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Literature summary extracted from

  • Keough, D.T.; Hockova, D.; Holy, A.; Naesens, L.M.; Skinner-Adams, T.S.; Jersey, J.; Guddat, L.W.
    Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics (2009), J. Med. Chem., 52, 4391-4399.
    View publication on PubMed

Application

EC Number Application Comment Organism
2.4.2.8 drug development the enzyme is a target for antimalarial inhibitor design and development Plasmodium falciparum

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.4.2.8 enzyme in complex with 2-(phosphonoethoxy)ethyl guanine, 2-(phosphonoethoxy)ethyl hypoxanthine, and (R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine, hanging drop vapor diffusion method, mixing of equal volumes of well solution, containing 0.1 M citrate pH 5.5, 10% isopropyl alcohol and 29% PEG 4000, and protein inhibitor complex with 17 mg/ml prtoein, and 3.3 mM for 2-(phosphonoethoxy)ethyl guanine, 3.9 mM (R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine, and 3.0 mM for 2-(phosphonoethoxy)ethyl hypoxanthine, X-ray diffraction structure determination and analysis at 2.6-2.78 A resolution Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
2.4.2.8 C22A/C105A/C205A site-directed mutagenesis, the exchanges stabilize the enzyme protein, but kinetic and structural properties of the mutant enzyme are identical to wild-type human HGPRT Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.4.2.8 (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate
-
 Homo sapiens
2.4.2.8 (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate
-
 Plasmodium falciparum
2.4.2.8 (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate
-
 Homo sapiens
2.4.2.8 (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate
-
 Plasmodium falciparum
2.4.2.8 (R)-9-[2-(phosphonomethoxy)propyl]hypoxanthine
-
 Plasmodium falciparum
2.4.2.8 (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine
-
 Homo sapiens
2.4.2.8 (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine
-
 Plasmodium falciparum
2.4.2.8 (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Homo sapiens
2.4.2.8 (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Plasmodium falciparum
2.4.2.8 (S)-9-[2-(phosphonomethoxy)propyl]guanine
-
 Homo sapiens
2.4.2.8 (S)-9-[2-(phosphonomethoxy)propyl]guanine
-
 Plasmodium falciparum
2.4.2.8 (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine
-
 Homo sapiens
2.4.2.8 (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine
-
 Plasmodium falciparum
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-azaguanine
-
 Homo sapiens
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-azaguanine
-
 Plasmodium falciparum
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine
-
 Homo sapiens
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine
-
 Plasmodium falciparum
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Homo sapiens
2.4.2.8 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Plasmodium falciparum
2.4.2.8 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate
-
 Homo sapiens
2.4.2.8 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate
-
 Plasmodium falciparum
2.4.2.8 9-[2-(2-phosphonoethoxy)ethyl]guanine
-
 Homo sapiens
2.4.2.8 9-[2-(2-phosphonoethoxy)ethyl]guanine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine
-
 Homo sapiens
2.4.2.8 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine
-
 Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]guanine is toxic to cells and arrests cell growth Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethyl]guanine is toxic to cells and arrests cell growth Plasmodium falciparum
2.4.2.8 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine
-
 Homo sapiens
2.4.2.8 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine
-
 Plasmodium falciparum
2.4.2.8 acyclic nucleoside phosphonates analogues of the nucleotide reaction product, comprising a purine base joined by a linker to a phosphonate moiety, inhibitor design and potencies, overview. The inhibitors are selectivity for the enzyme of the human parasite Plasmodium falciparum, up to factor 58, compared to the human enzyme, overview Homo sapiens
2.4.2.8 acyclic nucleoside phosphonates analogues of the nucleotide reaction product, comprising a purine base joined by a linker to a phosphonate moiety, inhibitor design and potencies, overview. Selectivity for the parasite enzyme of up to 58 compared to the Homo sapiens enzyme, overview, design of potent and selective acyclic nucleoside phosphonates inhibitors of Plasmodium falciparum HGXPRT as antimalarial drug leads Plasmodium falciparum
2.4.2.8 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Homo sapiens
2.4.2.8 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Plasmodium falciparum
2.4.2.8 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Homo sapiens
2.4.2.8 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine is toxic to cells and arrests cell growth Plasmodium falciparum
2.4.2.8 guanine ribose 5'-phosphate
-
 Homo sapiens
2.4.2.8 guanine ribose 5'-phosphate
-
 Plasmodium falciparum
2.4.2.8 hypoxanthine ribose 5'-phosphate
-
 Homo sapiens
2.4.2.8 hypoxanthine ribose 5'-phosphate
-
 Plasmodium falciparum
2.4.2.8 additional information cytotoxicity studies using human lung carcinoma A549 cells at 37°C. The binding site for the 5'-phosphate is located at residues 132-141. No inhibition by (R)-9-[2-(phosphonomethoxy)propyl]hypoxanthine Homo sapiens
2.4.2.8 propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate
-
 Homo sapiens
2.4.2.8 propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate
-
 Plasmodium falciparum

