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dihydrofolate synthase/folylpolyglutamate synthase
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Folylpoly-gamma-glutamate synthetase
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Folate polyglutamate synthetase
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Folylpoly(.gamma.-glutamate) synthase
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Folylpoly-.gamma.-glutamate synthase
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Folylpoly-gamma-glutamate synthetase
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Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase
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Folylpolyglutamate synthase
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Folylpolyglutamate synthetase
Folylpolyglutamyl synthetase
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Formyltetrahydropteroyldiglutamate synthetase
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N10-Formyltetrahydropteroyldiglutamate synthetase
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Synthetase, folylpolyglutamate
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Tail length regulator
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tetrahydrofolate:L-glutamate gamma-ligase (ADP-forming)
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tetrahydrofolylpolyglutamate synthase
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additional information
cf. EC 6.3.2.12
Folylpolyglutamate synthetase
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Folylpolyglutamate synthetase
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FPGS
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ATP + 5,10-methylene-5,6,7,8-tetrahydrofolic acid + L-Glu
ADP + phosphate + 5,10-methylene-5,6,7,8-tetrahydrofolyl-L-Glu
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?
ATP + 5,6,7,8-tetrahydrofolic acid + L-Glu
ADP + phosphate + 5,6,7,8-tetrahydrofolyl-Glu
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?
ATP + 5,6,7,8-tetrahydrofolyl-gamma-(L-Glu)2 + L-Glu
ADP + phosphate + 5,6,7,8-tetrahydrofolyl-gamma-(L-Glu)3
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?
ATP + 7,8-dihydropteroate + L-Glu
ADP + phosphate + 7,8-dihydropteroyl-L-Glu
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?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
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?
ATP + (6R,S)-5,6,7,8-tetrahydrofolic acid + L-glutamate
ADP + phosphate + (6S)-5,6,7,8-tetrahydrofolyl-gamma-Glu
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ir
ATP + 10-formyl-5,6,7,8-tetrahydropteroyl-Glu + Glu
ADP + phosphate + 10-formyl-5,6,7,8-tetrahydropteroyl-Glu2
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ATP + 5,10-methylene-5,6,7,8-tetrahydrofolate-Glu2 + L-glutamate
ADP + phosphate + 5,10-methylene-5,6,7,8-tetrahydrofolyl-Glu3
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ATP + 5,6,7,8-tetrahydrofolate-Glu2 + L-glutamate
ADP + phosphate + 5,6,7,8-tetrahydrofolyl-Glu3
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?
ATP + dihydropteroic acid + L-glutamate
ADP + dihydropteroyl-Glu
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enhancement of ATP binding is observed in the presence of this substrate. The substrate causes a conformational change in the inactive fraction of the enzyme which allows it to bind ATP
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additional information
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additional information
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additional information
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enzyme also posseses dihydrofolate synthetase activity
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additional information
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enzyme also posseses dihydrofolate synthetase activity
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additional information
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enzyme also posseses dihydrofolate synthetase activity
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additional information
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enzyme also posseses dihydrofolate synthetase activity
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additional information
?
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the enzyme catalyzes the MgATP-dependent ligation of L-glutamate to tetrahydrofolate coenzymes or to antifolates at the gamma-carboxyl of the terminal glutamate to form polyglutamate derivatives
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?
