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Information on EC 2.5.1.15 - dihydropteroate synthase and Organism(s) Streptococcus pneumoniae and UniProt Accession P59655

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IUBMB Comments
The enzyme participates in the biosynthetic pathways for folate (in bacteria, plants and fungi) and methanopterin (in archaea). The enzyme exists in varying types of multifunctional proteins in different organisms. The enzyme from the plant Arabidopsis thaliana also harbors the activity of EC 2.7.6.3, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase , while the enzyme from yeast Saccharomyces cerevisiae is trifunctional with the two above mentioned activities as well as EC 4.1.2.25, dihydroneopterin aldolase .
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Streptococcus pneumoniae
UNIPROT: P59655
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The taxonomic range for the selected organisms is: Streptococcus pneumoniae
The enzyme appears in selected viruses and cellular organisms
Synonyms
dihydropteroate synthase, pfdhps, pvdhps, dihydropteroate synthetase, folp1, folp2, pvhppk-dhps, pppk-dhps, rv1207, hppk-dhps, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dihydropteroate synthase
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7,8-dihydropteroate synthase
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7,8-dihydropteroate synthetase
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7,8-dihydropteroic acid synthetase
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dihydropteroate diphosphorylase
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dihydropteroate synthetase
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dihydropteroic synthetase
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synthase, dihydropteroate
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
aryl group transfer
folate biosynthesis
aryl group transfer
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-
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PATHWAY SOURCE
PATHWAYS
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-, -
SYSTEMATIC NAME
IUBMB Comments
(7,8-dihydropterin-6-yl)methyl diphosphate:4-aminobenzoate 2-amino-4-hydroxy-7,8-dihydropteridine-6-methenyltransferase
The enzyme participates in the biosynthetic pathways for folate (in bacteria, plants and fungi) and methanopterin (in archaea). The enzyme exists in varying types of multifunctional proteins in different organisms. The enzyme from the plant Arabidopsis thaliana also harbors the activity of EC 2.7.6.3, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase [4], while the enzyme from yeast Saccharomyces cerevisiae is trifunctional with the two above mentioned activities as well as EC 4.1.2.25, dihydroneopterin aldolase [3].
CAS REGISTRY NUMBER
COMMENTARY hide
9055-61-2
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
p-aminobenzoic acid + 6-hydroxymethyl-7,8-dihydropterin diphosphate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
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
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?
(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
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-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
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-
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
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-
-
-
?
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate + 4-aminobenzoate
diphosphate + 7,8-dihydropteroate
show the reaction diagram
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-
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
sulfamethoxazole
a sulfonamide, KD = 2.3 +/-0.1 microM as revealed by fluorescence spectroscopy
(E)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(ethylamino)-3-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosylthio)acrylamide
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(E)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(ethylamino)-3-(ethylthio)-acrylamide
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(E)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(ethylamino)-3-mercapto-acrylamide
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(E)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(methylamino)-3-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosylthio)acrylamide
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(E)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-mercapto-3-(methylamino)acrylamide
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(E)-3-(allylamino)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl) amino]sulfonyl]phenyl)-3-(2',3',4',6'-tetra-O-acetyl-beta-D-galactopyranosylthio)acrylamide
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(E)-3-(allylamino)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosylthio)acrylamide
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(E)-3-(allylamino)-2-cyano-N-(4-[[(3,4-dimethylisoxazol-5-yl)amino]sulfonyl]phenyl)-3-(ethylthio)-acrylamide
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dihydrofolate
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sulfamethoxazole
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sulfanilamide
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sulfaquinoxazoline
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sulfathiazole
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competitive to 4-aminobenzoate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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activity in Streptococcus pneumoniae strains with different repeats of amino acids
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.015
folate
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0.00059
sulfamethoxazole
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0.00085
sulfanilamide
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0.025
sulfaquinoxazoline
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additional information
additional information
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KI values of sulfathiazole inhibition on Streptococcus pneumoniae strains with different repeats of amino acids
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
GS60
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
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
gel filtration and ion-exchange chromatography
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Superdex-200 HR and other chromatographic columns
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
from Streptococcus pneumoniae for expression in Escherichia coli XL2-Blue
expression in different Escherichia coli strains
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Vinnicombe, H.G.; Derrick, J.P.
Dihydropteroate synthase from Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition
Biochem. Biophys. Res. Commun.
258
752-757
1999
Streptococcus pneumoniae
Manually annotated by BRENDA team
Haasum, Y.; Strom, K.; Wehelie, R.; Luna, V.; Roberts, M.C.; Maskell, J.P.; Hall, L.M.C.; Swedberg, G.
Amino acid repetitions in the dihydropteroate synthase of Streptococcus pneumoniae lead to sulfonamide resistance with limited effects on substrate Km
Antimicrob. Agents Chemother.
45
805-809
2001
Streptococcus pneumoniae
Manually annotated by BRENDA team
Levy, C.; Minnis, D.; Derrick, J.P.
Dihydropteroate synthase from Streptococcus pneumoniae: structure, ligand recognition and mechanism of sulfonamide resistance
Biochem. J.
412
379-388
2008
Streptococcus pneumoniae (P59655), Streptococcus pneumoniae
Manually annotated by BRENDA team
Nasr, T.; Bondock, S.; Ibrahim, T.M.; Fayad, W.; Ibrahim, A.B.; AbdelAziz, N.A.; Sakr, T.M.
New acrylamide-sulfisoxazole conjugates as dihydropteroate synthase inhibitors
Bioorg. Med. Chem.
28
115444
2020
Bacillus subtilis, Streptococcus pneumoniae, Escherichia coli, Proteus vulgaris, Syncephalastrum racemosum, Yersinia pestis (A0A384KP04), Yersinia pestis KIM D27 (A0A384KP04), Escherichia coli ATCC 25922
Manually annotated by BRENDA team