cite journal | author=Sege-Peterson K, Chambers J, Page T, ''et al.'' |title=Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency. |journal=Hum. Mol. Genet. |volume=1 |issue= 6 |pages= 427-32 |year= 1993 |pmid= 1301916 |doi= }}
* {{cite journal | vauthors = Lightfoot T, Joshi R, Nuki G, Snyder FF | title = The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction | journal = Human Genetics | volume = 88 | issue = 6 | pages = 695–6 | date = Mar 1992 | pmid = 1551676 | doi = 10.1007/BF02265300 }}
*{{cite journal | author=Lightfoot T, Joshi R, Nuki G, Snyder FF |title=The point mutation of hypoxanthine-guanine phosphoribosyltransferase (HPRTEdinburgh) and detection by allele-specific polymerase chain reaction. |journal=Hum. Genet. |volume=88 |issue= 6 |pages= 695-6 |year= 1992 |pmid= 1551676 |doi= 10.1007/BF02265300}}
* {{cite journal | vauthors = Yamada Y, Goto H, Ogasawara N | title = Identification of two independent Japanese mutant HPRT genes using the PCR technique | journal = Advances in Experimental Medicine and Biology | volume = 309B | pages = 121–4 | date = 1992 | pmid = 1840476 | doi = 10.1007/978-1-4615-7703-4_27 | isbn = 978-1-4615-7705-8 | series = Advances in Experimental Medicine and Biology }}
*{{cite journal | author=Yamada Y, Goto H, Ogasawara N |title=Identification of two independent Japanese mutant HPRT genes using the PCR technique. |journal=Adv. Exp. Med. Biol. |volume=309B |issue=  |pages= 121-4 |year= 1992 |pmid= 1840476 |doi= }}
* {{cite journal | vauthors = Sculley DG, Dawson PA, Beacham IR, Emmerson BT, Gordon RB | title = Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification | journal = Human Genetics | volume = 87 | issue = 6 | pages = 688–92 | date = Oct 1991 | pmid = 1937471 | doi = 10.1007/BF00201727 }}
*{{cite journal | author=Sculley DG, Dawson PA, Beacham IR, ''et al.'' |title=Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification. |journal=Hum. Genet. |volume=87 |issue= 6 |pages= 688-92 |year= 1991 |pmid= 1937471 |doi= 10.1007/BF00201727}}
* {{cite journal | vauthors = Tarlé SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD | title = Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects | journal = Genomics | volume = 10 | issue = 2 | pages = 499–501 | date = Jun 1991 | pmid = 2071157 | doi = 10.1016/0888-7543(91)90341-B }}
*{{cite journal | author=Tarlé SA, Davidson BL, Wu VC, ''et al.'' |title=Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects. |journal=Genomics |volume=10 |issue= 2 |pages= 499-501 |year= 1991 |pmid= 2071157 |doi= 10.1016/0888-7543(91)90341-B}}
* {{cite journal | vauthors = Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT | title = Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE) | journal = Journal of Inherited Metabolic Disease | volume = 13 | issue = 5 | pages = 692–700 | date = 1991 | pmid = 2246854 | doi = 10.1007/BF01799570 }}
*{{cite journal | author=Gordon RB, Sculley DG, Dawson PA, ''et al.'' |title=Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE). |journal=J. Inherit. Metab. Dis. |volume=13 |issue= 5 |pages= 692-700 |year= 1991 |pmid= 2246854 |doi= }}
* {{cite journal | vauthors = Edwards A, Voss H, Rice P, Civitello A, Stegemann J, Schwager C, Zimmermann J, Erfle H, Caskey CT, Ansorge W | title = Automated DNA sequencing of the human HPRT locus | journal = Genomics | volume = 6 | issue = 4 | pages = 593–608 | date = Apr 1990 | pmid = 2341149 | doi = 10.1016/0888-7543(90)90493-E }}
*{{cite journal | author=Edwards A, Voss H, Rice P, ''et al.'' |title=Automated DNA sequencing of the human HPRT locus. |journal=Genomics |volume=6 |issue= 4 |pages= 593-608 |year= 1990 |pmid= 2341149 |doi= 10.1016/0888-7543(90)90493-E}}
* {{cite journal | vauthors = Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT | title = Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families | journal = Genomics | volume = 7 | issue = 2 | pages = 235–44 | date = Jun 1990 | pmid = 2347587 | doi = 10.1016/0888-7543(90)90545-6 }}
*{{cite journal | author=Gibbs RA, Nguyen PN, Edwards A, ''et al.'' |title=Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. |journal=Genomics |volume=7 |issue= 2 |pages= 235-44 |year= 1990 |pmid= 2347587 |doi= 10.1016/0888-7543(90)90545-6}}