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5,6,7,8-tetrahydrofolyl-Glu2
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60% inhibition of ATP binding at 0.1 mM
dihydrofolate
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treatment of cells with trimethoprim leads to inhibition due to accumulation of dihydrofolate through the inhibition of dihydrofolate reductase. Therefore falling dihydrofolate reductase activity leads to falling folylpolyglutamate synthase activity in a domino-like cascade
Dihydropteroic acid
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5% inhibition of ATP binding at 0.1 mM
Endogenous inhibitor from Neurospora crassa
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the inhibitor is present in either polyglutamate-deficient mutants and in wild type. This factor is non-dialyzable, thermolabile and inactivated by urea and trypsin treatment
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trimethoprim
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treatment of cells leads to inhibition due to accumulation of dihydrofolate through the inhibition of dihydrofolate reductase. Therefore falling dihydrofolate reductase activity leads to falling folylpolyglutamate synthase activity in a domino-like cascade
additional information
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in Escherichia coli, the addition of L-glutamate to dihydropteroate (dihydrofolate synthetase activity) and the subsequent additions of L-glutamate to tetrahydrofolate (folylpolyglutamate synthetase (FPGS) activity) are catalyzed by the same enzyme, FolC. The presence of a folate binding site in Escherichia coli FolC, which is different from the one seen in folylpolyglutamate synthetases, provides avenues for the design of specific inhibitors of this enzyme in antimicrobial therapy
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0.05 - 0.59
5,10-methylene-5,6,7,8-tetrahydrofolic acid
0.01 - 0.448
5,6,7,8-tetrahydrofolic acid
0.3
5,6,7,8-tetrahydrofolyl-gamma-(L-Glu)2
mutant D154A, pH 9.8
0.0063 - 0.98
7,8-dihydropteroate
0.014
10-formyl-5,6,7,8-tetrahydropteroyl-Glu
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0.333
Glu
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reaction with 10-formyl-5,6,7,8-tetrahydropteroyl-Glu
0.05
5,10-methylene-5,6,7,8-tetrahydrofolic acid
wild-type
0.071
5,10-methylene-5,6,7,8-tetrahydrofolic acid
chimera containing N-terminal residues 1-81 of Escherichia coli enzyme, residues 72-82 of Lactobacillus casei enzyme, and residues 93-422 of Escherichia coli enzyme, pH 9.8
0.118
5,10-methylene-5,6,7,8-tetrahydrofolic acid
chimera containing N-terminal residues 1-71 of Lactobacillus casei enzyme, residues 82-93 of Escherichia coli enzyme, and residues 83-428 of Lactobacillus casei enzyme, pH 9.8
0.59
5,10-methylene-5,6,7,8-tetrahydrofolic acid
chimera containing N-terminal residues 1-298 of Lactobacillus casei enzyme, residues 288-422 of Escherichia coli enzyme, pH 9.8
0.01
5,6,7,8-tetrahydrofolic acid
mutant A155W, pH 9.8
0.34
5,6,7,8-tetrahydrofolic acid
mutant D154A, pH 9.8
0.39
5,6,7,8-tetrahydrofolic acid
mutant T122W, pH 9.8
0.4
5,6,7,8-tetrahydrofolic acid
mutant T122H, pH 9.8
0.448
5,6,7,8-tetrahydrofolic acid
mutant A155H, pH 9.8
0.0063
7,8-dihydropteroate
wild-type, pH 9.8
0.08
7,8-dihydropteroate
mutant A155W, pH 9.8
0.134
7,8-dihydropteroate
chimera containing N-terminal residues 1-81 of Escherichia coli enzyme, residues 72-82 of Lactobacillus casei enzyme, and residues 93-422 of Escherichia coli enzyme, pH 9.8
0.14
7,8-dihydropteroate
mutant D154A, pH 9.8
0.15
7,8-dihydropteroate
mutant T122W, pH 9.8
0.485
7,8-dihydropteroate
mutant A155H, pH 9.8
0.98
7,8-dihydropteroate
mutant T122H, pH 9.8
0.037
ATP
mutant D154A, pH 9.8 cosubstrate 7,8-dihydropteroate
0.054
ATP
wild-type, pH 9.8
0.065
ATP
mutant A155H, pH 9.8 cosubstrate 7,8-dihydropteroate
0.076
ATP
mutant A155H, pH 9.8, cosubstrate 5,6,7,8-tetrahydrofolic acid
0.23
ATP
mutant D154A, pH 9.8, cosubstrate 5,6,7,8-tetrahydrofolic acid
0.555
ATP
mutant A155W, pH 9.8 cosubstrate 7,8-dihydropteroate
5.7
ATP
chimera containing N-terminal residues 1-298 of Lactobacillus casei enzyme, residues 288-422 of Escherichia coli enzyme, pH 9.8
0.12
L-Glu
mutant A155H, pH 9.8, cosubstrate 5,6,7,8-tetrahydrofolic acid
0.17
L-Glu
mutant A155H, pH 9.8, cosubstrate 7,8-dihydropteroate
0.2
L-Glu
mutant D154A, pH 9.8, cosubstrate 5,6,7,8-tetrahydrofolic acid
0.292
L-Glu
chimera containing N-terminal residues 1-298 of Lactobacillus casei enzyme, residues 288-422 of Escherichia coli enzyme, pH 9.8
0.3
L-Glu
wild-type, pH 9.8
