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Information on EC 6.3.2.17 - tetrahydrofolate synthase and Organism(s) Homo sapiens and UniProt Accession Q05932
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6.3.2.17 tetrahydrofolate synthaseIUBMB Comments
In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.12, dihydrofolate synthase , the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates (H4folate). In contrast, the activities are located on separate proteins in most eukaryotes studied to date . In Arabidopsis thaliana, this enzyme is present as distinct isoforms in the mitochondria, the cytosol and the chloroplast. Each isoform is encoded by a separate gene, a situation that is unique among eukaryotes . As the affinity of folate-dependent enzymes increases markedly with the number of glutamic residues, the tetrahydropteroyl polyglutamates are the preferred coenzymes of C1 metabolism. (reviewed in ). The enzymes from different sources (particularly eukaryotes versus prokaryotes) have different substrate specificities with regard to one-carbon substituents and the number of glutamate residues present on the tetrahydrofolates.
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Word Map
- 6.3.2.17
- methotrexate
- antifolate
- thymidylate
- leukemia
-
polyglutamylation
-
folate-dependent
-
ccrf-cem
-
one-carbon
- aminopterin
- casei
- glycinamide
-
mtx-resistant
- methylenetetrahydrofolate
- monoglutamate
-
ddathf
- trimetrexate
-
transformylase
- pemetrexed
- raltitrexed
-
formyltransferase
- leucovorin
- 7-hydroxymethotrexate
-
poly-gamma-glutamylation
- 5,10-methylenetetrahydrofolate
- pentaglutamate
- 5-formyltetrahydrofolate
- garft
- 5,10-dideazatetrahydrofolate
- quinazoline
- lometrexol
- tomudex
-
folate-based
-
methotrexate-resistant
- triglutamate
- tetraglutamate
- dihydropteroate
-
monoglutamylated
- analysis
- pteroylmonoglutamate
- medicine
-
n10-propargyl-5,8-dideazafolic
- pharmacology
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
folylpolyglutamate synthetase, mthfd1l, folylpoly-gamma-glutamate synthetase, folylpolyglutamate synthase, folypolyglutamate synthetase, fpgs1, atdfb, cfpgs, mfpgs, folylpolyglutamyl synthetase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Folate polyglutamate synthetase
-
-
-
-
Folylpoly(.gamma.-glutamate) synthase
-
-
-
-
Folylpoly-.gamma.-glutamate synthase
-
-
-
-
Folylpoly-gamma-glutamate synthetase
Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase
-
-
-
-
Folylpolyglutamate synthase
Folylpolyglutamate synthetase
Folylpolyglutamyl synthetase
-
-
-
-
Formyltetrahydropteroyldiglutamate synthetase
-
-
-
-
FPGS
N10-Formyltetrahydropteroyldiglutamate synthetase
-
-
-
-
Synthetase, folylpolyglutamate
-
-
-
-
Tail length regulator
-
-
-
-
tetrahydrofolate:L-glutamate gamma-ligase (ADP-forming)
-
-
-
-
tetrahydrofolylpolyglutamate synthase
-
-
-
-
Folylpoly-gamma-glutamate synthetase
-
-
-
-
Folylpolyglutamate synthase
-
-
-
-
Folylpolyglutamate synthetase
-
-
-
-
FPGS
-
-
-
-
FPGS
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate = ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
processive mechanism, in which the folate is the first substrate to bind and the folate-Glu product is the last to be released
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
carboxylic acid amide formation
-
-
-
-
carboxamide formation
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
tetrahydropteroyl-gamma-polyglutamate:L-glutamate gamma-ligase (ADP-forming)
In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.12, dihydrofolate synthase [3], the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates (H4folate). In contrast, the activities are located on separate proteins in most eukaryotes studied to date [4]. In Arabidopsis thaliana, this enzyme is present as distinct isoforms in the mitochondria, the cytosol and the chloroplast. Each isoform is encoded by a separate gene, a situation that is unique among eukaryotes [4]. As the affinity of folate-dependent enzymes increases markedly with the number of glutamic residues, the tetrahydropteroyl polyglutamates are the preferred coenzymes of C1 metabolism. (reviewed in [5]). The enzymes from different sources (particularly eukaryotes versus prokaryotes) have different substrate specificities with regard to one-carbon substituents and the number of glutamate residues present on the tetrahydrofolates.
CAS REGISTRY NUMBER
COMMENTARY
63363-84-8
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
ADP + methotrexate-Glu3 + phosphate
ATP + methotrexate-Glu2 + L-glutamate
-
-
-
-
?
ADP + methotrexate-Glu4 + phosphate
ATP + methotrexate-Glu3 + L-glutamate
-
-
-
-
?
ADP + phosphate + 7,8-dihydropteroyl-Glu
ATP + 7,8-dihydropteroate + L-glutamate
-
-
-
-
?