* {{cite journal | vauthors = Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ | title = Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures | journal = Human Genetics | volume = 85 | issue = 1 | pages = 111–6 | date = Jun 1990 | pmid = 2358296 | doi = 10.1007/BF00276334 }}
*{{cite journal | author=Skopek TR, Recio L, Simpson D, ''et al.'' |title=Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures. |journal=Hum. Genet. |volume=85 |issue= 1 |pages= 111-6 |year= 1990 |pmid= 2358296 |doi= 10.1007/BF00276334}}
* {{cite journal | vauthors = Davidson BL, Tarlé SA, Palella TD, Kelley WN | title = Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts | journal = The Journal of Clinical Investigation | volume = 84 | issue = 1 | pages = 342–6 | date = Jul 1989 | pmid = 2738157 | pmc = 303988 | doi = 10.1172/JCI114160 }}
*{{cite journal | author=Davidson BL, Tarlé SA, Palella TD, Kelley WN |title=Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts. |journal=J. Clin. Invest. |volume=84 |issue= 1 |pages= 342-6 |year= 1989 |pmid= 2738157 |doi= 10.1172/JCI114160}}
* {{cite journal | vauthors = Ogasawara N, Stout JT, Goto H, Sonta S, Matsumoto A, Caskey CT | title = Molecular analysis of a female Lesch-Nyhan patient | journal = The Journal of Clinical Investigation | volume = 84 | issue = 3 | pages = 1024–7 | date = Sep 1989 | pmid = 2760209 | pmc = 329751 | doi = 10.1172/JCI114224 }}
*{{cite journal | author=Ogasawara N, Stout JT, Goto H, ''et al.'' |title=Molecular analysis of a female Lesch-Nyhan patient. |journal=J. Clin. Invest. |volume=84 |issue= 3 |pages= 1024-7 |year= 1989 |pmid= 2760209 |doi= 10.1172/JCI114224}}
* {{cite journal | vauthors = Yang TP, Stout JT, Konecki DS, Patel PI, Alford RL, Caskey CT | title = Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement | journal = Somatic Cell and Molecular Genetics | volume = 14 | issue = 3 | pages = 293–303 | date = May 1988 | pmid = 2835825 | doi = 10.1007/BF01534590 }}
*{{cite journal | author=Yang TP, Stout JT, Konecki DS, ''et al.'' |title=Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement. |journal=Somat. Cell Mol. Genet. |volume=14 |issue= 3 |pages= 293-303 |year= 1988 |pmid= 2835825 |doi= 10.1007/BF01534590}}
* {{cite journal | vauthors = Fujimori S, Hidaka Y, Davidson BL, Palella TD, Kelley WN | title = Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor) | journal = Human Genetics | volume = 79 | issue = 1 | pages = 39–43 | date = May 1988 | pmid = 2896620 | doi = 10.1007/BF00291707 }}
*{{cite journal | author=Fujimori S, Hidaka Y, Davidson BL, ''et al.'' |title=Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor). |journal=Hum. Genet. |volume=79 |issue= 1 |pages= 39-43 |year= 1988 |pmid= 2896620 |doi= 10.1007/BF00291707}}
* {{cite journal | vauthors = Davidson BL, Pashmforoush M, Kelley WN, Palella TD | title = Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville) | journal = The Journal of Biological Chemistry | volume = 264 | issue = 1 | pages = 520–5 | date = Jan 1989 | pmid = 2909537 }}
*{{cite journal | author=Davidson BL, Pashmforoush M, Kelley WN, Palella TD |title=Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville). |journal=J. Biol. Chem. |volume=264 |issue= 1 |pages= 520-5 |year= 1989 |pmid= 2909537 |doi=  }}
* {{cite journal | vauthors = Fujimori S, Davidson BL, Kelley WN, Palella TD | title = Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome | journal = The Journal of Clinical Investigation | volume = 83 | issue = 1 | pages = 11–3 | date = Jan 1989 | pmid = 2910902 | pmc = 303636 | doi = 10.1172/JCI113846 }}
*{{cite journal | author=Fujimori S, Davidson BL, Kelley WN, Palella TD |title=Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome. |journal=J. Clin. Invest. |volume=83 |issue= 1 |pages= 11-3 |year= 1989 |pmid= 2910902 |doi= 10.1172/JCI113846}}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Hypoxanthine+phosphoribosyltransferase}}
* [http://www.genome.jp/kegg/pathway/map/map00230.html Purine metabolism at genome.jp]
* [http://www.genome.jp/kegg/pathway/map/map00230.html Purine metabolism at genome.jp]
* {{MeshName|Hypoxanthine+phosphoribosyltransferase}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lns  GeneReviews/NCBI/NIH/UW entry on Lesch-Nyhan Syndrome]