3.3
L-Glu
mutant D154A, pH 9.8, cosubstrate 5,6,7,8-tetrahydrofolic acid
0.0665
ATP
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reaction with 10-formyl-5,6,7,8-tetrahydropteroyl-Glu + Glu
0.07
ATP
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pH 9.75, temperature conditions not mentioned
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0.138
chimera containing N-terminal residues 1-81 of Escherichia coli enzyme, residues 72-82 of Lactobacillus casei enzyme, and residues 93-422 of Escherichia coli enzyme, substrate 5,10-methylene-5,6,7,8-tetrahydrofolic acid, pH 9.8
0.376
chimera containing N-terminal residues 1-81 of Escherichia coli enzyme, residues 72-82 of Lactobacillus casei enzyme, and residues 93-422 of Escherichia coli enzyme, substrate 7,8-dihydropteroate, pH 9.8
0.912
chimera containing N-terminal residues 1-71 of Lactobacillus casei enzyme, residues 82-93 of Escherichia coli enzyme, and residues 83-428 of Lactobacillus casei enzyme, substrate 5,10-methylene-5,6,7,8-tetrahydrofolic acid, pH 9.8
1.3
chimera containing N-terminal residues 1-298 of Lactobacillus casei enzyme, residues 288-422 of Escherichia coli enzyme, substrate 5,10-methylene-5,6,7,8-tetrahydrofolic acid, pH 9.8
13.2
substrate 5,10-methylene-5,6,7,8-tetrahydrofolic acid, pH 9.8
4.1
substrate 7,8-dihydropteroate, pH 9.8
0.2
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wild type enzyme, pH 9.75
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A155H
drastic increases in Km values
A155W
13fold increase in Km value for dihydropteroate
D154A
mutation in residue specific for dihydropteroate binding, 200fold increase in Km value for substrate 5,6,7,8-tetrahydropteroyl-gamma-(L-Glu)2
T122H
drastic increases in Km values
T122W
drastic increases in Km values
E146Q
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completely inactive, no ATP binding is observed with this mutant
additional information
expression of the amino-terminal domain with residues 1-287. The domain binds tetrahydrofolate and dihydropteroate with the same affinity as the intact enzyme. Construction of domain-swap chimera proteins between the Escherichia coli and the Lactobacillus casei enzymes. Chimera possess both folate or pteroate binding properties and enzymatic activities of their amino terminal portion, suggesting that the N-terminal domain determines the folate substrate specificity. Mutants with swapped omega loops, containing a folate binding site, retain the activities and folate or pteroate binding properties of the rest of the enzyme. Mutating Lactobacillus casei folypolyglutamate synthetase to contain an Escherichia coli folypolyglutamate synthetase dihydropteroate binding loop does not alter its substrate specificity to using dihydropteroate as a substrate
additional information
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expression of the amino-terminal domain with residues 1-287. The domain binds tetrahydrofolate and dihydropteroate with the same affinity as the intact enzyme. Construction of domain-swap chimera proteins between the Escherichia coli and the Lactobacillus casei enzymes. Chimera possess both folate or pteroate binding properties and enzymatic activities of their amino terminal portion, suggesting that the N-terminal domain determines the folate substrate specificity. Mutants with swapped omega loops, containing a folate binding site, retain the activities and folate or pteroate binding properties of the rest of the enzyme. Mutating Lactobacillus casei folypolyglutamate synthetase to contain an Escherichia coli folypolyglutamate synthetase dihydropteroate binding loop does not alter its substrate specificity to using dihydropteroate as a substrate
additional information
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the enzyme cloned in a pUc19 vector is mutagenized by progressive deletion from both the 5'-end and the 3ïend and by TAB linker insertion. The specific activities of the extracts of the mutant enzyme are 4-16% that of the wild type enzyme. Non of the carboxy terminal or linker insertion mutants has a specific activity greater than 0.5% that of the wild type enzyme
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Bognar, A.L.; Shane, B.
Bacterial folylpoly(gamma-glutamate) synthase-dihydrofolate synthase
Methods Enzymol.
122
349-359
1986
Corynebacterium sp., Escherichia coli, Lacticaseibacillus casei
brenda
Bognar, A.L.; Osborne, C.; Shane, B.; Singer, S.C.; Ferone, R.
Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product
J. Biol. Chem.
260
5625-5630
1985
Escherichia coli
brenda
Shane, B.
