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6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
6-hydroxymethyl-7,8-dihydropterin + MgATP2-
6-hydroxymethyl-7,8-dihydropterin diphosphate + MgAMP
biosynthesis of folate cofactors
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 7,8-dihydro-6-(diphosphooxymethyl)pteridine
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + H+ + (7,8-dihydropterin-6-yl)methyl diphosphate
-
-
-
?
dATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
dAMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
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?
additional information
?
-
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
tetrahydrofolate biosynthesis
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-
?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
-
-
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?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
folate biosynthesis
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-
?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
-
biosynthesis of folic acid
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-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
-
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
key step in biosynthesis of folic acid
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
ATP binding is followed by binding of 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
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?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
-
-
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?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
enzyme binds ATP first, followed by 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
the product 6-hydroxymethyl-7,8-dihydropterin diphosphate is an intermediate in the pathway for folic acid biosynthesis
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
ordered bi-bi mechanism with ATP as the first substrate
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?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
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ir
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
ir
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
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?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
ordered bi bi mechanism where ATP binds first and 6-hydroxymethyl-7,8-dihydropterin diphosphate is released last
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?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
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ir
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/7,8-dihydropteroate synthase, i.e. mitHPPK/DHPS, is a bifunctional mitochondrial enzyme, which catalyzes the first two consecutive steps of tetrahydrofolate biosynthesis, folate biosynthesis in Arabidopsis thaliana, overview
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-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
fourth step in folate biosynthesis, detailed overview
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?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
the enzyme is absolutely specific for the substrate
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?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
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-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
step in the folate biosynthetic pathway, overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
fourth step in folate biosynthesis, detailed overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
the enzyme is absolutely specific for the substrate
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
Q7CKD7
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?
additional information
?
-
binding affinity for GTP and GMP, 75fold weaker than for ATP
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?
additional information
?
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-
binding affinity for GTP and GMP, 75fold weaker than for ATP
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?
additional information
?
-
the enzyme does not hydrolyze alpha,beta-methyleneadenosine 5-triphosphate
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?
additional information
?
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-
the enzyme does not hydrolyze alpha,beta-methyleneadenosine 5-triphosphate
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?
additional information
?
-
the bifunctional enzyme comprises the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) activity and dihydropteroate synthase (DHPS) activity, EC 2.5.1.15, the latter is very low due, at least in part, to the lack of a key residue that interacts with the substrate p-aminobenzoic acid
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?
additional information
?
-
the enzyme does not hydrolyze alpha,beta-methyleneadenosine 5-triphosphate
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-
?
additional information
?
-
the bifunctional enzyme comprises the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) activity and dihydropteroate synthase (DHPS) activity, EC 2.5.1.15, the latter is very low due, at least in part, to the lack of a key residue that interacts with the substrate p-aminobenzoic acid
-
-
?
additional information
?
-
the bifunctional HPPK-DHPS enzyme catalyzes sequential steps in the folate biosynthesis, i.e. the 6-hydroxymethylpterin pyrophosphokinase reaction and the dihydropteroate synthase, DHPS, reaction, EC 2.5.1.15
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?
additional information
?
-
coupled assay method development using reduction of DHPS reaction product dihydropteroate to tetrahydropteroate by excess dihydrofolate reductase with the cofactor NADPH, the oxidation of NADPH is monitored, overview
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?
additional information
?
-
Q7CKD7
HPPK is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals
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-
?
additional information
?
-
-
HPPK is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
6-hydroxymethyl-7,8-dihydropterin + MgATP2-
6-hydroxymethyl-7,8-dihydropterin diphosphate + MgAMP
biosynthesis of folate cofactors
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + 2-amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine
key step in biosynthesis of folic acid
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
additional information
?
-
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
tetrahydrofolate biosynthesis
-
-
?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
-
-
-
?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
folate biosynthesis
-
-
?
6-hydroxymethyl-7,8-dihydropterin + ATP
6-hydroxymethyl-7,8-dihydropterin diphosphate + AMP
-
biosynthesis of folic acid
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
?
ATP + 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
AMP + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropteridine
AMP + 6-hydroxymethyl-7,8-dihydropteridine diphosphate
the product 6-hydroxymethyl-7,8-dihydropterin diphosphate is an intermediate in the pathway for folic acid biosynthesis
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/7,8-dihydropteroate synthase, i.e. mitHPPK/DHPS, is a bifunctional mitochondrial enzyme, which catalyzes the first two consecutive steps of tetrahydrofolate biosynthesis, folate biosynthesis in Arabidopsis thaliana, overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
fourth step in folate biosynthesis, detailed overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
step in the folate biosynthetic pathway, overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
-
fourth step in folate biosynthesis, detailed overview
-
-
?
