Information on EC 2.5.1.15 - dihydropteroate synthase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
2.5.1.15
-
RECOMMENDED NAME
GeneOntology No.
dihydropteroate synthase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate = diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate = diphosphate + 7,8-dihydropteroate
show the reaction diagram
the reaction catalyzed by DHPS involves a nucleophilic attack by the amino nitrogen of 4-aminobenzoate on the exocyclic methyl carbon of DHPP. This results in the formation of the N-C bond and the elimination of the pyrophosphate moiety as a leaving group. A partial carbocation intermediate is believed to form at the extra-cyclic methylene in the transition state, which is stabilized by delocalization of the charge in the adjacent double bond of the pterin ring. Evidence supporting transient carbocation intermediate is shown by the inability of the oxidized form of DHPP (pterin-6-hydroxymethyl pyrophosphate) to act as a DHPS substrate
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate = diphosphate + 7,8-dihydropteroate
show the reaction diagram
SN1 reaction mechanism via formation of a novel cationic pterin intermediate, quantum chemical modelling of the initial step, overview. Two conserved loops generate a substructure during catalysis that creates a specific binding pocket for 4-aminobenzoic acid, one of the two DHPS substrates. The carboxylate moiety of 4-aminobenzoic acid is accommodated by Ser221 and the helix dipole of helix alphaLoop7
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
aryl group transfer
-
-
-
-
aryl group transfer
P59655
folate biosynthesis
aryl group transfer
-
-
aryl group transfer
-
folate biosynthesis
aryl group transfer
A1KPU3
folate biosynthesis
aryl group transfer
-, P64139
folate biosynthesis; folate biosynthesis
PATHWAY
KEGG Link
MetaCyc Link
Folate biosynthesis
-
Metabolic pathways
-
tetrahydrofolate biosynthesis
-
SYSTEMATIC NAME
IUBMB Comments
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl-diphosphate:4-aminobenzoate 2-amino-4-hydroxydihydropteridine-6-methenyltransferase
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6-hydroxymethyl-7,8-dihydropteroate synthase
-
-
7,8-dihydropteroate synthase
-
-
-
-
7,8-dihydropteroate synthase
Q1ENB6
-
7,8-dihydropteroate synthase
Haemophilus parasuis serovar
-
-
7,8-dihydropteroate synthase
Q49HL6
-
7,8-dihydropteroate synthase
P0C0X2
-
7,8-dihydropteroate synthase
Q27735
-
7,8-dihydropteroate synthase
Q00LY0
-
7,8-dihydropteroate synthase
Q9UUP4
-
7,8-dihydropteroate synthase
P53848
-
7,8-dihydropteroate synthetase
-
-
-
-
7,8-dihydropteroic acid synthetase
-
-
-
-
DHPS
-
-
-
-
DHPS
Q81VW8
-
DHPS
Haemophilus parasuis serovar
-
-
DHPS
Q49HL6
-
DHPS
Q00LY0
-
DHPS/DHPR
Q1ENB6
-
DHPS/DHPR
Q49HL6
-
dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
-
trifunctional enzyme
dihydropteroate diphosphorylase
-
-
-
-
dihydropteroate synthase
Q1ENB6
-
dihydropteroate synthase
Q81VW8
encoded by folP gene
dihydropteroate synthase
Q49HL6
-
dihydropteroate synthase
-
-
dihydropteroate synthase
-
-
dihydropteroate synthase
P53848
-
dihydropteroate synthase
-
-
dihydropteroate synthetase
-
-
-
-
dihydropteroate synthetase
Haemophilus parasuis serovar
-
-
dihydropteroate synthetase
P0C0X2
-
dihydropteroate synthetase
Q27735
-
dihydropteroate synthetase
Q00LY0
-
dihydropteroate synthetase
Q9UUP4
-
dihydropteroic synthetase
-
-
-
-
FolP
Q49HL6
-
folP1
P0C0X2
-
hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase
-
bifunctional enzyme
MbDHPS
A1KPU3
BCG3672c gene
Mycobacterium tuberculosis dihydropteroate synthase
P0A578
folP1 gene
pfPPK-DHPS
-
recombinant hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase
putative dihydropteroate synthase ortholog
P64139
-
pvdhps
Q00LY0
-
Rv1207
P64139
folP2 gene
synthase, dihydropteroate
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9055-61-2
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
-
Q81VW8
UniProt
Manually annotated by BRENDA team
Escherichia coli MC4100
-
SwissProt
Manually annotated by BRENDA team
Haemophilus parasuis serovar
-
-
-
Manually annotated by BRENDA team
-
Q49HL6
SwissProt
Manually annotated by BRENDA team
strain BCG
UniProt
Manually annotated by BRENDA team
no activity in Homo sapiens
-
-
-
Manually annotated by BRENDA team
fragment of dihydropteroate synthase
SwissProt
Manually annotated by BRENDA team
fragment of dihydropteroate synthase
SwissProt
Manually annotated by BRENDA team
QSAR studies of a series of sulfa drugs
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
evolution
-
dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes
malfunction
-
prevalence and frequency of the dihydropteroate synthetase mutations associated with sulfadoxine-pyrimethamine resistance in southern Mozambique are examined between 1999 and 2004. The dihydropteroate synthetase double mutation frequency peaks in 2001 but declines to baseline levels by 2004. Parasites with both dihydrofolate reductase triple and dihydropteroate synthetase double mutations increase in 2001 but decrease by 2004. The peaking of sulfadoxine-pyrimethamine resistance markers in 2001 coincides with a sulfadoxine-pyrimethamine-resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in dihydropteroate synthetase (but not dihydrofolate reductase) mutations correspond with replacement of sulfadoxine-pyrimethamine with artemether-lumefantrine as malaria treatment policy in KwaZulu-Natal
metabolism
-, Q1BXC8
the enzyme supports the biosynthesis of folate, a key metabolite required to support the synthesis of DNA, and proteins
physiological function
-
the prevalence of DHPS mutations in Pneumocystis jirovecii strains isolated from South African Pneumocystis jirovecii pneumonia patients are examined. Mutations resulting in amino-acid substitutions Thr55Ala and/or Pro57Ser are detected in Pneumocystis jirovecii from 85/151 (56%) patients. The high frequency of PCP episodes with Pneumocystis jirovecii harbouring DHPS mutations in South Africa indicates that populations of this fungus are evolving under considerable selective pressure exerted by sulfa-containing antibiotics
physiological function
-
mutation at DHPS locus amongst Pneumocystis jiroveci isolates obtained at a tertiary care hospital in north India are investigated. Using microscopic examination Pneumocystis jiroveci is detected in four cases and major surface glycoprotein gene is amplified in five cases. Further, amplification of DHPS gene is successful in four of the five cases positive by major surface glycoprotein gene PCR. No point mutation is observed and all four isolates presented wild-type sequences at DHPS gene by RFLP analysis
metabolism
-
dihydropteroate synthase is a key enzyme in the folate pathway of bacteria and primitive eukaryotes
additional information
-
the 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops
additional information
-, Q1BXC8
analysis of DHPS active site and interactions with the enzyme product 7,8-dihydropteroate, overview. DHPS shows plasticity near the substrate-binding pocket and a range of loop conformations that contribute to the architecture of the DHPS active site
