Literature summary for 2.4.2.8 extracted from

Keough, D.T.; Rejman, D.; Pohl, R.; Zbornikova, E.; Hockova, D.; Croll, T.; Edstein, M.D.; Birrell, G.W.; Chavchich, M.; Naesens, L.M.J.; Pierens, G.K.; Brereton, I.M.; Guddat, L.W.
Design of Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase inhibitors as potential antimalarial therapeutics (2018), ACS Chem. Biol., 13, 82-90 .

Application

Application	Comment	Organism
drug development	hypoxanthine-guanine phosphoribosyltransferase is an excellent target for antimalarial drug discovery	Plasmodium falciparum

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified recombinant enzyme PvHGPRT in complex with inhibitor [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, 21 mg/ml protein is incubated with 6.4 mM inhibitor on ice for 5 min, hanging drop method, mixing of 0.001 ml of protein and inhibitor with 0.001 ml of reservoir solution containing 0.3 M potassium thiocyanate, 0.1 M Bis-tris propane, pH 8.5, 18°C, X-ray diffraction structure determination and analysis at 2.85 A resolution, molecular replacement using the protein coordinates of subunit A of human HGPRT in complex with [(2-[(guanin-9H-yl)methyl]-propane-1,3-diyl)bis(oxy)]bis-(methylene)diphosphonic acid as template (PDB ID 4IJQ), model building	Plasmodium falciparum

Crystallization (Comment)

Organism

purified recombinant enzyme PvHGPRT in complex with inhibitor [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, 21 mg/ml protein is incubated with 6.4 mM inhibitor on ice for 5 min, hanging drop method, mixing of 0.001 ml of protein and inhibitor with 0.001 ml of reservoir solution containing 0.3 M potassium thiocyanate, 0.1 M Bis-tris propane, pH 8.5, 18°C, X-ray diffraction structure determination and analysis at 2.85 A resolution, molecular replacement using the protein coordinates of subunit A of human HGPRT in complex with [(2-[(guanin-9H-yl)methyl]-propane-1,3-diyl)bis(oxy)]bis-(methylene)diphosphonic acid as template (PDB ID 4IJQ), model building

Plasmodium falciparum

Inhibitors

Inhibitors	Comment	Organism
(2-[(3R,4R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-[(2R)-2-hydroxy-2-phosphonoethoxy]pyrrolidin-1-yl]-2-oxoethyl)phosphonic acid	enzyme-bound crystal structure analysis	Homo sapiens
(2-[(3R,4R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-[(2R)-2-hydroxy-2-phosphonoethoxy]pyrrolidin-1-yl]-2-oxoethyl)phosphonic acid	enzyme-bound crystal structure analysis; enzyme-bound crystal structure analysis	Plasmodium falciparum
(2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl)phosphonic acid	-	Homo sapiens
(2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl)phosphonic acid	-	Plasmodium falciparum
(S)-3-(guanin-9-yl)-pyrrolidin-N-ylacetylphosphonic acid	-	Homo sapiens
(S)-3-(guanin-9-yl)-pyrrolidin-N-ylacetylphosphonic acid	-	Plasmodium falciparum
additional information	design of Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase inhibitors as potential antimalarial therapeutics, rational structure-based methods, binding structure and comparison to the human enzyme, overview	Homo sapiens
additional information	design of Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase inhibitors as potential antimalarial therapeutics, rational structure-based methods, overview; design of Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase inhibitors as potential antimalarial therapeutics, rational structure-based methods, overview	Plasmodium falciparum
[(1S)-1-hydroxy-2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl]phosphonic acid	-	Homo sapiens
[(1S)-1-hydroxy-2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl]phosphonic acid	-	Plasmodium falciparum
[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	-	Homo sapiens
[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	-	Plasmodium falciparum

Natural Substrates/ Products (Substrates)

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

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P00492	-	-
Plasmodium falciparum	A0A1G4HBT9	-	-
Plasmodium falciparum	Q8IJS1	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
guanosine + 5-phospho-alpha-D-ribose 1-diphosphate	-	Homo sapiens	GMP + diphosphate	-	?
guanosine + 5-phospho-alpha-D-ribose 1-diphosphate	-	Plasmodium falciparum	GMP + diphosphate	-	?
hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate	-	Homo sapiens	IMP + diphosphate	-	?
hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate	-	Plasmodium falciparum	IMP + diphosphate	-	?

Synonyms

Synonyms	Comment	Organism
HG[X]PRT	-	Plasmodium falciparum
hypoxanthine-guanine phosphoribosyltransferase	-	Homo sapiens
hypoxanthine-guanine phosphoribosyltransferase	-	Plasmodium falciparum
hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase	-	Plasmodium falciparum
More	cf. EC 2.4.2.22	Plasmodium falciparum
PvHGPRT	-	Homo sapiens
PvHGPRT	-	Plasmodium falciparum

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.0000013	-	[(1S)-1-hydroxy-2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl]phosphonic acid	pH not specified in the publication, 37°C	Homo sapiens
0.000002	-	[(1S)-1-hydroxy-2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl]phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.000003	-	[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	pH not specified in the publication, 37°C	Homo sapiens
0.000006	-	[(1S)-1-hydroxy-2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl]phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.000007	-	[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	pH not specified in the publication, 37°C	Plasmodium falciparum
0.000008	-	(2-[(3R,4R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-[(2R)-2-hydroxy-2-phosphonoethoxy]pyrrolidin-1-yl]-2-oxoethyl)phosphonic acid	pH not specified in the publication, 37°C	Homo sapiens
0.000008	-	[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	pH not specified in the publication, 37°C	Plasmodium falciparum
0.00001	-	(2-[(3R,4R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-[(2R)-2-hydroxy-2-phosphonoethoxy]pyrrolidin-1-yl]-2-oxoethyl)phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.000014	-	(2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl)phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.00002	-	[3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine	pH not specified in the publication, 37°C	Homo sapiens
0.00006	-	(2-[(3R,4R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-[(2R)-2-hydroxy-2-phosphonoethoxy]pyrrolidin-1-yl]-2-oxoethyl)phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.00008	-	(2-[[(3R,4R)-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(phosphonoacetyl)pyrrolidin-3-yl]oxy]ethyl)phosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.0004	-	(S)-3-(guanin-9-yl)-pyrrolidin-N-ylacetylphosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.0026	-	(S)-3-(guanin-9-yl)-pyrrolidin-N-ylacetylphosphonic acid	pH not specified in the publication, 37°C	Plasmodium falciparum
0.073	-	(S)-3-(guanin-9-yl)-pyrrolidin-N-ylacetylphosphonic acid	pH not specified in the publication, 37°C	Homo sapiens

General Information

General Information	Comment	Organism
physiological function	the activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT is essential for the growth of Plasmodium parasites	Plasmodium falciparum