ATP + 6-hydroxymethyl-7,8-dihydropterin
AMP + (7,8-dihydropterin-6-yl)methyl diphosphate
Q7CKD7
-
-
-
?
additional information
?
-
the bifunctional enzyme comprises the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) activity and dihydropteroate synthase (DHPS) activity, EC 2.5.1.15, the latter is very low due, at least in part, to the lack of a key residue that interacts with the substrate p-aminobenzoic acid
-
-
?
additional information
?
-
the bifunctional enzyme comprises the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) activity and dihydropteroate synthase (DHPS) activity, EC 2.5.1.15, the latter is very low due, at least in part, to the lack of a key residue that interacts with the substrate p-aminobenzoic acid
-
-
?
additional information
?
-
the bifunctional HPPK-DHPS enzyme catalyzes sequential steps in the folate biosynthesis, i.e. the 6-hydroxymethylpterin pyrophosphokinase reaction and the dihydropteroate synthase, DHPS, reaction, EC 2.5.1.15
-
-
?
additional information
?
-
Q7CKD7
HPPK is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals
-
-
?
additional information
?
-
-
HPPK is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-5-fluorobenzonitrile
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-diethylacetamide
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-dimethylacetamide
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-ethyl-N-methylpropanamide
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-isobutylacetamide
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-methylacetamide
2-Amino-4-hydroxy-6-carboxydihydropteridine
-
competitive with 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine
2-amino-6-[(2-[4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl]-ethylamino)-methyl]-3H-pteridin-4-one
-
2-amino-6-[(2-[4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl]-ethylamino)-methyl]-7,7-dimethyl-7,8-dihydro-3H-pteridin-4-one
-
2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-(2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-thylcarbamoyl)-ethyl)-amide
2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-(2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-thylcarbamoyl)-ethyl)-amide, structure of the enzyme complex with HP-26. HP-26 has significant isozyme selectivity. HP-26 is an excellent lead for developing therapeutic agents for tularemia
2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-[4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethylsulfanyl]-piperidin-1-yl]-ethyl)-amide
-
2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxylic acid (2-[2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-ethylcarbamoyl]-ethyl)-amide
about 45% residual activity at 0.01 mM, about 30% residual activity at 0.02 mM, about 15% residual activity at 0.05 mM, almost complete inhibition at 0.1 mM
2-amino-8-((2,3-dihydroxypropyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2,3-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2,6-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-(2-oxopyrrolidin-1-yl)ethyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-(4-bromophenyl)-2-oxoethyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-fluoro-5-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((2-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-hydroxyethyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-methoxyethyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((2-oxo-2-phenylethyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((3,3,3-trifluoro-2-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3,5-bis(trifluoromethyl)benzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((3-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((3-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((4-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((4-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((4-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((4-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((4-fluoro-2-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((4-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
2-amino-8-((4-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-((4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
2-amino-8-(2-oxo-2-phenylethoxy)-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-(benzylthio)-1,9-dihydro-6H-purin-6-one
2-amino-8-hydroxy-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(2-methylphenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(3-methylphenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(4-fluorophenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(4-hydroxyphenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(4-methoxyphenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[2-(4-methylphenyl)-2-oxoethoxy]-1,4,5,9-tetrahydro-6H-purin-6-one