additional information
-
the enzyme is bifunctional exhibiting 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, HPPK, EC 2.7.6.3, and dihydropteroate synthase, DHPS, activities, that catalyze sequential metabolic reactions in the folate biosynthetic pathway of bacteria and lower eukaryotes, structural organization between FtHPPK and FtDHPS which are tethered together by a short linker, overview. Each active site binds substrate in the same manner observed in the monofunctional forms. Structures of the active site loops in the DHPS module
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, Q1BXC8
-
-
-
r
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, Q1BXC8
-
7,8-dihydropteroate binding mode, overview
-
r
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + 4-aminobenzoate
7,8-dihydropteroate + diphosphate
show the reaction diagram
P53848
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + 4-aminobenzoate
7,8-dihydropteroate + diphosphate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
O05701, -
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-, 1014
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Escherichia coli MC4100
P0AC13
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
P0A578
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
P0C0X1
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
P0C0X2
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q27735
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q1ENB6
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q00LY0
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Haemophilus parasuis serovar
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q9UUP4
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q49HL6
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoylglutamate
diphosphate + dihydrofolate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + sulfamethoxazole
diphosphate + dihydropterin-sulfamethoxazole
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + sulfanilamide
diphosphate + dihydropterin-sulfanilamide
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + sulfathiazole
diphosphate + dihydropterin-sulfathiazole
show the reaction diagram
-
-
-
?
4-aminobenzoate + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, P0A578
-
-
-
?
6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
pH 7.5, folate biosynthesis
coupled with diphosphate-dependent phosphofructokinase, aldolase, triosephosphate isomerase, alpha-glycerophosphate dehydrogenase, in presence of NADH and D-fructose 6-phosphate, decrease in NADH monitored as change of absorbance at 340 nm
-
?
p-aminobenzoate + 6-hydroxymethyl-7,8-dihydropterin-diphosphate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, P64139
5 mM MgCl2, 1 mM dithiothreitol, 37C, pH 7-9.5
-
-
?
p-aminobenzoic acid + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
P59655
substrate binding order: 6-hydroxymethyl-7,8-dihydropterin diphosphate binds prior to p-aminobenzoic acid, 6-hydroxymethyl-7,8-dihydropterin diphosphate binding with KD: 33 +/-6 microM (k(on): 260000 1/M*s, k(off): 8.7 1/s) as revealed by fluorescence spectroscopy, p-aminobenzoic acid binding to diphosphate-enzyme complex: KD: 0.13 +/-0.02 microM
diphosphate-binding allows binding of p-aminobenzoic acid or p-aminobenzoic acid analogues, diphosphate binding with KD: 350 +/-20 microM (k(on): 56000 1/M*s, k(off): 21 1/s) as revealed by fluorescence spectroscopy
-
?
sulfadiazine + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 4-[[(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino]-N-pyrimidin-2-ylbenzenesulfonamide
show the reaction diagram
-
-
-
-
?
sulfamethazole + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 4-[[(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide
show the reaction diagram
-
-
-
-
?
sulfamethizole + 6-hydroxymethyl-7,8-dihydropterin diphosphate
?
show the reaction diagram
-
-
-
-
?
sulfamethoxazole + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 4-[[(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino]-N-(5-methylisoxazol-3-yl)benzenesulfonamide
show the reaction diagram
-
-
-
-
?
sulfanilamide + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 4-[[(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino]benzenesulfonamide
show the reaction diagram
-
-
-
-
?
sulfathiazole + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 4-[[(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino]-N-1,3-thiazol-2-ylbenzenesulfonamide
show the reaction diagram
-
-
-
-
?
sulfisoxazole + 6-hydroxymethyl-7,8-dihydropterin diphosphate
?
show the reaction diagram
-
-
-
-
?
dapson + Mg-6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 2-amino-6-[([4-[(4-aminophenyl)sulfonyl]phenyl]amino)methyl]-7,8-dihydropteridin-4(3H)-one
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
amino acid V585 may be responsible for resistance of Plasmodium vivax to sulfadoxine
-
-
-
additional information
?
-
-, P64139
binding of 6-hydroxymethyl-7,8-dihydropterin-diphosphate with KD: 117 microM, revealed by fluorescence spectroscopy
-
-
-
additional information
?
-
-, P64139
binding of 6-hydroxymethyl-7,8-dihydropterin-diphosphate with KD: 4.6 microM, revealed by fluorescence spectroscopy
-
-
-
additional information
?
-
-, P64139
binding of dapsone (p-aminobenzoate substrate analog) with KD: 168 microM, in absence of 6-hydroxymethyl-7,8-dihydropterin-diphosphate, , revealed by fluorescence spectroscopy
-
-
-
additional information
?
-
-, P64139
binding of dapsone (p-aminobenzoate substrate analog) with KD: 96 microM, in absence of 6-hydroxymethyl-7,8-dihydropterin-diphosphate, revealed by fluorescence spectroscopy
-
-
-
additional information
?
-
-, P64139
Rv1207 lacks dihydropteroate synthase activity in presence of 10 microM p-aminobenzoate and 10 microM 6-hydroxymethyl-7,8-dihydropterin-diphosphate, 5 mM MgCl2, 1 mM dithiothreitol, 37C, pH 7-9.5
-
-
-
additional information
?
-
-
the enzyme is bifunctional exhibiting 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, HPPK, and dihydropteroate synthase, DHPS, activities
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, Q1BXC8
-
-
-
r
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
O05701, -
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
P0C0X2
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q27735
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q1ENB6
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q00LY0
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Haemophilus parasuis serovar
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q9UUP4
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
Q49HL6
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoylglutamate
diphosphate + dihydrofolate
show the reaction diagram
-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + sulfamethoxazole
diphosphate + dihydropterin-sulfamethoxazole
show the reaction diagram
-
-
-
?
4-aminobenzoate + (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
-, P0A578
-
-
-
?
additional information
?
