| Structural highlights
Disease
HPRT_HUMAN Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:300322. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:300323; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.[11] [12] [13] [14] [15] [16] [:]
Function
HPRT_HUMAN Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Publication Abstract from PubMed
Pathogens such as Plasmodium and Trypanosoma spp. are unable to synthesize purine nucleobases. They rely on the salvage of these purines and their nucleosides from the host cell to synthesize the purine nucleotides required for DNA/RNA production. The key enzymes in this pathway are purine phosphoribosyltransferases (PRTs). Here, we synthesized 16 novel acyclic nucleoside phosphonates, 12 with a chiral center at C-2', and eight bearing a second chiral center at C-6'. Of these, bisphosphonate (S,S)-48 is the most potent inhibitor of the Plasmodium falciparum and P. vivax 6-oxopurine PRTs and the most potent inhibitor of two Trypanosoma brucei (Tbr) 6-oxopurine PRTs yet discovered, with Ki values as low as 2 nM. Crystal structures of (S,S)-48 in complex with human and Tbr 6-oxopurine PRTs show that the inhibitor binds to the enzymes in different conformations, providing an explanation for its potency and selectivity (i.e., 35-fold in favor of the parasite enzymes).
Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases.,Klejch T, Keough DT, King G, Dolezelova E, Cesnek M, Budesinsky M, Zikova A, Janeba Z, Guddat LW, Hockova D J Med Chem. 2022 Feb 17. doi: 10.1021/acs.jmedchem.1c01881. PMID:35175749[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wilson JM, Kelley WN. Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome. J Clin Invest. 1983 May;71(5):1331-5. PMID:6853716
- ↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Genetic basis of hypoxanthine guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome (HPRTFlint). Gene. 1988 Mar 31;63(2):331-6. PMID:3384338
- ↑ Davidson BL, Palella TD, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase: a single nucleotide substitution in cDNA clones isolated from a patient with Lesch-Nyhan syndrome (HPRTMidland). Gene. 1988 Aug 15;68(1):85-91. PMID:3265398
- ↑ Fujimori S, Davidson BL, Kelley WN, Palella TD. Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome. J Clin Invest. 1989 Jan;83(1):11-3. PMID:2910902 doi:http://dx.doi.org/10.1172/JCI113846
- ↑ Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT. Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics. 1990 Jun;7(2):235-44. PMID:2347587
- ↑ Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ. Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures. Hum Genet. 1990 Jun;85(1):111-6. PMID:2358296
- ↑ Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT. 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. 1990;13(5):692-700. PMID:2246854
- ↑ Tarle SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD. Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects. Genomics. 1991 Jun;10(2):499-501. PMID:2071157
- ↑ Burgemeister R, Rotzer E, Gutensohn W, Gehrke M, Schiel W. Identification of a new missense mutation in exon 2 of the human hypoxanthine phosphoribosyltransferase gene (HPRTIsar): a further example of clinical heterogeneity in HPRT deficiencies. Hum Mutat. 1995;5(4):341-4. PMID:7627191 doi:http://dx.doi.org/10.1002/humu.1380050413
- ↑ Liu G, Aral B, Zabot MT, Kamoun P, Ceballos-Picot I. The molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in French families; report of two novel mutations. Hum Mutat. 1998;Suppl 1:S88-90. PMID:9452051
- ↑ Wilson JM, Kobayashi R, Fox IH, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1983 May 25;258(10):6458-60. PMID:6853490
- ↑ Wilson JM, Tarr GE, Kelley WN. Human hypoxanthine (guanine) phosphoribosyltransferase: an amino acid substitution in a mutant form of the enzyme isolated from a patient with gout. Proc Natl Acad Sci U S A. 1983 Feb;80(3):870-3. PMID:6572373
- ↑ Wilson JM, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. Structural alteration in a dysfunctional enzyme variant (HPRTMunich) isolated from a patient with gout. J Biol Chem. 1984 Jan 10;259(1):27-30. PMID:6706936
- ↑ Cariello NF, Scott JK, Kat AG, Thilly WG, Keohavong P. Resolution of a missense mutant in human genomic DNA by denaturing gradient gel electrophoresis and direct sequencing using in vitro DNA amplification: HPRT Munich. Am J Hum Genet. 1988 May;42(5):726-34. PMID:3358423
- ↑ Davidson BL, Chin SJ, Wilson JM, Kelley WN, Palella TD. Hypoxanthine-guanine phosphoribosyltransferase. Genetic evidence for identical mutations in two partially deficient subjects. J Clin Invest. 1988 Dec;82(6):2164-7. PMID:3198771 doi:http://dx.doi.org/10.1172/JCI113839
- ↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville). J Biol Chem. 1989 Jan 5;264(1):520-5. PMID:2909537
- ↑ Klejch T, Keough DT, King G, Dolezelova E, Cesnek M, Budesinsky M, Zikova A, Janeba Z, Guddat LW, Hockova D. Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases. J Med Chem. 2022 Feb 17. doi: 10.1021/acs.jmedchem.1c01881. PMID:35175749 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01881
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