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Literature summary for 2.4.2.8 extracted from
- Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics (2009), J. Med. Chem., 52, 4391-4399.
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | the enzyme is a target for antimalarial inhibitor design and development | Plasmodium falciparum |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| 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
| Protein Variants | Comment | Organism |
|---|---|---|
| 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
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate | - |
Homo sapiens |  |
| (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate | - |
Plasmodium falciparum | |
| (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate | - |
Homo sapiens | |
| (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate | - |
Plasmodium falciparum | |
| (R)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | - |
Plasmodium falciparum | |
| (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine | - |
Homo sapiens | |
| (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine | - |
Plasmodium falciparum | |
| (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Homo sapiens | |
| (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Plasmodium falciparum | |
| (S)-9-[2-(phosphonomethoxy)propyl]guanine | - |
Homo sapiens | |
| (S)-9-[2-(phosphonomethoxy)propyl]guanine | - |
Plasmodium falciparum | |
| (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | - |
Homo sapiens | |
| (S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | - |
Plasmodium falciparum | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-azaguanine | - |
Homo sapiens | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-azaguanine | - |
Plasmodium falciparum | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine | - |
Homo sapiens | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-8-bromoguanine | - |
Plasmodium falciparum | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Homo sapiens | |
| (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Plasmodium falciparum | |
| 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate | - |
Homo sapiens | |
| 6-methylheptyl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate | - |
Plasmodium falciparum | |
| 9-[2-(2-phosphonoethoxy)ethyl]guanine | - |
Homo sapiens | |
| 9-[2-(2-phosphonoethoxy)ethyl]guanine | - |
Plasmodium falciparum | |
| 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine | - |
Homo sapiens | |
| 9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethyl]-6-thioguanine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethyl]-8-azaguanine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine | - |
Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethyl]guanine | is toxic to cells and arrests cell growth | Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethyl]guanine | is toxic to cells and arrests cell growth | Plasmodium falciparum | |
| 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine | - |
Homo sapiens | |
| 9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine | - |
Plasmodium falciparum | |
| 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 | |
| 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 | |
| cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Homo sapiens | |
| cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Plasmodium falciparum | |
| cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Homo sapiens | |
| cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | is toxic to cells and arrests cell growth | Plasmodium falciparum | |
| guanine ribose 5'-phosphate | - |
Homo sapiens | |
| guanine ribose 5'-phosphate | - |
Plasmodium falciparum | |
| hypoxanthine ribose 5'-phosphate | - |
Homo sapiens | |
| hypoxanthine ribose 5'-phosphate | - |
Plasmodium falciparum | |
| 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 | |
| propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate | - |
Homo sapiens | |
| propan-2-yl hydrogen {[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy]methyl}phosphonate | - |
Plasmodium falciparum | |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | a divalent cation is required for activity | Plasmodium falciparum | |
| Mg2+ | a divalent cation is required for activity | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| guanine + 5-phospho-alpha-D-ribose 1-diphosphate | Plasmodium falciparum | - |
GMP + diphosphate | - |
? | |
| guanine + 5-phospho-alpha-D-ribose 1-diphosphate | Homo sapiens | - |
GMP + diphosphate | - |
? | |
| hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate | Plasmodium falciparum | - |
IMP + diphosphate | - |
? | |
| hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate | Homo sapiens | - |
IMP + diphosphate | - |
? | |
| xanthine + 5-phospho-alpha-D-ribose 1-diphosphate | Plasmodium falciparum | - |
? + diphosphate | - |
? | |
| xanthine + 5-phospho-alpha-D-ribose 1-diphosphate | Homo sapiens | - |
? + diphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P00492 | - |
- |
| Plasmodium falciparum | - |
- |
- |
Reaction
| Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|
| 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 |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| guanine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Plasmodium falciparum | GMP + diphosphate | - |
? | |
| guanine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Homo sapiens | GMP + diphosphate | - |
? | |
| hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Plasmodium falciparum | IMP + diphosphate | - |
? | |
| hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Homo sapiens | IMP + diphosphate | - |
? | |