-
-
amino acid V585 may be responsible for resistance of Plasmodium vivax to sulfadoxine
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
flavin adenine dinucleotide
Q49HL6
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
KCl
-
0.4 M activates
Mg2+
-
required to synthesize product
Mg2+
-
required to synthesize product
Mg2+
-
required to synthesize product
Mg2+
-
required to synthesize product
Mg2+
-
dependent on
NaCl
-
0.2 M activates
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)acetic acid
-
-
(7-amino-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)acetic acid
-
-
2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydorpyrimido[4,5-c]pyridazin-3-yl)propanoic acid
-
binding structure, interactions with the DHPS module and the HPPK module, modeling, ovverview
-
2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)propanoic acid
-
-
2-(7-amino-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)propanoic acid
-
-
2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine
-
-
3-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)butanoic acid
-
-
3-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)propanoic acid
-
-
3-(7-amino-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)propanoic acid
-
-
4,4-Diaminodiphenyl sulfone
-
-
5-nitro-6-methylamino-isocytosine
-
-
-
6-hydroxymethylpterin monophosphate
-
6HMP, competitive inhibitor, 6-hydroxymethyl-7,8-dihydropterin diphosphate analogue
7,8-Dihydropteroic acid
-
-
7,8-Dihydropteroic acid
-
-
7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazine-3-carboxylic acid
-
-
7-amino-3-(1-carboxyethyl)-1-methyl-pyrimido (4,5-c)-pyridazine-4,5(1H,6H)-dione
-
-
7-amino-3-(1-carboxyethyl)-1-methyl-pyrimido (4,5-c)-pyridazine-4,5(1H,6H)-dione
-
-
cycloguanil
Q00LY0
-
dapson
-
KD: 0.2 microM according to molecular modelling
dapsone
-
effective against wild-type enzyme and mutants A437G/K540E and A437G. Ineffective against mutants A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
dihydrofolate monoglutamate
-
-
Guanidine HCl
-
0.25 M, 50% inhibition
p-Aminobenzoate
-
-
p-Aminobenzoylglutamate
-
weak
p-Aminosalicylate
-
-
p-Aminosalicylate
P0A578
-
p-Aminosalicylic acid
-
-
p-Aminosalicylic acid
-
-
phosphanilic acid
-
28% inhibition at 2.0 mM, complete inhibition at 20 mM
phosphanilic acid
-
22% inhibition at 2.0 mM, 84% inhibition at 20 mM
potassium 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(2-phosphonoethyl)-amino]-methyl)-benzoate
-
the oxidized analogue shows significant DHPS inhibition and significant antimicrobial activity
-
potassium 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(3-phosphonopropyl)-amino]-methyl)-benzoate
-
the oxidized analogue shows significant DHPS inhibition and significant antimicrobial activity
-
Pteroic acid
-
PTA, product analog, binds pterin- and 4-aminobenzoate-binding regions
Pyrimethamine
Q00LY0
-
sulfacetamide
-
effective against wild-type enzyme and mutant enzymes A437G/K540E, A437G, A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
sulfachloropyridazine
-
effective against wild-type enzyme and mutant enzymes A437G/K540E, A437G, A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
sulfachloropyridazine
-
-
sulfachloropyridazine
-
-
sulfachlorpyridazine
-
-
Sulfadiazine
-
0.2 mM, complete inhibition
sulfadimethoxine
-
effective against wild-type enzyme and mutant A437G. Ineffective against mutants A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T
sulfadimethoxine
-
-
sulfadimethoxine
-
-
sulfadoxine
-
effective against wild-type enzyme. Ineffective against mutants A437G, A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T. IC50 for wild-type enzyme: 0.071 mg/ml, IC50 for mutant enzyme A437G: 0.203 mg/ml, IC50 for mutant enzyme A437G/K540E: 0.423 mg/ml, IC50 for mutant enzyme A437G/A581G: 0.775 mg/ml, IC50 for mutant enzymes S436F/A437G/A613S and S436F/A437G/A613T is above 1 mg/ml
sulfadoxine-pyrimethamine
-
-
sulfamerazine
-
effective against wild-type enzyme and mutants A437G/K540E and A437G. Ineffective against mutants A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
sulfamethoxazole
-
competitive to 4-aminobenzoate
sulfamethoxazole
-
-
sulfamethoxazole
-
effective against wild-type enzyme and mutant A437G. Ineffective against mutants A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T
sulfamethoxazole
-
-
sulfamethoxazole
P59655
a sulfonamide, KD = 2.3 +/-0.1 microM as revealed by fluorescence spectroscopy
sulfamethoxypyridazine
-
-
sulfamethoxypyridazine
P0A578
-
sulfamethoxypyridazine
-
-
sulfamethoxypyridazine
-
-
sulfamoxisole
-
effective against wild-type enzyme and mutant enzymes A437G/K540E, A437G, S436F/A437G/A613S and S436F/A437G/A613T. Ineffective against A437G/A581G
-
sulfanilamide
-
-
sulfanilamide
-
effective against wild-type enzyme and mutants A437G/K540E and A437G. Ineffective against mutants A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
Sulfanilic acid
-
-
sulfaquinoxaline
-
effective against wild-type enzyme and mutant A437G. Ineffective against mutants A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T
sulfaquinoxaline
-
-
sulfaquinoxaline
-
-
sulfaquinoxazoline
-
-
-
sulfathiazole
-
competitive to 4-aminobenzoate
sulfathiazole
-
competitive to 4-aminobenzoate
sulfathiazole
-
competitive to 4-aminobenzoate
sulfathiazole
-
competitive to 4-aminobenzoate
sulfathiazole
-
competitive to 4-aminobenzoate
sulfathiazole
-
effective against wild-type enzyme and mutants A437G/K540E and A437G. Ineffective against mutants A437G/A581G, S436F/A437G/A613S and S436F/A437G/A613T
sulfisoxazole
-
effective against wild-type enzyme and mutant A437G. Ineffective against mutants A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T
sulfonamide
-
competitive to 4-aminobenzoate
sulfonamide
-
competitive to 4-aminobenzoate
Sulfonamides
-
act as competitive inhibitors with respect to the 4-amino benzoic acid substrate within the DHPS enzyme active site. The 4-amino benzoic acid/sulfonamide binding site is formed close to the protein surface by flexible protein loops facilitating rapid development of sulfonamide resistance. Study of inhibitors designed to target the conserved central pterin binding site within DHPS, molecular dynamics simulation and molecular modeling, overview. Design and synthesis of transition state analogues with ability to mimic the intermediate transient carbocation by the incorporation of a basic amine at the 6-position of the pterin ring
sulfpyridine
-
effective against wild-type enzyme. Ineffective against mutants A437G, A437G/A581G, A437G/K540E, S436F/A437G/A613S and S436F/A437G/A613T
