Hypoxanthine-guanine phosphoribosyltransferase

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

hypoxanthine phosphoribosyltransferase
Identifiers
AliasesHPRTinosinic pyrophosphorylaseinosinate pyrophosphorylaseinosinic acid pyrophosphorylaseinosine 5'-phosphate pyrophosphorylaseIMP:diphosphate phospho-D-ribosyltransferaseHGPRTaseIMP diphosphorylaseIMP pyrophosphorylaseIMP-GMP pyrophosphorylase
External IDsGeneCards:
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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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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:

SubstrateProductNotes
hypoxanthineinosine monophosphate—
guanineguanosine monophosphateOften called HGPRT. Performs this function only in some species.
xanthinexanthosine monophosphateOnly 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 HPRT1. The plasma cells in the culture eventually die from senescence, leaving pure hybridoma cells.

gollark: * syscalls and whatever
gollark: So I should work out some way to live-patch the kernel to increase the amount of signal-safe functions?
gollark: ```c#include <stdio.h>#include <signal.h>#include <string.h>#include <stdlib.h>#include <sys/mman.h>#include <unistd.h>static void handler(int sig, siginfo_t *info, void *literally_bee) { printf("oh bee oh apio segfault %08x\n", info->si_addr); int ps = getpagesize(); long ad = (long)info->si_addr; ad = ad - (ad % ps); mmap((void*)ad, 0x10000, PROT_NONE, MAP_ANONYMOUS|MAP_FIXED, -1, 0);}int main() { struct sigaction sa; sigemptyset(&sa.sa_mask); sa.sa_flags = SA_NODEFER; sa.sa_sigaction = handler; sigaction(SIGSEGV, &sa, NULL); *(int*)NULL = -3; printf("thing done\n"); return 0;}```
gollark: Unfortunately, mmap appears to be uncooperative.
gollark: I wanted to implement coral's `idea: trap segfaults and mmap data at the erroring position`.

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
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