-
2-amino-8-[[(2-fluorophenyl)methyl]sulfanyl]-1,9-dihydro-6H-purin-6-one
-
compound shows high binding affinity. The guanine moiety interacts with the binding pocket residues through hydrogen bond interaction with residues T43, A44, V46, N56, R121 and is further stabilized by pi-stacking interaction between the aromatic rings of F54 and F123
2-amino-8-[[2-(4-methoxyphenyl)-2-oxoethyl]sulfanyl]-1,9-dihydro-6H-purin-6-one
-
compound forms hydrogen bond and pi-pi interactions between the guanine moiety and the binding site residues. The imidazole-NH forms a hydrogen bond interaction with residue V46. The atoms in the pyrimidine ring interact with a cluster of residues including T43, A44, V46, F54, N56 and F123
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzoic acid
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-3-fluorobenzonitrile
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
4-[(2-amino-6-oxo-4,5,6,9-tetrahydro-1H-purin-8-yl)methyl]benzonitrile
-
4-[[(2-amino-6-oxo-4,5,6,9-tetrahydro-1H-purin-8-yl)oxy]acetyl]benzonitrile
-
5'-(1-[2-[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carbonyl)amino]ethyl]-2-carboxypiperidine-4-sulfonyl)-5'-deoxyadenosine
bisubstrate inhibitor, Kd value is 0.000047 microM, compound is not sufficiently stable under the experimental conditions
5'-S-(1-[2-[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carbonyl)amino]ethyl]-2-carboxypiperidin-4-yl)-5'-thioadenosine
bisubstrate inhibitor, the carboxylic group in the piperidine system mimics the gamma-phosphate of AMPCPP and the carboxylic group interacts with the side chains of H115, Y116, and R121
5'-S-[1-(2-([(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)carbonyl]amino)ethyl)piperidin-4-yl]-5'-thioadenosine
5'-S-[1-(2-([(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)carbonyl]amino)ethyl)piperidin-4-yl]-5'-thioadenosine, structure of the enzyme complex with HP-18. HP-18 has significant isozyme selectivity
5'-S-[1-(2-{[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)carbonyl]amino}ethyl)piperidin-4-yl]-5'-thioadenosine
-
5-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-2-fluorobenzonitrile
6-hydroxymethyl-7,7-dimethyl-7,8-dihydropterin
-
6-hydroxymethyl-7,8-dihydropterin diphosphate
-
competitive inhibitor of ATP, mixed type inhibitor of 6-hydroxymethyl-7,8-dihydropteridine
6-hydroxymethyl-7-methyl-7-phenethyl-7,8-dihydropterin
-
8-((2-(1,3-dioxan-2-yl)ethyl)thio)-2-amino-1,9-dihydro-6Hpurin-6-one
8-((2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)thio)-2-amino-1,9-dihydro-6H-purin-6-one
alpha,beta-methyleneadenosine triphosphate
competitive with respect to ATP
Guanidine-HCl
-
0.25 M, 50% inhibitioin
KCl
-
activation at 0.4 M, inhibition at higher concentration
NaCl
-
activation at 0.2 M, inhibition at higher concentration
P1-(6-hydroxymethylpterin)-P2-(5'-adenosyl)diphosphate
-
P1-(6-hydroxymethylpterin)-P3-(5'-adenosyl)triphosphate
-
P1-(6-hydroxymethylpterin)-P4-(5'-adenosyl)tetraphosphate
-
Pteroate
inhibition of dihydropteroate synthase activity
sulfadimethoxine
inhibition of dihydropteroate synthase activity
sulfamethazine
inhibition of dihydropteroate synthase activity
sulfamonomethoxine
inhibition of dihydropteroate synthase activity
Urea
-
0.9 M, 50% inhibition
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-5-fluorobenzonitrile
-
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-5-fluorobenzonitrile
-
-
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
2-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-diethylacetamide
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-diethylacetamide
-
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-dimethylacetamide
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N,N-dimethylacetamide
-
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-ethyl-N-methylpropanamide
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-ethyl-N-methylpropanamide
-
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-isobutylacetamide
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-isobutylacetamide
-
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-methylacetamide
-
2-((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-methylacetamide
-
-