-
tetrahydrofolate monoglutamate
-
-
trimethoprim-sulfamethoxazole
-
-
Trp-Lys
-
WK, highly potent with KD: 0.23 nM according to structure-based molecular modelling and docking, overlaps with pterin monophosphate and pteroic acid binding regions, highly selective for microbial DHPS compared to human pterin and folate-binding enzymes (dihydrofolate reductase, thymidylate synthase)
Urea
-
0.9 M, 50% inhibition
WR99210
Q00LY0
-
additional information
-
no inhibition by sulfadiazine sodium salt, sulfamethoxazole, sulfamethazole, sulfanilamide, sulfathiazole sodium salt in presence of both substrates
-
additional information
-
compounds 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(2-phosphono-ethyl)-amino]-methyl)-benzoic acid and 4-([(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-(3-phosphono-propyl)-amino]-methyl)-benzoic acid are inactive in inhibition of DHPS, sp2 centers are required at the pterin 5-6 positions for inhibition
-
additional information
-
a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines are designed to improve binding affinity as dihydropteroate synthase inhibitors, overview. The N-methyl ring substitution is removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid is optimized to fully engage the diphosphate binding site. Evaluation by evaluated an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives
-
additional information
-
simultaneously targeting of the two modules of the bifunctional enzyme with pterin binding inhibitors
-
additional information
-
structural, computational and mutagenesis studies on the catalytic and resistance mechanisms of DHPS with sulfonamide antibiotics, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Sulfadiazine
-
reaction rate increased by sulfadiazine sodium salt, sulfamethoxazole, sulfamethazole, sulfanilamide, sulfathiazole sodium salt in presence of both substrates
sulfamethoxazole
-
reaction rate increased by sulfadiazine sodium salt, sulfamethoxazole, sulfamethazole, sulfanilamide, sulfathiazole sodium salt in presence of both substrates
sulfanilamide
-
reaction rate increased by sulfadiazine sodium salt, sulfamethoxazole, sulfamethazole, sulfanilamide, sulfathiazole sodium salt in presence of both substrates
sulfathiazole
-
reaction rate increased by sulfadiazine sodium salt, sulfamethoxazole, sulfamethazole, sulfanilamide, sulfathiazole sodium salt in presence of both substrates
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0036
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA257-306
0.0063
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA247-306
0.0148
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
wild type
0.0514
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA74-80
0.0004
-
2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
0.00122
-
2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
-
0.0014
-
2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate
-
-
0.0019
-
2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate
Escherichia coli MC4100
P0AC13
-
0.0005
-
4-Aminobenzoate
Escherichia coli MC4100
P0AC13
-
0.00057
-
4-Aminobenzoate
-
-
0.00125
-
4-Aminobenzoate
-
-
0.0015
-
4-Aminobenzoate
-
-
0.0026
-
4-Aminobenzoate
-
20 microM DHP-PP, 25 C
0.0038
-
4-Aminobenzoate
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
0.0025
-
4-Aminobenzoic acid
-
-
0.0028
-
4-Aminobenzoic acid
-
-
0.0027
-
6-hydroxymethyl-7,8-dihydropterin diphosphate
-
100 microM 4-aminobenzoate, 25 C
0.03
-
6-hydroxymethyldihydropteridine diphosphate
-
-
0.0026
-
p-Aminobenzoate
-
mutant DELTA257-306
0.0039
-
p-Aminobenzoate
-
wild type
0.00708
-
p-Aminobenzoate
-
mutant DELTA74-80
0.008
-
p-Aminobenzoate
-
mutant DELTA247-306
0.00037
-
p-Aminobenzoic acid
P0A578
-
0.0006
-
p-Aminobenzoic acid
-
-
0.0006
-
p-Aminobenzoic acid
-
-
0.00085
-
p-Aminobenzoic acid
-
sulfonamide resistant enzyme
0.0034
-
p-Aminobenzoic acid
-
wild type
0.0485
-
p-Aminobenzoic acid
-
mutant P559S
0.103
-
p-Aminobenzoic acid
-
mutant T557A
1.161
-
p-Aminobenzoic acid
-
mutant T557V/P559S
4.02
-
p-Aminobenzoic acid
-
mutant T557A/P559S
0.00289
-
Sulfadiazine
-
in absence of 4-aminobenzoate
0.0007
-
sulfamethizole
-
in absence of 4-aminobenzoate
0.00012
-
sulfamethoxazole
-
-
0.0027
-
sulfamethoxazole
-
in absence of 4-aminobenzoate
0.0006
-
sulfanilamide
-
in absence of 4-aminobenzoate
0.0048
-
sulfanilamide
-
-
0.00033
-
sulfathiazole
-
in absence of 4-aminobenzoate
0.001
-
sulfathiazole
-
-
0.0015
-
sulfisoxazole
-
in absence of 4-aminobenzoate
0.000058
-
dapson
-
in absence of 4-aminobenzoate
additional information
-
additional information
-
values for recombinant enzymes
-
additional information
-
additional information
-
values for recombinant enzymes
-
additional information
-
additional information
-
activity in Escherichia coli C600 and recombinant strains; activity in Escherichia coli C600 and recombinant strains
-
additional information
-
additional information
-
activity in Streptococcus pneumoniae strains with different repeats of amino acids
-
additional information
-
additional information
-
activity in plant enzyme and recombinant enzyme
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.032
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA74-80
0.035
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA257-306
0.068
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA247-306
0.069
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
wild type
0.109
-
4-Aminobenzoate
-
100 microM DHP-PP, 25 C
0.1243
-
Sulfadiazine
-
in absence of 4-aminobenzoate
0.079
-
sulfamethizole
-
in absence of 4-aminobenzoate
0.12
-
sulfamethoxazole
-
in absence of 4-aminobenzoate
0.08
-
sulfanilamide
-
in absence of 4-aminobenzoate
0.0887
-
sulfathiazole
-
in absence of 4-aminobenzoate
0.11
-
sulfisoxazole
-
in absence of 4-aminobenzoate
0.0578
-
dapson
-
in absence of 4-aminobenzoate
additional information
-
additional information
-
linear dependency on DHPS concentration when concentration of enzyme versus initial velocity in the coupled enzymatic assay
-
kcat/KM VALUE [1/mMs-1]
kcat/KM VALUE [1/mMs-1] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1.08
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA247-306
221662
4.7
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
wild type
221662
5.86
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA257-306
221662
6.23
-
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
-
mutant DELTA74-80
221662
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.043
-
