Hypoxanthine-guanine phosphoribosyltransferase

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Hypoxanthine phosphoribosyltransferase 1

Ribbon diagram of a human HPRT tetramer. Magnesium ions visible in green. From PDB 1BZY.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HPRT1 ; HGPRT; HPRT
External IDs OMIM308000 MGI96217 HomoloGene56590 ChEMBL: 2360 GeneCards: HPRT1 Gene
EC number 2.4.2.8
RNA expression pattern
PBB GE HPRT1 202854 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3251 15452
Ensembl ENSG00000165704 ENSMUSG00000025630
UniProt P00492 P00493
RefSeq (mRNA) NM_000194 NM_013556
RefSeq (protein) NP_000185 NP_038584
Location (UCSC) Chr X:
133.59 – 133.65 Mb
Chr X:
52.99 – 53.02 Mb
PubMed search [1] [2]

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[edit]

hypoxanthine phosphoribosyltransferase
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 / EGO

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, catalyzes in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP.

Substrates and inhibitors[edit]

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]

Role in disease[edit]

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.[4]
  • Lesch-Nyhan syndrome is due to HPRT mutationstivity.members[5]
  • Some mutations have been linked to gout, the risk of which is increased in hy.

Application to hybridomas[edit]

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 (hybridoma cell) can be cloned to produce many identical daughter clones. These daughter clones subsequently secrete the monoclonal antibody product.

See also[edit]

References[edit]

  1. ^ "Entrez Gene: hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)". 
  2. ^ Finette BA, Kendall H, Vacek PM (August 2002). "Mutational spectral analysis at the HPRT locus in healthy children". Mutat. Res. 505 (1–2): 27–41. doi:10.1016/S0027-5107(02)00119-7. PMID 12175903. 
  3. ^ Ansari MY, Dikhit MR, Sahoo GC, Das P (April 2012). "Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP". Int. J. Biol. Macromol. 50 (3): 637–49. doi:10.1016/j.ijbiomac.2012.01.010. PMID 22327112. 
  4. ^ Khattak FH, Morris IM, Harris K (May 1998). "Kelley-Seegmiller syndrome: a case report and review of the literature". Br. J. Rheumatol. 37 (5): 580–1. doi:10.1093/rheumatology/37.5.580c. PMID 9651092. 
  5. ^ Hladnik U, Nyhan WL, Bertelli M (September 2008). "Variable expression of HPRT deficiency in 5 members a family with the same mutation". Arch. Neurol. 65 (9): 1240–3. doi:10.1001/archneur.65.9.1240. PMID 18779430. 

Further reading[edit]

External links[edit]