2-amino-8-((2,3-dihydroxypropyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2,3-dihydroxypropyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2,3-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2,3-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2,6-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2,6-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-(2-oxopyrrolidin-1-yl)ethyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-(2-oxopyrrolidin-1-yl)ethyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-(4-bromophenyl)-2-oxoethyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-(4-bromophenyl)-2-oxoethyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-fluoro-5-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2-fluoro-5-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((2-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-hydroxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-hydroxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-methoxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-methoxyethyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((2-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((2-oxo-2-phenylethyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((2-oxo-2-phenylethyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((3,3,3-trifluoro-2-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3,3,3-trifluoro-2-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3,4-difluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3,5-bis(trifluoromethyl)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3,5-bis(trifluoromethyl)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((3,5-dimethylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((3-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-hydroxypropyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-methylbenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((3-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((3-nitrobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((4-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((4-(trifluoromethoxy)benzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((4-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((4-(trifluoromethyl)benzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((4-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((4-bromobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((4-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((4-chlorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((4-fluoro-2-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((4-fluoro-2-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((4-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
2-amino-8-((4-fluoro-3-methylbenzyl)thio)-1,9-dihydro-6Hpurin-6-one
-
-
2-amino-8-((4-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((4-fluorobenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-((4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-((4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
-
2-amino-8-(benzylthio)-1,9-dihydro-6H-purin-6-one
-
2-amino-8-(benzylthio)-1,9-dihydro-6H-purin-6-one
-
-
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzoic acid
-
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzoic acid
-
-
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
3-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
-
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-3-fluorobenzonitrile
-
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-3-fluorobenzonitrile
-
-
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-benzonitrile
-
-
5-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-2-fluorobenzonitrile
-
5-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)-2-fluorobenzonitrile
-
-
8-((2-(1,3-dioxan-2-yl)ethyl)thio)-2-amino-1,9-dihydro-6Hpurin-6-one
-
8-((2-(1,3-dioxan-2-yl)ethyl)thio)-2-amino-1,9-dihydro-6Hpurin-6-one
-
-
8-((2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)thio)-2-amino-1,9-dihydro-6H-purin-6-one
-
8-((2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)thio)-2-amino-1,9-dihydro-6H-purin-6-one
-
-
8-mercaptoguanine
-
dapsone
inhibition of dihydropteroate synthase activity
sulfadoxine
-
competitive, moderately potent
sulfadoxine
inhibition of dihydropteroate synthase activity
sulfamethoxazole
inhibition of dihydropteroate synthase activity
sulfathiazole
-
competitive
sulfathiazole
inhibition of dihydropteroate synthase activity
additional information
identification of several enzyme inhibitors that contain an aryl substituted 8-thioguanine scaffold. The compounds engage the enzyme pterin-binding pocket and an induced cryptic pocket, preliminary structure activity relationship profile, binding structures, overview
-
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
-
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
-
additional information
-