2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine
-
-
0.0036
-
6-hydroxymethylpterin monophosphate
-
100 microM 4-aminobenzoate
0.005
0.008
7,8-dihydropteroate
-
inhibitor of p-aminobenzoic acid
0.007
0.011
7,8-dihydropteroate
-
inhibitor of 6-hydroxymethyl-7,8-dihydropteridine diphosphate
0.000011
-
dapsone
-
-
0.000013
-
dapsone
P0A578
-
0.00068
-
dapsone
-
wild tpye
0.001
-
dapsone
-
-
0.00205
-
dapsone
-
mutant T557A
0.0148
-
dapsone
-
mutant P559S
1.16
-
dapsone
-
mutant T557A/P559S
1.29
-
dapsone
-
mutant T557V/P559S
1
-
p-Aminobenzoylglutamate
-
-
0.0082
-
p-Aminosalicylic acid
-
-
0.023
-
p-Aminosalicylic acid
-
-
0.0941
-
sulfacetamide
-
-
0.0015
-
sulfachloropyridazine
-
-
0.00295
-
sulfachloropyridazine
-
wild tpye
0.0063
-
sulfachloropyridazine
-
mutant T557A
0.0513
-
sulfachloropyridazine
-
mutant P559S
0.096
-
sulfachloropyridazine
-
mutant T557A/P559S
0.94
-
sulfachloropyridazine
-
mutant T557V/P559S
0.0068
-
Sulfadiazine
-
-
0.0018
-
sulfadimethoxine
-
-
0.011
-
sulfadoxine
-
-
0.069
-
Sulfaguanidine
-
-
0.0048
-
sulfamerazine
-
-
0.000028
-
sulfamethoxazole
P0A578
-
0.00003
-
sulfamethoxazole
-
-
0.00013
-
sulfamethoxazole
-
-
0.00059
-
sulfamethoxazole
-
-
0.00371
-
sulfamethoxazole
-
mutant T557A
0.0044
-
sulfamethoxazole
-
-
0.0085
-
sulfamethoxazole
-
wild tpye
0.0543
-
sulfamethoxazole
-
mutant P559S
0.76
-
sulfamethoxazole
-
mutant T557V/P559S
1.17
-
sulfamethoxazole
-
mutant T557A/P559S
0.000025
-
sulfamethoxypyridazine
-
-
0.000031
-
sulfamethoxypyridazine
P0A578
-
0.0033
-
sulfamethoxypyridazine
-
-
0.0027
-
sulfamoxole
-
-
0.00085
-
sulfanilamide
-
-
0.0057
-
sulfanilamide
-
-
0.0437
-
sulfanilamide
-
-
0.13
-
sulfanilamide
-
-
0.14
-
Sulfanilic acid
-
-
0.0019
-
sulfapyridine
-
-
0.0016
-
sulfaquinoxaline
-
-
0.025
-
sulfaquinoxazoline
-
-
-
0.0006
-
sulfathiazole
-
-
0.014
-
sulfathiazole
-
-
0.5
-
sulfathiazole
-
resistant enzyme
0.0076
-
sulfisoxazole
-
-
0.00053
-
sulfonamide
-
-
additional information
-
additional information
-
KI values of sulfadoxine for recombinant enzymes
-
additional information
-
additional information
-
KI values of sulfathiazole for wild-type and mutant enzyme
-
additional information
-
additional information
-
KI values of sulfathiazole inhibition on Streptococcus pneumoniae strains with different repeats of amino acids
-
additional information
-
additional information
-
KI values of folate derivatives
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.0000483
-
-
crude extract of Escherichia coli MG1655
0.005
-
-, P64139
+/-3, assumed inactive because 100times less than folP1 gene product
0.174
-
-
recombinant enzyme
0.425
-
-
-
0.577
-
-, P64139
+/-12, pH 9
0.596
-
P0A578
recombinant enzyme
1.25
-
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
3.7
-
Escherichia coli MC4100
P0AC13
-
additional information
-
-
specific activity in different strains
additional information
-
-
specific activity in plant enzyme and recombinant enzyme
additional information
-
-
0.906 +/-0.002 microM/min, with respect to dapson, in absence of 4-aminobenzoate; 1.24 +/-0.03 microM/min, with respect to sulfamethizole, in absence of 4-aminobenzoate; 1.26 +/-0.07 microM/min, with respect to sulfanilamide, in absence of 4-aminobenzoate; 1.39 +/-0.01 microM/min, with respect to sulfathiazole, in absence of 4-aminobenzoate; 1.71 +/-0.03 microM/min, with respect to 4-aminobenzoate; 1.80 +/-0.03 microM/min, with respect to sulfisoxazole, in absence of 4-aminobenzoate; 1.88 +/-0.05 microM/min, with respect to sulfamethoxazole, in absence of 4-aminobenzoate; 1.947 +/-0.03 microM/min, with respect to sulfadiazine, in absence of 4-aminobenzoate
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.6
-
-
assay at
8.5
-
-
dihydropteroate synthase activity of the recombinant bifunctional fusion protein consisting of dihydropterin diphosphokinase and dihyropteroate synthase domains
9
-
-, P64139
according to specific activity
9
-
-
assay at
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
10.5
-
70% of maximal activity at pH 7.0 and 10.5
7
9.3
-
pH 7.0: about 50% of maximal activity, pH 9.3: about 60% of maximal activity, dihydropteroate synthase activity of the recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
8.5
10.5
-
pH 8.5: about 40% of maximal activity, pH 10.5: about 85% of maximal activity
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
Escherichia coli MC4100
P0AC13
assay at
37
-
-
assay at
TEMPERATURE RANGE
TEMPERATURE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
55
-
30C: about 40% of maximal activity, 55C: about 10% of maximal activity
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.11
-
-
recombinant hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
A1KPU3
logarithmic growing bacteria, Western blotting; qiescent bacteria, lower expression level under anaerobic conditions compared to nutrient starvation, Western blotting
Manually annotated by BRENDA team
additional information
-
bronchoalveolar lavage isolates from AIDS patient in Brazil
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Escherichia coli MC4100
P0AC13
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Bacillus anthracis (strain A0248)
Burkholderia cenocepacia (strain ATCC BAA-245 / DSM 16553 / LMG 16656 / NCTC 13227 / J2315 / CF5610)
Burkholderia cenocepacia (strain ATCC BAA-245 / DSM 16553 / LMG 16656 / NCTC 13227 / J2315 / CF5610)
Coxiella burnetii (strain RSA 493 / Nine Mile phase I)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Staphylococcus aureus (strain Mu50 / ATCC 700699)
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
29000
-
-, P64139
recombinant, hexa-His tagged enzyme, SDS-PAGE
33000
-
-, P64139
recombinant, hexa-His tagged enzyme, SDS-PAGE
34070
-
-, P64139
deduced from primary structure
50000
-
-
gel filtration
52000
54000
Escherichia coli MC4100
P0AC13
gel filtration
52000
-
-
polyacrylamide gel electrophoresis
53000
-
-
SDS-PAGE analysis of soluble protein
53000
-
-
gel filtration, analytical sedimentation centrifugation
60000
-
-
gel filtration of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase
60000
-
P0A578
gel filtration of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase
61300
-
O05701, -
-
68000
-
-, Q1BXC8
recombinant enzyme, gel filtration
71500
-
-
polyacrylamide gel electrophoresis
75000
-
-, P64139
recombinant hexa-His tagged enzyme, gel filtration chromatography
83000
-
-
bifunctional hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase, gel filtration
110000
-
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase, gel filtration
190000
-