ATP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid + L-glutamate
ADP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butanoyl-L-Glu + phosphate
-
-
-
?
ATP + (6S)-5,6,7,8-tetrahydropteroylglutamate + L-glutamate
ADP + phosphate + (6S)-5,6,7,8-tetrahydropteroyl-Glu2
-
-
-
-
?
ATP + (S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))glutaric acid + L-glutamate
ADP + (S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))glutaryl-L-Glu + phosphate
-
-
-
?
ATP + 10-formyl-5,6,7,8-tetrahydropteroyl-Glu + L-glutamate
ADP + phosphate + 10-formyl-5,6,7,8-tetrahydropteroyl-gamma-Glu2
-
-
-
-
?
ATP + 10-formyl-5,6,7,8-tetrahydropteroyl-Glu + L-glutamate
ADP + phosphate + 10-formyl-5,6,7,8-tetrahydropteroyl-Glu2
-
-
-
-
?
ATP + 3,5-difluoromethotrexate + Glu
ADP + phosphate + 3,5-difluoromethotrexyl-Glu
-
-
-
?
ATP + 3,5-difluoropteroyl-Glu + Glu
ADP + phosphate + 3,5-difluoropteroyl-Glu2
-
-
-
?
ATP + 5,10-dideaza-5,6,7,8-tetrahydrofolic acid + L-glutamate
ADP + 5,10-dideaza-5,6,7,8-tetrahydrofolyl-L-Glu + phosphate
-
lometrexol
-
?
ATP + 5,10-dideazatetrahydrofolic acid + L-glutamate
ADP + 5,10-dideazatetrahydrofolyl-L-Glu + phosphate
-
-
-
?
ATP + 5,6,7,8-tetrahydrofolate-Glu2 + L-glutamate
ADP + phosphate + 5,6,7,8-tetrahydrofolyl-Glu3
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glu3 + L-glutamate
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-Glu4
-
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glu5 + L-glutamate
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-Glu6
-
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glun + Glu
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-gamma-Glun+1
ATP + 5-formyl-5,6,7,8-tetrahydropteroyl-gamma-Glun + Glu
ADP + phosphate + 5-formyl-5,6,7,8-tetrahydropteroyl-gamma-Glu2
-
-
-
-
?
ATP + 5-formyl-5,6,7,8-tetrahydropteroyl-Glu + L-glutamate
ADP + phosphate + 5-formyl-5,6,7,8-tetrahydropteroyl-gamma-Glu2
-
-
-
-
?
ATP + 5-formyl-5,6,7,8-tetrahydropteroyl-Glu + L-glutamate
ADP + phosphate + 5-formyl-5,6,7,8-tetrahydropteroyl-Glu2
-
-
-
-
?
ATP + 5-methyl-5,6,7,8-tetrahydropteroyl-gamma-Glun + Glu
ADP + phosphate + 5-methyl-5,6,7,8-tetrahydropteroyl-gamma-Glun+1
-
n: 1
-
-
?
ATP + 7,8-dihydropteroyl-(4-aminobutanoyl)-Glu + L-glutamate
ADP + phosphate + 7,8-dihydropteroyl-(4-aminobutanoyl)-Glu2
-
-
-
-
?
ATP + 7,8-dihydropteroyl-Glu + L-glutamate
ADP + phosphate + 7,8-dihydropteroyl-gamma-Glu2
-
-
-
-
?
ATP + 7,8-dihydropteroyl-Glu + L-glutamate
ADP + phosphate + 7,8-dihydropteroyl-Glu2
-
-
-
-
?
ATP + 7,8-dihydropteroyl-Glun + Glu
ADP + phosphate + 7,8-dihydropteroyl-Glun+1
-
n: 1
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydrofolate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + L-glutamate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
ADP + phosphate + (6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
-
-
?
ATP + methotrexate + L-glutamate
ADP + phosphate + L-glutamyl-methotrexate
-
-
-
-
?
ATP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-glutamic acid + L-glutamate
ADP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-Glu2 + phosphate
-
-
-
?
ATP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid + L-glutamate
ADP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-Glu2 + phosphate
-
-
-
?
ATP + N-(p(((2-amino-4-hydroxy-6-pteridinyl)methyl)-amino)benzoyl)glutamic acid + L-glutamate
ADP + phosphate + N-(p(((2-amino-4-hydroxy-6-pteridinyl)methyl)-amino)benzoyl)Glu2
-
folic acid, poor substrate
-
?
ATP + Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine + L-glutamate
?
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
dATP + aminopterin + Glu
dADP + phosphate + aminopteryl-Glu
-
112% of the activity relative to ATP
-
-
?
dGTP + aminopterin + Glu
dGDP + phosphate + aminopteryl-Glu
-
37% of the activity relative to ATP
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glun + Glu
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-gamma-Glun+1
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glun + Glu
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-gamma-Glun+1
-
-
-
-
?