structure-based design and development of functionalized mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin diphosphokinase from Staphylococcus aureus, binding of an S8-functionalized derivative of 8-mercaptoguanine, overview. Synthesis and binding analysis of a set of analogues including a compound displaying over 20fold higher affinity for SaHPPK than 8-mercaptoguanine. A number of the compounds exhibit low micromolar affinity for dihydropteroate synthase (DHPS, EC 2.5.1.15), the adjacent, downstream enzyme to HPPK, and may thus represent bienzyme inhibitors
-
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
-
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0.043
2-Amino-4-hydroxy-6-carboxydihydropteridine
-
pH 8.5, 37°C
0.0024
2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-(2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-thylcarbamoyl)-ethyl)-amide
pH 8.3, 30°C, recombinant enzyme
0.085
5'-S-[1-(2-([(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)carbonyl]amino)ethyl)piperidin-4-yl]-5'-thioadenosine
pH 8.3, 30°C, recombinant enzyme
0.005 - 0.013
6-hydroxymethyl-7,8-dihydropterin diphosphate
0.00031
alpha,beta-methyleneadenosine triphosphate
-
0.0008 - 0.116
sulfadimethoxine
0.0052 - 0.198
sulfadoxine
0.0008 - 0.058
sulfamethazine
0.034 - 0.731
sulfamethoxazole
0.0006 - 0.035
sulfamonomethoxine
0.0016 - 0.027
sulfathiazole
0.005
6-hydroxymethyl-7,8-dihydropterin diphosphate
-
versus ATP
0.013
6-hydroxymethyl-7,8-dihydropterin diphosphate
-
versus 6-hydroxymethyl-7,8-dihydropteridine
0.4
AMP
-
versus 6-hydroxymethyl-7,8-dihydropteridine
0.0007
dapsone
mutant A613T, pH 9, 37°C
0.0008
dapsone
wild-type, pH 9, 37°C
0.0011
dapsone
mutant K540E, pH 9, 37°C
0.0014
dapsone
mutant A613S, pH 9, 37°C
0.0019
dapsone
mutant A437G, pH 9, 37°C
0.0039
dapsone
mutant A437G/K540E, pH 9, 37°C
0.04
dapsone
mutant A581G, pH 9, 37°C
0.058
dapsone
mutant S436A/A437G/A613S, pH 9, 37°C
0.156
dapsone
mutant S436A/A437G/A613T, pH 9, 37°C
0.177
dapsone
mutant S436F/A613S, pH 9, 37°C
0.192
dapsone
mutant S436F/A613T, pH 9, 37°C
0.0006
Pteroate
mutant S436A/A437G/A613T, pH 9, 37°C
0.0009
Pteroate
mutant S436A/A437G/A613S, pH 9, 37°C
0.001
Pteroate
mutant S436A/A437G, pH 9, 37°C
0.0014
Pteroate
wild-type, pH 9, 37°C
0.0017
Pteroate
mutant S436F/A613T, pH 9, 37°C
0.003
Pteroate
mutant K540E, pH 9, 37°C
0.0033
Pteroate
mutant A613S, pH 9, 37°C
0.0037
Pteroate
mutant S436F/A613S, pH 9, 37°C
0.0038
Pteroate
mutant A437G, pH 9, 37°C
0.0069
Pteroate
mutant A437G/K540E, pH 9, 37°C
0.03
Pteroate
mutant A613T, pH 9, 37°C
0.039
Pteroate
mutant A581G, pH 9, 37°C
0.0008
sulfadimethoxine
wild-type, pH 9, 37°C
0.0024
sulfadimethoxine
mutant A437G, pH 9, 37°C
0.014
sulfadimethoxine
mutant S436A/A437G, pH 9, 37°C
0.016
sulfadimethoxine
mutant A437G/K540E, pH 9, 37°C
0.04
sulfadimethoxine
mutant S436A/A437G/A613S, pH 9, 37°C
0.116
sulfadimethoxine
mutant S436A/A437G/A613T, pH 9, 37°C
0.0052
sulfadoxine
mutant A613T, pH 9, 37°C
0.007
sulfadoxine
mutant A437G, pH 9, 37°C
0.0071
sulfadoxine
wild-type, pH 9, 37°C
0.0092
sulfadoxine
mutant A613S, pH 9, 37°C
0.02
sulfadoxine
mutant S436A/A437G, pH 9, 37°C
0.023
sulfadoxine
mutant K540E, pH 9, 37°C
0.07
sulfadoxine
mutant A437G/K540E, pH 9, 37°C
0.084
sulfadoxine
mutant S436A/A437G/A613S, pH 9, 37°C
0.086
sulfadoxine
mutant S436F/A613S, pH 9, 37°C
0.124
sulfadoxine
mutant S436F/A613T, pH 9, 37°C
0.196
sulfadoxine
mutant S436A/A437G/A613T, pH 9, 37°C
0.198
sulfadoxine
mutant A581G, pH 9, 37°C
0.0008
sulfamethazine
wild-type, pH 9, 37°C
0.0016
sulfamethazine
mutant A437G, pH 9, 37°C
0.0071
sulfamethazine
mutant A437G/K540E, pH 9, 37°C
0.021
sulfamethazine
mutant S436A/A437G/A613S, pH 9, 37°C
0.058
sulfamethazine
mutant S436A/A437G/A613T, pH 9, 37°C
0.034
sulfamethoxazole
wild-type, pH 9, 37°C
0.153
sulfamethoxazole
mutant A437G, pH 9, 37°C
0.462
sulfamethoxazole
mutant S436A/A437G/A613S, pH 9, 37°C
0.48
sulfamethoxazole
mutant A437G/K540E, pH 9, 37°C
0.731
sulfamethoxazole
mutant S436A/A437G/A613T, pH 9, 37°C
0.0006
sulfamonomethoxine
wild-type, pH 9, 37°C
0.0018
sulfamonomethoxine
mutant A437G, pH 9, 37°C
0.0091
sulfamonomethoxine
mutant A437G/K540E, pH 9, 37°C
0.014
sulfamonomethoxine
mutant S436A/A437G/A613S, pH 9, 37°C
0.035
sulfamonomethoxine
mutant S436A/A437G/A613T, pH 9, 37°C
0.0016
sulfathiazole
mutant A437G, pH 9, 37°C
0.005
sulfathiazole
wild-type, pH 9, 37°C
0.0072
sulfathiazole
mutant S436A/A437G, pH 9, 37°C
0.018
sulfathiazole
mutant A437G/K540E, pH 9, 37°C
0.025
sulfathiazole
mutant S436A/A437G/A613T, pH 9, 37°C
0.027
sulfathiazole
mutant S436A/A437G/A613S, pH 9, 37°C
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apo W89A and its ternary complex with Mg-alpha,beta-methyleneadenosine triphosphate and 6-hydroxymethyl-7,8-dihydropterin are crystallized at 19°C using the hanging-drop vapor-diffusion technique. The structure of the ternary complex is determined at 1.25 A resolution