-
Sephadex chromatography
222000
-
-
gel filtration
280000
300000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
Escherichia coli MC4100
P0AC13
2 * 30000, SDS-PAGE
dimer
O05701, -
-
dimer
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
dimer
-, Q1BXC8
structure and sequence comparison, overview
homodimer
-, P64139
2 * 34070, gel filtration chromatography
monomer
-
1 * 50509, sequence calculation
additional information
-
primary and secondary structures of the HPPK-DHPS bifunctional enzyme, structure comparisons, three-dimensional structure, overview
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
purified recombinant apo-enzyme and enzyme in complex with inhibitor sulphadoxine or product 7,8-dihydropteroate, sitting drop vapor diffusion method, mixing of 0.001 ml of protein solution, containing 7.5 mg/ml protein in 50 mM Tris-HCl, 250 mM NaCl pH 7.5, with 0.001 ml of reservoir solution, containing 0.1 M Tris-HCl, pH 8, 10% PEG 8000, 0.3 M MgCl2, 4C, X-ray diffraction structure determinationation and analysis at 1.95-2.35 A resolution, molecular replacement and modeling
-, Q1BXC8
apo-enzyme, and enzyme in complex with HPPK substrate 6-hydroxymethyl-7,8-dihydropterin or inhibitor 2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydorpyrimido[4,5-c]pyridazin-3-yl)propanoic acid, X-ray diffraction structure determination and analysis at 2.2-2.3 A resolution
-
PDB: 2VP8, conforms classical triosephosphate isomerase (TIM) barrel arrangement, 6-hydroxymethyl-7,8-dihydropterin-diphosphate-binding pocket occupied by the histidine 220 side chain compared to leucine 180 in the functional ortholog MtDHPS (PDB: 1EYE), crystals: space group P3(1)21, 2 molecules per asymmetric unit, noncrystallographic dimer in the crystal structure, unit cell parameters: a, b: 80.73, c: 215.94, hanging drop vapour method: 25% ethylene glycole + protein solution (16 mg/ml), 2 days, 18C
-, P64139
structure-based molecular modelling of the missing loop 2 (PDB: 1EYE) using Escherichia coli DHPS (PDB: 1AJZ) for further docking approaches, (i) extraction and docking of pterin monophosphate (PtP), KD(PtP): 0.5 microM, (ii) ternary complex of dapson docked with enzyme-PtP complex, KD(dapson): 0.2 microM, contacts with residues S53, R54, P55, F182, K213, (iii) ternary complex of pteroic acid (PTA) docked with enzyme-PtP complex, contacts with pterin- and 4-aminobenzoate-binding regions, (iv) inhibitor complex with dipeptide Trp-Lys (WK), contacts with residues E51, S53, D21, D86, K213, R253, and four water molecules, KD(WK): 0.23 nM
-
more putative structural model of five mutations in DHPS to explain sulfadoxine resistance, structural model based on crystal structures of Saccharomyces cerevisiae (PPPK-DHPS), Mycobacterium tuberculosis (DHPS), Bacillus anthracis (DHPS), and Escherichia coli (PPPK)
-
a complex of the purified bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase with a pterin monophosphate substrate analogue, structure solved by molecular replacement and refined to 2.3 A resolution
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
-
apoenzyme (PDB: 2VEF), complex with 6-hydroxymethyl-7,8-dihydropterin monophosphate (DHPP) (PDB: 2VEG), TIM alpha/beta barrel fold with highly conserved 6-hydroxymethyl-7,8-dihydropterin diphosphate-binding pocket, crystals: space group P2(1)2(1)2(1), unit cell parameters: a: 45, b: 90, c: 137, loop 1 and 2 highly flexible, dimer of two identical monomers in the asymmetric unit, in complex with DHPP only one monomer of the dimer has substrate bound wide-scale rearrangement of active site upon 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPPP) binding mediated by diphosphate moiety, hanging-drop method: 2 microlitre protein solution (13 mg/ml) + 2 microl precipitant (0.2 M ammonium iodide, 20% (w/v) poly(ethylene glycol) 3350) +/-2.5 mM DHPPP (hydrolysis to DHPP during crystallization), 7-14 days, molecular replacement-based structure determination
P59655
apo-structure and structure of the complex with pteroate, analysis, overview
-
pH STABILITY
pH STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.5
10
-
stable, dihydropteroate synthase activity of the recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
55
-
-
inactivation above
60
-
-
10 min, loss of activity
100
-
-
60 min, 75% loss of activity
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-20C, sucrose, indefinitely stable
-
-20C or -70C, 20 mM Tris/HCl, pH 8.0, 5 weeks
Escherichia coli MC4100
P0AC13
-80C, pH 7.0, 20% glycerol, 10-30% loss of activity in 1 month
-
-80C, pH 7.0, 20% glycerol, 10-30% loss of activity in 1 month
P0A578
-20C and -80C stable for 3 months in 20 mM TrisHCl, pH 8.0 buffer containing 10% or 20% glycerol
-
-20C or -80C, in buffer without glycerol, 30% and 50% of the enzyme activity is lost when stored for 6 months
-
-20C, enzyme remains active in 50% glycerol, 1 mM MgCl2, 5 mM 2-mercaptoethanol, stable for long term-storage, dihydropteroate synthase activity of the recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
-
4C, or -20C, without glycerol, enzyme denaturates, dihydropteroate synthase activity of the recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
overexpression of the N-terminal His6 fusion protein in Escherichia coli, coexpression with chaperone genes to increase solubility
Q1ENB6
His-tagged recombinant protein by fast-performance liquid chromatography
-
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3)by nickel affinity chromatography and gel filtration
-, Q1BXC8
gel filtration on Sephadex G-100
-
precipitation with ammonium sulfate followed by column chromatography
-
Q-Sepharose column
-
precipitation with ammonium sulfate followed by column chromatography
Escherichia coli MC4100
P0AC13
precipitation with ammonium sulfate followed by column chromatography
-
mycobacterial enzymes, from DEAE-Sepharose and other chromatography steps
-
recombinant, hexa-His tagged enzyme from bacterial lysate by nickel-nitrilotriacetic acid agarose, elution with 200 mM imidazole, stored at -80C in 10% glycerol or further purified on by Superdex 200 16/60 gel filtration chromatography; recombinant, hexa-His tagged enzyme from bacterial lysate by nickel-nitrilotriacetic acid agarose, elution with 200 mM imidazole, stored at -80C in 10% glycerol or further purified on by Superdex 200 GL 10/300 gel filtration chromatography
-, P64139
mycobacterial enzymes, from DEAE-Sepharose and other chromatography steps
P0A578
anion exchange and affinity column
-
recombinant enzyme, affinity column
-