| additional information | the binding site for the 5'-phosphate is located at residues 132-141 | Plasmodium falciparum | ? | - |
? | |
| additional information | the binding site for the 5'-phosphate is located at residues 132-141 | Homo sapiens | ? | - |
? | |
| xanthine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Plasmodium falciparum | ? + diphosphate | - |
? | |
| xanthine + 5-phospho-alpha-D-ribose 1-diphosphate | - |
Homo sapiens | ? + diphosphate | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| HGXPRT | - |
Plasmodium falciparum |
| HGXPRT | - |
Homo sapiens |
| hypoxanthine-guanine phosphoribosyltransferase | - |
Plasmodium falciparum |
| hypoxanthine-guanine phosphoribosyltransferase | - |
Homo sapiens |
| hypoxanthine-guanine-xanthine phosphoribosyltransferase | - |
Plasmodium falciparum |
| hypoxanthine-guanine-xanthine phosphoribosyltransferase | - |
Homo sapiens |
Temperature Optimum [°C]
| Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 25 | - |
assay at | Plasmodium falciparum |
| 25 | - |
assay at | Homo sapiens |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 8.5 | - |
- |
Plasmodium falciparum |
| 8.5 | - |
- |
Homo sapiens |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.0001 | - |
9-[2-(2-phosphonoethoxy)ethyl]guanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0003 | - |
9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0006 | - |
(R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.001 | - |
cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.001 | - |
9-[2-(2-phosphonoethoxy)ethyl]guanine | pH 7.4, 25°C | Homo sapiens | |
| 0.0012 | - |
9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0014 | - |
cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.0016 | - |
9-[2-(phosphonomethoxy)ethyl]guanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.003 | - |
9-[2-(phosphonomethoxy)ethyl]-8-azaguanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0036 | - |
hypoxanthine ribose 5'-phosphate | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0036 | - |
9-[2-(2-phosphonoethoxy)ethyl]hypoxanthine | pH 7.4, 25°C | Homo sapiens | |
| 0.0036 | - |
9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.0043 | - |
9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine | pH 7.4, 25°C | Homo sapiens | |
| 0.0054 | - |
hypoxanthine ribose 5'-phosphate | pH 7.4, 25°C | Homo sapiens | |
| 0.0058 | - |
guanine ribose 5'-phosphate | pH 7.4, 25°C | Homo sapiens | |
| 0.0059 | - |
(R,S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Homo sapiens | |
| 0.0072 | - |
9-[2-(phosphonomethoxy)ethyl]-7-deaza-8-azahypoxanthine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.008 | - |
cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.01 | - |
guanine ribose 5'-phosphate | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.01 | - |
9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.011 | - |
(S)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0123 | - |
cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Homo sapiens | |
| 0.015 | - |
(S)-9-[2-(phosphonomethoxy)propyl]-8-azaguanine | pH 7.4, 25°C | Homo sapiens | |
| 0.0189 | - |
9-[2-(phosphonomethoxy)ethyl]guanine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.019 | - |
cyclic (R)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Homo sapiens | |
| 0.02 | - |
(R)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine | pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0227 | - |
9-[2-(phosphonomethoxy)-3-fluoro-propyl]guanine | pH 8.5, 25°C | Homo sapiens | |
| 0.0284 | - |
(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.029 | - |
9-[2-(phosphonomethoxy)ethyl]guanine | pH 7.4, 25°C | Homo sapiens | |
| 0.0377 | - |
cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.041 | - |
(R)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine | pH 7.4, 25°C | Homo sapiens | |
| 0.045 | - |
(S)-9-[2-(phosphonomethoxy)propyl]-8-azaguanine | above, pH 7.4, 25°C | Plasmodium falciparum | |
| 0.0559 | - |
9-[2-(phosphonomethoxy)ethyl]guanine | pH 8.5, 25°C | Homo sapiens | |
| 0.0648 | - |
(S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | pH 8.5, 25°C | Plasmodium falciparum | |
| 0.068 | - |
9-[2-(phosphonomethoxy)ethy]-8-hydroxyguanine | pH 7.4, 25°C | Homo sapiens | |
| 0.09 | - |
cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 7.4, 25°C | Homo sapiens | |
| 0.1 | - |
9-[2-(phosphonomethoxy)ethyl]-6-thioguanine | above, pH 7.4, 25°C | Plasmodium falciparum | |
| 0.1151 | - |
cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Homo sapiens | |
| 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 | |
| 0.175 | - |
9-[2-(phosphonomethoxy)ethyl]-8-azaguanine | pH 7.4, 25°C | Homo sapiens | |
| 0.1768 | - |
(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine | pH 8.5, 25°C | Homo sapiens | |
| 0.1823 | - |
(S)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | pH 8.5, 25°C | Homo sapiens | |
| 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 | |
| 0.3 | - |
(S)-9-[2-(phosphonomethoxy)propyl]-8-bromoguanine | above, pH 7.4, 25°C | Homo sapiens | |
| 0.4 | - |
9-[2-(phosphonomethoxy)ethyl]-8-bromoguanine | above, pH 7.4, 25°C | Homo sapiens | |
| 0.4373 | - |
(R)-9-[2-(phosphonomethoxy)propyl]hypoxanthine | pH 8.5, 25°C | Plasmodium falciparum | |
| 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 | |
| 1 | - |
9-[2-(phosphonomethoxy)ethyl]-6-thioguanine | above, pH 7.4, 25°C | Homo sapiens | |
| 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
| General Information | Comment | Organism |
|---|---|---|
| physiological function | the purine salvage enzyme HGXPRT is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite | Plasmodium falciparum |
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