complexed with inhibitor 2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxylic acid (2-[2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-ethylcarbamoyl]-ethyl)-amide, sitting drop vapor diffusion method, using 25% (w/v) PEG 3350 and 0.2 M NaCl in 0.1 M HEPES, pH 7.5
hanging-drop vapor-diffusion method. At 0.89-A resolution, two distinct conformations are observed for each of the two residues in the crystal structure of the wild-type enzyme in complex with two 6-hydroxymethyl-7,8-dihydropterin variants, two Mg2+ ions, and an ATP analogue. 1. Complex of wild-type enzyme with 6-hydroxymethylpterin, 6-carboxypterin and alpha,beta-methyleneadenosine 5'-triphosphate, 2. complex of mutant enzyme R82A with 6-hydroxymethyl-7,8-dihydropterin and alpha,beta-methyleneadenosine 5'-triphosphate, 3. complex of mutant enzyme R92A with 6-hydroxymethyl-7,8-dihydropterin and alpha,beta-methyleneadenosine 5'-triphosphate, 4. matant apoenzyme of R82A, 5. mutant apoenzyme of R92A, 6. mutant enzyme R92A in complex with Mg2+
in complex with 2-amino-6-[(2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl}-ethylamino)-methyl]-3H-pteridin-4-one, 2-amino-6-[(2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl}-ethylamino)-methyl]-7,7-dimethyl-7,8-dihydro-3H pteridin-4-one, or 2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethylsulfanyl]-piperidin-1-yl}-ethyl)-amide, sitting drop vapor diffusion method, using 20% or 25% (w/v) PEG 3350 as precipitant, at 19°C
in complex with inhibitors (2R,4R)-1-(2-(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamido)ethyl)-4-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio) piperidine-2-carboxylic acid and (2R,4R)-1-(2-(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamido)ethyl)-4-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl) piperidine-2-carboxylic acid
molecular dynamics simulations to investigate the loop dynamics in the binary HPPK-MgATP complex. With loop 3 closed, multiple conformations of loop 2, including the open, semiopen, and closed forms, are all accessible to the binary complex. Loop 3 is unlikely to be opened due to the blockage caused by the binding of ATP
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
structure-based model upon ligand binding, molecular dynamics simulation. HPPK can switch to the activated holo state upon the ordered binding of ligands ATP and HP. The ligand-free HPPK can execute large-scale conformational fluctuations around the apo and open basins. ATP prefers to bind to the open conformations and promotes the population of the open state. Only when both ligands are bound, the conformational transitions among all of the three native states can emerge. Higher temperatures promote population shift, while the induced fit pathway is always the predominant activation route of the HPPK system
V83Gdel84-89 and its complex with alpha,beta--methyleneadenosine triphosphate and 6-hydroxymethyl-7,8-dihydropterin are crystallized at 19°C using the hanging-drop vapor-diffusion technique
apoenzyme and in complex with substrate 6-hydroxymethyl-7,8-dihydropteridine or 2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydorpyrimido[4,5-c]pyridazin-3-yl)propanoic acid, sitting drop vapor diffusion method, using 90 mM Tris (pH 8.0), 190 mM sodium acetate, 24% (w/v) polyethylene glycol (PEG) 4000, and 17% (v/v) glycerol, at 18°C
purified enzyme in complex with inhibitor HP-26, sitting drop vapour diffusion method, mixing of 300 nl 11 mg/ml protein in 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and saturated HP-26, with 300 nl well solution containing 28% w/v poly(ethylene glycol) monomethyl ether 2000, and 100 mM Bis-Tris, pH 6.5, X-ray diffraction structure determination and analysis at 1.7 A resolution
a complex of the purified protein with a substrate analog is crystallized and its structure is solved by multiple anomalous dispersion using phase information obtained from a single crystal of selenomethionine-labeled protein
-
structures of the enzyme from wild-type and sulfa-resistant mutants, both as apoenzyme and as complexes with pteroate and sulfa derivatives. Pteroate stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants
crystal structure of HPPk-DHPS in complex with four substrates/analogs. Sulfadoxine's effect on HPPK-DHPS is due to 4-amino benzoic acid mimicry, and resistance mutations surrounding the 4-amino benzoic acid-binding site are present within loop 2 (S382/F/A/Cand A383G), loop 5 (Lys512), loop 6 (Ala553), and 7' helix in loop7 (Val585)
structure of HPPk-DHPS in complex with four substrates/analogs.