precipitation with ammonium sulfate followed by column chromatography
-
enzyme from recombinant clones in Sephacryl S-300 HR, enzyme isolated form Escherichia coli, several chromatographic columns
-
recombinant hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase
-
recombinant bifunctional fusion protein encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase
-
gel filtration and ion-exchange chromatography
-
precipitation from bacterial lysate by ammonium sufate (50% saturation), resuspension in Tris/HCl pH 8, Resource Q ion-exchange chromatography (elution with NaCl gradient), dialysis, Mono Q ion-exchange chromatography (elution with NaCl gradient), for crystallisation followed by Superdex 200 gel-filtration chromatography
P59655
Superdex-200 HR and other chromatographic columns
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression in Escherichia coli as N-terminal His6 fusion; expression in Saccharomyces cerevisiae Fol1 knockout Y26466
Q1ENB6
crystal structure of the liganded enzyme and of the enzyme in complex with 6-hydroxymethyl-pterine-diphosphate, 6-hydroxymethyl-pterine-monophosphate, 6-methylamino-5-nitroisocytosine, or pteroic acid. Hanging drop vapor diffusion method, the crystals are space group P6(2)22 with cell dimensions a = b = 97.4 A, c = 263.6 A
-
recombinant expression of the His-tagged enzyme in Escherichia coli strain BL21(DE3)
-, Q1BXC8
cloning of a sulfonamide resistant strain
-
engineering dihydropteroate synthase for efficient expression on M13 phage
-
expression in Escherichia coli
Haemophilus parasuis serovar
-
expression in Escherichia coli
Q49HL6
expression in dihydroxypteroate synthase deficient strain of Escherichia coli
-
expression in Escherichia coli C600 and in Escherichia coli folP knockout mutant; expression in Escherichia coli C600 and in Escherichia coli folP knockout mutant
-
from genomic DNA (strain H37Rv) in pET-21a for expression with C-terminal hexa-His tag in Escherichia coli BL21 (DE3); from genomic DNA (strain H37Rv) in pQE60 for expression with C-terminal hexa-His tag in Escherichia coli M15
-, P64139
expression in dihydroxypteroate synthase deficient strain of Escherichia coli
P0A578
expression of recombinant enzyme in Escherichia coli
-
expressed in Escherichia coli
-
expressed under the control of the T5 promoter in a DHPS-deficient Escherichia coli strain
-
expression in Escherichia coli
-
a single polypeptide, Fas protein, expressed in cultured Spodoptera frugiperda SF9 insect cells
-
expression in Escherichia coli
-
cDNA encoding dihydropterin pyrophosphokinase and dihyropteroate synthase domains of the trifunctional enzyme dihydroneopterin aldolase-dihydropterin pyrophosphokinase-dihydropteroate synthase is cloned. This bi-functional enzyme is expressed as a His6 fusion protein in Escherichia coli
-
expression in Escherichia coli
-
gene encoding bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase, cloned and expressed in Escherichia coli
-
expression in Escherichia coli
O05701, -
expression in different Escherichia coli strains
-
from Streptococcus pneumoniae for expression in Escherichia coli XL2-Blue
P59655
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
D96N
-
mutation improves phage display efficiency of the enzyme
G58A
Q49HL6
site-directed mutagenesis, cannot replace DHPR in Escherichia coli, affects the binding affinity for FMN
K31A
Q49HL6
site-directed mutagenesis, can replace DHPR in Escherichia coli, affects the binding affinity for FMN
K51A
Q49HL6
site-directed mutagenesis, can replace DHPR in Escherichia coli, affects the binding affinity for FMN
K92E
Q49HL6
site-directed mutagenesis, can replace DHPR in Escherichia coli, affects the binding affinity for FMN
P55A
-
mutation associated with dapsone resistance
P55L
-
mutation associated with dapsone resistance
T53A
-
mutation associated with dapsone resistance
T53I
-
mutation associated with dapsone resistance
T53V
-
mutation associated with dapsone resistance
A437G
-
mutant enzyme is resistant against inhibition by sulfadoxine and sulfpyridine (inhibitors of wild-type enzyme)
A437G
-
little association with between mutantion and sulfa drug resistance in patients
A437G/A581G
-
mutant enzyme is resistant against inhibition by sulfadoxine, sulfpyridine, sulfadimethoxine, sulfamethoxazole, sulfaquinoxaline and sulfisoxazole (inhibitors of wild-type enzyme)
A437G/K540E
-
sulfadoxine, sulfpyridine, sulfadimethoxine, sulfamethoxazole, sulfaquinoxaline, sulfisoxazole, sulfanilamide, sulfamerazine, sulfathiazole, dapsone, sulfamoxisole, sulfachloropyridazine and sulfacetamide (inhibitors of wild-type enzyme)
A613S
-
little association with between mutantion and sulfa drug resistance in patients
DELTA247-306
-
deletion of the parasite-specific insertion: Km values for (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate and p-aminobenzoate are increased compared to mutant DELTA257-306 but still decreased compared to wild type, catalytic efficacy (kcat) is comparable to wild type
DELTA257-306
-
deletion of the parasite-specific insertion: Km values for (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate and p-aminobenzoate are significantly decreased compared to wild type, catalytic efficacy (kcat) is at least 2fold decreased compared to wild type
DELTA74-80
-
deletion of the parasite-specific insertion: Km values for (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate and p-aminobenzoate are 2 to 3 fold higher compared to wild type, catalytic efficacy (kcat) is at least 2fold decreased compared to wild type
DELTA74-86
-
no DHPS activity is detected
K540E
-
correlation of polymorphisms in Plasmodium falciparum dihydropteroate synthase and in vitro parasite susceptibility to sulfadoxine and pyrimethamine and in vivo treatment are analyzed: Patients with the dihydropteroate synthase K540E mutation are 2.6times as likely to fail treatment compared to patients having wild-type form form
S436A
-
little association with between mutantion and sulfa drug resistance in patients
S436F/A437G/A613S
-
sulfadoxine, sulfpyridine, sulfadimethoxine, sulfamethoxazole, sulfaquinoxaline, sulfisoxazole, sulfanilamide, sulfamerazine, sulfathiazole and dapsone (inhibitors of wild-type enzyme)
P519S
-
mutant with implicated sulfa drug resistance
P57S
-
the prevalence of DHPS mutations in Pneumocystis jirovecii strains isolated from South African Pneumocystis jirovecii pneumonia patients are examined. Mutations resulting in amino-acid substitutions Thr55Ala and/or Pro57Ser are detected in Pneumocystis jirovecii from 85/151 (56%) patients. The high frequency of PCP episodes with Pneumocystis jirovecii harbouring DHPS mutations in South Africa indicates that populations of this fungus are evolving under considerable selective pressure exerted by sulfa-containing antibiotics