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.4.2.8 Mg2+ a divalent cation is required for activity Plasmodium falciparum
2.4.2.8 Mg2+ a divalent cation is required for activity Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.4.2.8 guanine + 5-phospho-alpha-D-ribose 1-diphosphate Plasmodium falciparum
-
 GMP + diphosphate
-
 ?
2.4.2.8 guanine + 5-phospho-alpha-D-ribose 1-diphosphate Homo sapiens
-
 GMP + diphosphate
-
 ?
2.4.2.8 hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate Plasmodium falciparum
-
 IMP + diphosphate
-
 ?
2.4.2.8 hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate Homo sapiens
-
 IMP + diphosphate
-
 ?
2.4.2.8 xanthine + 5-phospho-alpha-D-ribose 1-diphosphate Plasmodium falciparum
-
 ? + diphosphate
-
 ?
2.4.2.8 xanthine + 5-phospho-alpha-D-ribose 1-diphosphate Homo sapiens
-
 ? + diphosphate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.4.2.8 Homo sapiens P00492
-
-
2.4.2.8 Plasmodium falciparum
-
-
-

Reaction

EC Number Reaction Comment Organism Reaction ID
2.4.2.8 IMP + diphosphate = hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate ordered reaction mechanism, 5-phospho-alpha-D-ribose 1-diphosphate-Mg2+ binds first followed by the purine base. After the covalent reaction, diphosphate then dissociates from the complex and the nucleoside monophosphate is released in the rate-limiting step Homo sapiens
a

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.4.2.8 guanine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Plasmodium falciparum GMP + diphosphate
-
 ?
2.4.2.8 guanine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Homo sapiens GMP + diphosphate
-
 ?
2.4.2.8 hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Plasmodium falciparum IMP + diphosphate
-
 ?
2.4.2.8 hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Homo sapiens IMP + diphosphate
-
 ?
2.4.2.8 additional information the binding site for the 5'-phosphate is located at residues 132-141 Plasmodium falciparum ?
-
 ?
2.4.2.8 additional information the binding site for the 5'-phosphate is located at residues 132-141 Homo sapiens ?
-
 ?
2.4.2.8 xanthine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Plasmodium falciparum ? + diphosphate
-
 ?
2.4.2.8 xanthine + 5-phospho-alpha-D-ribose 1-diphosphate
-
 Homo sapiens ? + diphosphate
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.4.2.8 HGXPRT
-
 Plasmodium falciparum
2.4.2.8 HGXPRT
-
 Homo sapiens
2.4.2.8 hypoxanthine-guanine phosphoribosyltransferase
-
 Plasmodium falciparum
2.4.2.8 hypoxanthine-guanine phosphoribosyltransferase
-
 Homo sapiens
2.4.2.8 hypoxanthine-guanine-xanthine phosphoribosyltransferase
-
 Plasmodium falciparum
2.4.2.8 hypoxanthine-guanine-xanthine phosphoribosyltransferase
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.4.2.8 25
-
 assay at Plasmodium falciparum
2.4.2.8 25
-
 assay at Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.4.2.8 8.5
-
-
 Plasmodium falciparum
2.4.2.8 8.5
-
-
 Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
2.4.2.8 0.0001
-
 9-[2-(2-phosphonoethoxy)ethyl]guanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0003
-
 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0006
-
 (R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.001
-
 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.001
-
 9-[2-(2-phosphonoethoxy)ethyl]guanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0012
-
 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0014
-
 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.0016
-
 9-[2-(phosphonomethoxy)ethyl]guanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.003
-
 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0036
-
 hypoxanthine ribose 5'-phosphate pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0036
-
 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0036
-
 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.0043
-
 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0054
-
 hypoxanthine ribose 5'-phosphate pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0058
-
 guanine ribose 5'-phosphate pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0059
-
 (R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0072
-
 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.008
-
 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.01
-
 guanine ribose 5'-phosphate pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.01
-
 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.011
-
 (S)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0123
-
 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.015
-
 (S)-9-[2-(phosphonomethoxy)propyl]-8-azaguanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0189
-
 9-[2-(phosphonomethoxy)ethyl]guanine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.019
-
 cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.02
-
 (R)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0227
-
 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.0284
-
 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.029
-
 9-[2-(phosphonomethoxy)ethyl]guanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.0377
-
 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.041
-
 (R)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.045
-
 (S)-9-[2-(phosphonomethoxy)propyl]-8-azaguanine above, pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.0559
-
 9-[2-(phosphonomethoxy)ethyl]guanine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.0648
-
 (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.068
-
 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.09
-
 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.1
-
 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine above, pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.1151
-
 cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.14
-
 propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate pH 7.4, 25°C Homo sapiens
2.4.2.8 0.175
-
 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine pH 7.4, 25°C Homo sapiens
2.4.2.8 0.1768
-
 (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.1823
-
 (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine pH 8.5, 25°C Homo sapiens
2.4.2.8 0.2
-
 propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate above, pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 0.3
-
 (S)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine above, pH 7.4, 25°C Homo sapiens
2.4.2.8 0.4
-
 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine above, pH 7.4, 25°C Homo sapiens
2.4.2.8 0.4373
-
 (R)-9-[2-(phosphonomethoxy)propyl]hypoxanthine pH 8.5, 25°C Plasmodium falciparum
2.4.2.8 0.5
-
 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate above, pH 7.4, 25°C Plasmodium falciparum
2.4.2.8 1
-
 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine above, pH 7.4, 25°C Homo sapiens
2.4.2.8 1
-
 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate above, pH 7.4, 25°C Homo sapiens

General Information

EC Number General Information Comment Organism
2.4.2.8 physiological function the purine salvage enzyme HGXPRT is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite Plasmodium falciparum