Literature summary for 2.4.2.8 extracted from

Spacek, P.; Keough, D.T.; Chavchich, M.; Dracinsky, M.; Janeba, Z.; Naesens, L.; Edstein, M.D.; Guddat, L.W.; Hockova, D.
Synthesis and evaluation of asymmetric acyclic nucleoside bisphosphonates as inhibitors of Plasmodium falciparum and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (2017), J. Med. Chem., 60, 7539-7554 .

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified enzyme in complex with inhibitor [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid and ([3-(guanine-9-yl)-2-((2-phosphonoethoxy)-methyl)propoxy]methyl)phosphonic acid, hanging drop method, mixing of 0.001 ml of 11.1 mg/ml protein in 0.1 M Tris-HCl, 0.01 M MgCl2, 1 mM DTT, and 0.3 mM 5-phospho-alpha-D-ribose 1-diphosphate, pH 7.4, and 4.8 mM inhibitor, with 0.001 ml of reservoir solution containing 20% PEG 3350, 0.2 M sodium bromide, 0.1 M Bis-Tris propane, pH 7.5, at 18°C, X-ray diffraction structure determination and analysis at 2.0 A resolution, molecular replacement and modeling	Homo sapiens

Crystallization (Comment)

Organism

purified enzyme in complex with inhibitor [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid and ([3-(guanine-9-yl)-2-((2-phosphonoethoxy)-methyl)propoxy]methyl)phosphonic acid, hanging drop method, mixing of 0.001 ml of 11.1 mg/ml protein in 0.1 M Tris-HCl, 0.01 M MgCl2, 1 mM DTT, and 0.3 mM 5-phospho-alpha-D-ribose 1-diphosphate, pH 7.4, and 4.8 mM inhibitor, with 0.001 ml of reservoir solution containing 20% PEG 3350, 0.2 M sodium bromide, 0.1 M Bis-Tris propane, pH 7.5, at 18°C, X-ray diffraction structure determination and analysis at 2.0 A resolution, molecular replacement and modeling

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(2-[3-(8-bromoguanin-9-yl)-2-(2-(bishydroxyphosphoryl)-ethoxy)propoxy]ethyl)phosphonic acid	-	Homo sapiens
(2-[3-(8-bromoguanin-9-yl)-2-(2-(bishydroxyphosphoryl)-ethoxy)propoxy]ethyl)phosphonic acid	-	Plasmodium falciparum
([2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl)phosphonic acid	-	Homo sapiens
([2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl)phosphonic acid	-	Plasmodium falciparum
([2-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl)phosphonic acid	-	Homo sapiens
([2-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl)phosphonic acid	-	Plasmodium falciparum
([3-(7-deazaguanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(7-deazaguanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
([3-(7-deazahypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(7-deazahypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
([3-(8-bromoguanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(8-bromoguanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
([3-(8-bromohypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(8-bromohypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
([3-(guanine-9-yl)-2-((2-phosphonoethoxy)-methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(guanine-9-yl)-2-((2-phosphonoethoxy)-methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
([3-(hypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Homo sapiens
([3-(hypoxanthine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methyl)phosphonic acid	sodium salt	Plasmodium falciparum
diethyl (2S,15S)-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-8-[(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl]-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-8-[(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl]-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-8-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-8-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-2,15-dibenzyl-8-[(8-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-2,15-dibenzyl-8-[(8-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-4,13-bis[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-4,13-dioxo-8-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-bis(2-phenylethyl)-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	-	Homo sapiens
diethyl (2S,15S)-4,13-bis[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-4,13-dioxo-8-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-bis(2-phenylethyl)-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	-	Plasmodium falciparum
diethyl (2S,15S)-8-[(2-amino-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-8-[(2-amino-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-7,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-7,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,13-bis[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-4,13-dioxo-2,15-bis(2-phenylethyl)-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	-	Homo sapiens
diethyl (2S,15S)-8-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,13-bis[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-4,13-dioxo-2,15-bis(2-phenylethyl)-6,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	-	Plasmodium falciparum
diethyl (2S,15S)-8-[(2-amino-8-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-7,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Homo sapiens
diethyl (2S,15S)-8-[(2-amino-8-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-2,15-dibenzyl-4,13-bis[[(2S)-1-ethoxy-1-oxo-3-phenylpropan-2-yl]amino]-4,13-dioxo-7,10-dioxa-3,14-diaza-4lambda5,13lambda5-diphosphahexadecane-1,16-dioate	prodrug	Plasmodium falciparum
additional information	synthesis and evaluation of asymmetric acyclic nucleoside bisphosphonates as inhibitors of human hypoxanthine-guanine phosphoribosyltransferase	Homo sapiens
additional information	synthesis and evaluation of asymmetric acyclic nucleoside bisphosphonates as inhibitors of Plasmodium falciparum hypoxanthine-guanine-(xanthine) phosphoribosyltransferase. Low Ki values are achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups	Plasmodium falciparum
[3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid	structure bound in the active site of human HGPRT (PDB ID 4IJQ), molecular docking. The crystal structure shows that a magnesium ion is coordinated to one of the sulfate oxygen atoms and one of the phosphonate oxygen atoms of the inhibitor	Homo sapiens
[3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid	-	Plasmodium falciparum
[[2-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]propane-1,3-diyl]bis(oxymethylene)]bis(phosphonic acid)	-	Homo sapiens
[[2-[(6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]propane-1,3-diyl]bis(oxymethylene)]bis(phosphonic acid)	-	Plasmodium falciparum

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens
Mg2+	required	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	-	?
xanthine + 5-phospho-alpha-D-ribose 1-diphosphate	Plasmodium falciparum	reaction of EC 2.4.2.22	XMP + diphosphate	-	?

Organism

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

Source Tissue

Source Tissue	Comment	Organism	Textmining
A-549 cell	-	Homo sapiens	-

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	-	?
xanthine + 5-phospho-alpha-D-ribose 1-diphosphate	reaction of EC 2.4.2.22	Plasmodium falciparum	XMP + diphosphate	-	?

Synonyms

Synonyms	Comment	Organism
HGPRT	-	Homo sapiens
hypoxanthine-guanine phosphoribosyltransferase	-	Homo sapiens
hypoxanthine-guanine-(xanthine) phosphoribosyltransferase	-	Plasmodium falciparum
More	see also EC 2.4.2.22	Plasmodium falciparum
Pf HGXPRT	-	Plasmodium falciparum

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.4	-	assay at	Homo sapiens
7.4	-	assay at	Plasmodium falciparum

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.000006	-	[3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid	pH 7.4, temperature not specified in the publication	Plasmodium falciparum
0.00007	-	[3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid	pH 7.4, temperature not specified in the publication	Homo sapiens

General Information

General Information	Comment	Organism
physiological function	hypoxanthine-guanine-(xanthine) phosphoribosyltransferases, HG(X)PRTs, catalyze the formation of the 6-oxopurine nucleoside monophosphates from a nucleobase and from 5'-phospho-alpha-D-ribosyl-1-diphosphate	Plasmodium falciparum
physiological function	hypoxanthine-guanine-(xanthine) phosphoribosyltransferases, HG(X)PRTs, catalyze the formation of the 6-oxopurine nucleoside monophosphates from a nucleobase and from 5'-phospho-alpha-D-ribosyl-1-pyrophosphate	Homo sapiens