T517A
-
mutant with implicated sulfa drug resistance
P559S
-
mutant with implicated sulfa drug resistance
T557A
-
mutant with implicated sulfa drug resistance
T557A/P559S
-
mutant with implicated sulfa drug resistance
T557V/P559S
-
mutant with implicated sulfa drug resistance
T597V/P599S
-
the mutant has very low p-aminobenzoic acid dependence, short generation time and and high sulfamethoxazole resistance. Upregulated p-aminobenzoic acid synthesis is implicated as a mechanism for sulfa drug resistance
GS60
P59655
insertion of glycine-serine dipeptide into loop 2 beginning at position 60, sulfonamide resistant, no effect on diphosphate affinity, no effect on 6-hydroxymethyl-7,8-dihydropterin diphosphate binding: KD: 46 +/-5 microM (k(on): 260000 1/M*s, k(off): 12 1/s), reduced binding of p-aminobenzoic acid: KD: 16 +/-6 microM, no detectable binding of sulfamethoxazole
InsY63
P59655
insertion of tyrosine residue in loop 2, sulfonamide resistant, no effect on diphosphate affinity, no effect on 6-hydroxymethyl-7,8-dihydropterin diphosphate binding: KD: 48 +/-5 microM (k(on) = 240000 1/M*s, k(off): 11 1/sec), reduced binding of p-aminobenzoic acid: KD: 50 +/-6 microM, no detectable binding of sulfamethoxazole
additional information
Q1ENB6
bifunctional enzyme, mitochondrial enzyme ubiquitously expressed, cytosolic enzyme only in reproductive tisse, construction of a chimeric protein containing the first 224 amino acids of cytosolic DHPS fused to GFP, expression in Arabidopsis thaliana, Arabidopsis thaliana mutant lacking DHPS indicates a role of DHPS in seed stress
D96N/C137I/C172M/C242A
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130fold improvement in phage display efficiency compared to wild-type enzyme
additional information
Haemophilus parasuis serovar
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difference analysis in gene expression in Haemophilus parasuis serovar 1, 2, 3 and 5
M28E
Q49HL6
site-directed mutagenesis, can replace DHPR in Escherichia coli, affects the binding affinity for FMN
additional information
Q49HL6
DHPS contains also dihydropteroate reductase activity
additional information
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detection of mutations to predict dapsone resistance
K540N
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parasites collected during October 2005 have mutations associated with a lower level of pyrimethamine resistance and a higher level of sulfadoxine resistance, as well as a novel K540N mutation in PfDHPS gene. The emergence of this parasite population coincides with the widespread use of an additional antifolate drug, trimethoprim-sulfamethoxazole, to treat other infections during January-March 2005
additional information
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assessment of mutations in DHPS in West Africa
S436F/A437G/A613T
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sulfadoxine, sulfpyridine, sulfadimethoxine, sulfamethoxazole, sulfaquinoxaline, sulfisoxazole, sulfanilamide, sulfamerazine, sulfathiazole and dapsone (inhibitors of wild-type enzyme)
additional information
Q00LY0
assessment of mutations in DHPS associated with antifolate resistance in several geographical regions
T55A
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the prevalence of DHPS mutations in Pneumocystis jirovecii strains isolated from South African Pneumocystis jirovecii pneumonia patients are examined. Mutations resulting in amino-acid substitutions Thr55Ala and/or Pro57Ser are detected in Pneumocystis jirovecii from 85/151 (56%) patients. The high frequency of PCP episodes with Pneumocystis jirovecii harbouring DHPS mutations in South Africa indicates that populations of this fungus are evolving under considerable selective pressure exerted by sulfa-containing antibiotics
additional information
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coupled enzymatic spectrophotometric assay to measure the activity of DHPS
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
drug development
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targeting approach of the dihydropteroate synthase enzyme, which serves as the site of action for the sulfonamide class of antimicrobial agents, exploring a class of transition state mimics, that can bind to the pterin, phosphate and para-amino binding sites, as trivalent inhibitors, binding modeling, overview
molecular biology
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established coupled enzymatic assay for kinetic analyses of DHPS activity (coupled to pyrophosphate-dependent phosphofructokinase, aldolase, triosephosphate isomerase, alpha-glycerophosphate dehydrogenase) in presence or absence of activity-modulating compounds
medicine
-, Q1BXC8
DHPS is an antimicrobial therapeutic target by chemical and genetic means
drug development
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lead compound for design of antimicrobacterial inhibitors
drug development
-, P64139
cannot bypass DHPS activity during inhibition of the functional ortholog MtDHPS (folP1) as treatment of tuberculosis; target in treatment of tuberculosis
biotechnology
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the Bacillus anthracis DHPS pterin-binding pocket is analysed using five docking programs (FlexX, Surflex, Glide, GOLD, and DOCK) and nine scoring functions using pose selection/scoring and enrichment studies. Pose selection and scoring use the 7-amino-3-(1-carboxyethyl)-1-methyl-pyrimido (4,5-c)- pyridazine-4,5(1H; 6H)-dione (AMPPD) co-crystal structure as the source structure. RMSD calculations are used to determine how well specific docking/scoring combinations pose and score the ligand in the pterin site. Surflex with Surflex-Score and Glide with GlideScore are the best overall performers for use in virtual screening against the DHPS target, with neither combination showing statistically significant superiority over the other in enrichment studies or pose selection. Post-docking ligand relaxation and consensus scoring does not improve overall enrichment
medicine
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sulfonamide resistance in Pneumocystis jirovecii, determination of gene mutations in South African strain of Pneumocystis jirovecii, one of 53 DHPS genes sequenced contains the double mutation T55A/P57S