Folylpoly-gamma-glutamate synthetase
Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv. Chem. Biol. Clin. Aspects
719-728
1986
Corynebacterium sp., Escherichia coli, Lacticaseibacillus casei, Sus scrofa
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brenda
Cichowicz, D.J.; Foo, S.K.; Shane, B.
Folylpoly-gamma-glutamate synthesis by bacteria and mammalian cells
Mol. Cell. Biochem.
39
209-228
1981
Cricetulus griseus, Corynebacterium sp., Escherichia coli, Enterococcus faecalis, Lacticaseibacillus casei, Neurospora crassa, Rattus norvegicus, Sus scrofa
brenda
Pyne, C.; Bognar, A.L.
Replacement of the folC gene, encoding folylpolyglutamate synthetase-dihydrofolate synthetase in Escherichia coli, with genes mutagenized in vitro
J. Bacteriol.
174
1750-1759
1992
Escherichia coli
brenda
Kimlova, L.J.; Pyne, C.; Keshavjee, K.; Huy, J.; Beebakhee, G.; Bognar, A.L.
Mutagenesis of the folC gene encoding folylpolyglutamate synthetase-dihydrofolate synthetase in Escherichia coli
Arch. Biochem. Biophys.
284
9-16
1991
Escherichia coli
brenda
Shane, B.; Garrow, T.; Brenner, A.; Chen, L.; Choi, Y.J.; Hsu, J.C.; Stover, P.
Folylpoly-gamma-glutamate synthetase
Chem. Biol. Pteridines Folates (J. E. Ayling et al eds. ) Plenum Press New York
629-634
1993
Saccharomyces cerevisiae, Corynebacterium sp., Escherichia coli, eukaryota, Homo sapiens, Lacticaseibacillus casei, Sus scrofa
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brenda
Cossins, E.A.; Chan, P.Y.
An endogenous inhibitor of folylpolyglutamate synthetase in Neurospora crassa
Phytochemistry
27
3391-3399
1988
Bos taurus, Escherichia coli, Neurospora crassa, Pisum sativum
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brenda
Sheng, Y.; Cross, J.A.; Shen, Y.; Smith, C.A.; Bognar, A.L.
Mutation of an essential glutamate residue in folylpolyglutamate synthetase and activation of the enzyme by pteroate binding
Arch. Biochem. Biophys.
402
94-103
2002
Escherichia coli, Lacticaseibacillus casei
brenda
Mathieu, M.; Debousker, G.; Vincent, S.; Viviani, F.; Bamas-Jacques, N.; Mikol, V.
Escherichia coli FolC structure reveals an unexpected dihydrofolate binding site providing an attractive target for anti-microbial therapy
J. Biol. Chem.
280
18916-18922
2005
Escherichia coli
brenda
Naponelli, V.; Hanson, A.D.; Gregory, J.F.
Improved methods for the preparation of [(3)H]folate polyglutamates: biosynthesis with Lactobacillus casei and enzymatic synthesis with Escherichia coli folylpolyglutamate synthetase
Anal. Biochem.
371
127-134
2007
Escherichia coli
brenda
Sheng, Y.; Khanam, N.; Tsaksis, Y.; Shi, X.M.; Lu, Q.S.; Bognar, A.L.
Mutagenesis of folylpolyglutamate synthetase indicates that dihydropteroate and tetrahydrofolate bind to the same site
Biochemistry
47
2388-2396
2008
Escherichia coli (P08192), Escherichia coli, Lacticaseibacillus casei (P15925), Lacticaseibacillus casei
brenda
Kwon, Y.K.; Lu, W.; Melamud, E.; Khanam, N.; Bognar, A.; Rabinowitz, J.D.
A domino effect in antifolate drug action in Escherichia coli
Nat. Chem. Biol.
4
602-608
2008
Escherichia coli
brenda
Raz, S.; Stark, M.; Assaraf, Y.G.
Folylpoly-gamma-glutamate synthetase A key determinant of folate homeostasis and antifolate resistance in cancer
Drug Resist. Updat.
28
43-64
2016
Rattus norvegicus (M0R401), Escherichia coli (P08192), Lacticaseibacillus casei (P15925), Mus musculus (P48760), Homo sapiens (Q05932), Homo sapiens (Q96LE3), Cricetulus griseus (Q924L9)
brenda