crystallization of a complex of the purified bifunctional polypeptide with a pterin monophosphate substrate analogue, structure solved by molecular replacement and refined to 2.3 A resolution. Three-dimensional structure in complex with the oxidized substrate analogue 6-hydroxy-methyl-pterin monophosphate reveals how the HPPK and DHPS functional domains associate at both the ternary and quaternary levels
-
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
-
sitting drop vapor diffusion method, using 1.08 M sodium malonate pH 7, 0.09 M bis-Tris pH 6.5, 0.175 M sodium formate, and 0.01 M sodium acetate pH 4.6
-
X-ray diffraction crystal structure analysis of both the SaHPPK/inhibitor/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes
-
purified recombinant HPPK in complex with 6-hydroxymethyl-7,8-dihydropterin and an ATP analogue AMPCPP, 8.0 mg/ml HPPK in 15 mM HP, 25 mM AMPCPP, 50 mM MgCl2 and 10 mM Tris-HCl, pH 8.0 s mixed with well solution containing 0.18 M ammonium acetate, 30% w/v PEG 4000, 20 mM imidazole, and 0.1 M sodium acetate, pH 4.6, 1-3 weeks, X-ray diffraction structure determination and analysis, molecular replacement
Q7CKD7
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R82A
-
mutation causes a decrease in the rate constant for the chemical step by a factor of 380, no significant change in the binding energy or kinetics of either substrate
R92A
-
mutation causes a decrease in the rate constant for the chemical step by a factor of 35000. The mutation causes no significant change in the binding energy or binding kinetics of MgATP2-. It does not cause a significant change in the binding energy of 6-hydroxymethyl-7,8-dihydropterin either but causes a decrease in the association rate constant for the binding of 6-hydroxymethyl-7,8-dihydropterin by a factor of 1.4 and a decrease in the dissociation rate constant by a factor of 10
V83Gdel84-89
the deletion mutation does not have significant effects on the dissociation constants or the rate constants for the binding of the first substrate MgATP2- or its analogues. The dissociation constant of 6-hydroxymethyl-7,8-dihydropterin for the mutant increases by a factor of about 100, which is due to a large increase in the dissociation rate constant. The deletion mutation causes a shift of the rate-limiting step in the reaction and a decrease in the rate constant for the chemical step by a factor of 110000. The crystal structures reveal that the deletion mutation does not affect protein folding, but the catalytic center of the mutant is not fully assembled even upon the formation of the ternary complex and is not properly sealed. Loop 3 is dispensable for the folding of the protein and the binding of the first substrate MgATP2-, but is required for the assembling and sealing of the active center. The loop plays an important role in the stabilization of the ternary complex and is critical for catalysis
A437G
6fold increase in kcat/Km value of 4-aminobenzoate
A437G/K540E
decrease in Km value of 4-aminobenzoate
A581G
decrease in Km value of 4-aminobenzoate
A613S
decrease in Km value of 4-aminobenzoate
A613T
decrease in Km value of 4-aminobenzoate
K540E
decrease in Km value of 4-aminobenzoate
S436A/A437G
1.6fold increase in kcat/Km value for 4-aminobenzoate
S436F/A437G/A613S
2fold increase in kcat/Km value of 4-aminobenzoate
S436F/A437G/A613T
kinetic values similar to wild-type
S436F/A613S
decrease in Km value of 4-aminobenzoate
S436F/A613T
decrease in Km value of 4-aminobenzoate
R84A
little changes in the dissociation constants and kinetic constants of the HPPK-catalyzed reaction
R84A
the mutation causes little changes in either dissociation constants or kinetic constants of the enzyme-catalyzed reaction except that the rate constant for the chemical step of the forward reaction decreases by a factor of 4
W89A
mutation increases the Kd for the binding of MgATP2- by a factor of 3, whereas the Kd for 6-hydroxymethyl-7,8-dihydropterin increases by a factor of 6, which is due to the increase in the dissociation rate constant. The mutation decreases the rate constant for the chemical step of the forward reaction by a factor of 15 and the rate constant for the chemical step of the reverse reaction by a factor of 25. The crystal structures of W89A show that W89A has different conformations in loops 2 and 3, but the critical catalytic residues are positioned for catalysis
W89A
the mutation does not have any significant effects on the Kd and the rate constants for the binding of MgATP, but the Kd for 6-hydroxymethyl-7,8-dihydropteridine of the mutant increases by a factor of 6.5. The mutation decreases the rate constant for the chemical step of the forward reaction by a factor of about 23 and the rate constant for the chemical step of the reverse reaction by a factor of about 33
A383G
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
A383G
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
A553G
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
A553G
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
K512D
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
K512D