{{PDB Gallery|geneid=3251}}
{{Nucleotide metabolism}}
{{Glycosyltransferases}}
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{{Nucleotide metabolism}}
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[[Category:EC 2.4.2]]
[[Category:EC 2.4.2]]
{{transferase-stub}}
[[pl:Fosforybozylotransferaza hipoksantynowo-guaninowa]]
[[ja:ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼ]]
{{WikiDoc Sources}}

Revision as of 19:58, 7 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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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
Identifiers
EC number2.4.2.8
CAS number9016-12-0
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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:

  • 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.[5]
  • Lesch-Nyhan syndrome is due to deficiency of HGPRT caused by HPRT1 mutation [6]
  • 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.[7]

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 HRPT1. The plasma cells in the culture eventually die from senesence, leaving pure hybridoma cells.

See also

References

  1. ↑ "Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)".
  2. ↑ Finette BA, Kendall H, Vacek PM (Aug 2002). "Mutational spectral analysis at the HPRT locus in healthy children". Mutation Research. 505 (1–2): 27–41. doi:10.1016/S0027-5107(02)00119-7. PMID 12175903.
  3. ↑ 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. doi:10.1016/j.ijbiomac.2012.01.010. PMID 22327112.
  4. ↑ Ansari MY, Equbal A, Dikhit MR, Mansuri R, Rana S, Ali V, Sahoo GC, Das P (Nov 2015). "Establishment of Correlation between In-Silico &In-Vitro Test Analysis against Leishmania HGPRT to inhibitors". International Journal of Biological Macromolecules. 83: 78–96. doi:10.1016/j.ijbiomac.2015.11.051. PMID 26616453.
  5. ↑ Khattak FH, Morris IM, Harris K (May 1998). "Kelley-Seegmiller syndrome: a case report and review of the literature". British Journal of Rheumatology. 37 (5): 580–1. doi:10.1093/rheumatology/37.5.580c. PMID 9651092.
  6. ↑ Hladnik U, Nyhan WL, Bertelli M (Sep 2008). "Variable expression of HPRT deficiency in 5 members of a family with the same mutation". Archives of Neurology. 65 (9): 1240–3. doi:10.1001/archneur.65.9.1240. PMID 18779430.
  7. ↑ Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, Wright G (Feb 2015). "HIF-1α in the heart: Remodeling nucleotide metabolism". Journal of Molecular and Cellular Cardiology. 82: 194–200. doi:10.1016/j.yjmcc.2015.01.014. PMC 4405794. PMID 25681585.

Further reading

External links

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