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Literature summary for 2.7.6.3 extracted from

  • Dennis, M.L.; Pitcher, N.P.; Lee, M.D.; DeBono, A.J.; Wang, Z.C.; Harjani, J.R.; Rahmani, R.; Cleary, B.; Peat, T.S.; Baell, J.B.; Swarbrick, J.D.
    Structural basis for the selective binding of inhibitors to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus and Escherichia coli (2016), J. Med. Chem., 59, 5248-5263.
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of His6-tagged enzyme in Escherichia coli strain BL21(DE3) Escherichia coli

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant detagged enzyme in complex with different inhibitors and AMPCPP, sitting-drop vapor diffusion method, mixing of 2.2 mg/ml protein in 20 mM Tris-HCl buffer, pH 8.0, 100 mM NaCl, with reservoir solution containing 20% w/v PEG 4000, 0.1 M TrisCl, and 0.172 M CaCl2, or 0.1 M HEPES-NaOH, pH 7.5, 0.2 M CaCl2, and 25-30% PEG 4000, 16-20°C, addition of 2 mM MgCl2, 1 mM AMPCPP, and 1 mM of inhibitor, X-ray diffraction structure determination and analysis, molecular replacement Escherichia coli
purified recombinant enzyme in complex with AMPCPP and different inhibitors, sitting-drop vapor diffusion method, mixing of 6.9 mg/ml protein in in 20 mM Tris-HCl buffer, pH 8.0, 100 mM NaCl, with reservoir solution containing 0.186 M sodium nitrate, 18.4% w/v PEG 3000, 2 mM MgCl2, 1 mM AMPCPP, and 1 mM inhibitor or 0.1 M Tris-HCl, pH 8.5, 0.2 M MgCl2, 20% PEG 8000, 0.05 M sodium thiocyanate, 1 mM AMPCPP, and 1 mM inhibitor, X-ray diffraction structure determination and analysis, molecular replacement Staphylococcus aureus

Inhibitors

Inhibitors Comment Organism Structure
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-5-fluorobenzonitrile
-
Escherichia coli
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-5-fluorobenzonitrile
-
Staphylococcus aureus
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Escherichia coli
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Staphylococcus aureus
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-diethylacetamide
-
Escherichia coli
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-diethylacetamide
-
Staphylococcus aureus
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-dimethylacetamide
-
Escherichia coli
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-dimethylacetamide
-
Staphylococcus aureus
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-ethyl-N-methylpropanamide
-
Escherichia coli
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-ethyl-N-methylpropanamide
-
Staphylococcus aureus
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-isobutylacetamide
-
Escherichia coli
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-isobutylacetamide
-
Staphylococcus aureus
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-methylacetamide
-
Escherichia coli
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-methylacetamide
-
Staphylococcus aureus
2-amino-8-((2,3-dihydroxypropyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2,3-dihydroxypropyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2,3-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2,3-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2,6-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2,6-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-(2-oxopyrrolidin-1-yl)ethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-(2-oxopyrrolidin-1-yl)ethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-(4-bromophenyl)-2-oxoethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-(4-bromophenyl)-2-oxoethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-fluoro-5-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2-fluoro-5-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((2-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-hydroxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-hydroxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-methoxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-methoxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((2-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((2-oxo-2-phenylethyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((2-oxo-2-phenylethyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((3,3,3-trifluoro-2-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3,3,3-trifluoro-2-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3,5-bis(trifluoromethyl)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3,5-bis(trifluoromethyl)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((3,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((3-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((3-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((3-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((4-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((4-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((4-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((4-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((4-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((4-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((4-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((4-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((4-fluoro-2-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((4-fluoro-2-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((4-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
2-amino-8-((4-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
2-amino-8-((4-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((4-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-((4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-((4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
2-amino-8-(benzylthio)-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
2-amino-8-(benzylthio)-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzoic acid
-
Escherichia coli
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzoic acid
-
Staphylococcus aureus
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Escherichia coli
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Staphylococcus aureus
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-3-fluorobenzonitrile
-
Escherichia coli
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-3-fluorobenzonitrile
-
Staphylococcus aureus
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Escherichia coli
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
Staphylococcus aureus
5-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-2-fluorobenzonitrile
-
Escherichia coli
5-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-2-fluorobenzonitrile
-
Staphylococcus aureus
8-((2-(1,3-dioxan-2-yl)ethyl)thio)-2-amino-1,9-dihydro-6Hpurin-6-one
-
Escherichia coli
8-((2-(1,3-dioxan-2-yl)ethyl)thio)-2-amino-1,9-dihydro-6Hpurin-6-one
-
Staphylococcus aureus
8-((2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)thio)-2-amino-1,9-dihydro-6H-purin-6-one
-
Escherichia coli
8-((2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)thio)-2-amino-1,9-dihydro-6H-purin-6-one
-
Staphylococcus aureus
8-mercaptoguanine
-
Escherichia coli
8-mercaptoguanine
-
Staphylococcus aureus
additional information synthesis of a series of S-functionalized 8-mercaptoguanine analogues as substrate-site inhibitors of enzyme HPPK, binding structure analysis, and comparison of inhibition efficiency with the enzymes from Staphylococcus aureus and Escherichia coli, KD values, overview Escherichia coli
additional information synthesis of a series of S-functionalized 8-mercaptoguanine analogues as substrate-site inhibitors of enzyme HPPK, binding structure analysis, and comparison of inhibition efficiency with the enzymes from Staphylococcus aureus and Escherichia coli, KD values, overview Staphylococcus aureus

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Staphylococcus aureus
Mg2+ required Escherichia coli

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine Staphylococcus aureus
-
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine Escherichia coli
-
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
?

Organism

Organism UniProt Comment Textmining
Escherichia coli P26281
-
-
Staphylococcus aureus
-
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, tag cleavage by TEV protease, and gel filtration Escherichia coli

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
Staphylococcus aureus AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
Escherichia coli AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
?

Synonyms

Synonyms Comment Organism
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
-
Staphylococcus aureus
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
-
Escherichia coli
HPPK
-
Staphylococcus aureus
HPPK
-
Escherichia coli

Cofactor

Cofactor Comment Organism Structure
ATP
-
Staphylococcus aureus
ATP
-
Escherichia coli

General Information

General Information Comment Organism
metabolism the enzyme is a member of the folate biosynthesis pathway Staphylococcus aureus
metabolism the enzyme is a member of the folate biosynthesis pathway Escherichia coli