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
K512E
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
K512E
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
S382A
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
S382A
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
V585A
dominant drug resistance mutation. Mutation subtly alters the intricate enzyme-4-amino benzoic acid-sulfadoxine interactions such that DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
V585A
natural mutation, generates resistance to sulfadoxine. DHPS affinity for 4-amino benzoic acid is diminished only moderately, but its affinity for sulfadoxine is changed substantially
additional information
-
construction of a T-DNA insertion mutant in the cytHPPK/DHPS gene, resulting in lower germination rates as compared with the wild-type upon application of oxidative and osmotic stress, phenotype, overview
additional information
construction of a T-DNA insertion mutant in the cytHPPK/DHPS gene, resulting in lower germination rates as compared with the wild-type upon application of oxidative and osmotic stress, phenotype, overview
additional information
the enzyme is minimally biotinylated by reaction with EZ-Link sulfo-NHS-LC-LC-biotin
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Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties
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Escherichia coli (P26281)
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Pemble, C.W.; Mehta, P.K.; Mehra, S.; Li, Z.; Nourse, A.; Lee, R.E.; White, S.W.
Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthase bifunctional enzyme from Francisella tularensis
PLoS ONE
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Francisella tularensis (A0A6B2JKF9), Francisella tularensis, Francisella tularensis LVS (A0A6B2JKF9)
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Escherichia coli (P26281)
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Gao, K.; He, H.; Yang, M.; Yan, H.
Molecular dynamics simulations of the Escherichia coli HPPK apo-enzyme reveal a network of conformational transitions
Biochemistry
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2015
Escherichia coli (P26281), Escherichia coli
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Yun, M.K.; Hoagland, D.; Kumar, G.; Waddell, M.B.; Rock, C.O.; Lee, R.E.; White, S.W.
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Escherichia coli (P26281)
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Shaw, G.X.; Li, Y.; Shi, G.; Wu, Y.; Cherry, S.; Needle, D.; Zhang, D.; Tropea, J.E.; Waugh, D.S.; Yan, H.; Ji, X.
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Francisella tularensis (Q5NGA7), Francisella tularensis SCHU S4 (Q5NGA7)
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Structure-based design and development of functionalized mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus
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Staphylococcus aureus
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Staphylococcus aureus, Escherichia coli (P26281), Escherichia coli
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Chitnumsub, P.; Jaruwat, A.; Talawanich, Y.; Noytanom, K.; Liwnaree, B.; Poen, S.; Yuthavong, Y.
The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase reveals the basis of sulfa resistance
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Plasmodium falciparum (Q25704)
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Yogavel, M.; Nettleship, J.E.; Sharma, A.; Harlos, K.; Jamwal, A.; Chaturvedi, R.; Sharma, M.; Jain, V.; Chhibber-Goel, J.; Sharma, A.
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Plasmodium vivax (A5JZS1), Plasmodium vivax, Plasmodium vivax Salvador 1 (A5JZS1), Plasmodium vivax Salvador I (A5JZS1)
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Gao, K.; Jia, Y.; Yang, M.
A network of conformational transitions revealed by molecular dynamics simulations of the binary complex of Escherichia coli 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase with MgATP
Biochemistry
55
6931-6939
2016
Escherichia coli (P26281), Escherichia coli
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Shi, G.; Shaw, G.X.; Zhu, F.; Tarasov, S.G.; Ji, X.
Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase Transition state analogs for high affinity binding
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115847
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Escherichia coli (P26281)
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Marimuthu, P.; Singaravelu, K.; Namasivayam, V.
Probing the binding mechanism of mercaptoguanine derivatives as inhibitors of HPPK by docking and molecular dynamics simulations
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2017
Staphylococcus aureus
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Zhao, L.; Lu, H.P.; Wang, J.
Exploration of multistate conformational dynamics upon ligand binding of a monomeric enzyme involved in pyrophosphoryl transfer
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1885-1897
2018
Escherichia coli (P26281)
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