ATP + 5,6,7,8-tetrahydropteroyl-Glun + Glu
ADP + phosphate + 5,6,7,8-tetrahydropteroyl-gamma-Glun+1
-
n: 1
-
-
?
ATP + methotrexate + Glu
ADP + phosphate + methotrexyl-Glu
-
-
-
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
-
-
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
-
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
-
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
-
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
CHO cells expressing the human enzyme accumulate more metabolized drug than CHO cells expressing equivalent levels of endogenous hamster enzyme. Cells expressing only the mitochondrial isozyme do not metabolize this substrate
-
?
ATP + methotrexate-Glu + L-glutamate
ADP + methotrexate-Glu2 + phosphate
-
T-ALL and AML patients show inefficient polyglutamylation due to lower enzyme activity
-
?
ATP + methotrexate-Glun + Glu
ADP + phosphate + methotrexyl-Glun+1
-
n: 3
-
?
ATP + methotrexate-Glun + Glu
ADP + phosphate + methotrexyl-Glun+1
-
n: 5
-
?
ATP + methotrexate-Glun + Glu
ADP + phosphate + methotrexyl-Glun+1
-
n: 2
-
?
ATP + pteroyl-Glu + Glu
ADP + phosphate + pteroylmonoglutamyl-Glu
-
n: 1, i.e. pteroylmonoglutamate, folic acid
-
?
ATP + pteroyl-Glu + Glu
ADP + phosphate + pteroylmonoglutamyl-Glu
-
n: 1, i.e. pteroylmonoglutamate, folic acid
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
additional information
?
-
-
depressed activity of the enzyme is the predominant mechanism of high level resistance to polyglutamylation-dependent antifolates
-
?
additional information
?
-
-
mitochondrial enzyme activity is required for mitochondrial folate accumulation, and cells lacking this isozyme are auxotrophic for glycine. Overexpression of cytosolic enzyme does not complement the lack of mitochondrial activity
-
?
additional information
?
-
-
enzyme catalyzes the addition of glutamate residues to folates and antifolates to form the physiological active coenzymatic forms of the vitamin and more potent anti-folate agents
-
-
?
additional information
?
-
-
central enzyme in establishing and maintaining folylpolyglutamate pools in whole cells
-
?
additional information
?
-
-
the enzyme catalyzes the formation of an amide bond between glutamic acid and the gamma-carboxyl group of any of the naturally occurring folate compounds
-
?
additional information
?
-
-
the enzyme catalyzes the MgATP-dependent addition of glutamate residues to the gamma-carboxyl of folates to generate folylpolyglutamates
-
?
additional information
?
-
-
the enzyme synthesizes folate and antifolate poly(gamma-glutamate) metabolites
-
?
additional information
?
-
-
folylpoly-gamma-glutamate synthetase can catalyze the processive addition of approximately four glutamate residues to (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroylglutamic acid. The degree of processivity is dependent on the concentration of the folate substrate, thus suggesting a mechanism for the regulation of folate polyglutamate synthesis in cells
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
ATP + methotrexate + L-glutamate
ADP + phosphate + L-glutamyl-methotrexate
-
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
-
-
?
additional information
?
-
-
enzyme catalyzes the addition of glutamate residues to folates and antifolates to form the physiological active coenzymatic forms of the vitamin and more potent anti-folate agents
-
-
?
additional information
?
-
-
central enzyme in establishing and maintaining folylpolyglutamate pools in whole cells
-
?
additional information
?
-
-
the enzyme catalyzes the formation of an amide bond between glutamic acid and the gamma-carboxyl group of any of the naturally occurring folate compounds
-
?
additional information
?
-
-
the enzyme catalyzes the MgATP-dependent addition of glutamate residues to the gamma-carboxyl of folates to generate folylpolyglutamates
-
?
additional information
?
-
-
the enzyme synthesizes folate and antifolate poly(gamma-glutamate) metabolites
-
?
additional information
?
-
-
folylpoly-gamma-glutamate synthetase can catalyze the processive addition of approximately four glutamate residues to (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroylglutamic acid. The degree of processivity is dependent on the concentration of the folate substrate, thus suggesting a mechanism for the regulation of folate polyglutamate synthesis in cells
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
K+
Mg2+
NaHCO3
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid
-
IC50 of 0.0000153 mM in the wild type cell line, IC50 of 0.000008 mM to 0.0016 mM in the antifolates-resistant sublines
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
(S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))-glutaric acid
-
IC50 of 0.0000009 mM in the wild type cell line, IC50 of 0.0000012 mM to 0.000539 mM in the antifolates-resistant sublines
2-[[[(4S)-4-carboxy-4-[(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)amino]butyl](hydroxy)phosphoryl]methyl]pentanedioic acid
-
-
2-[[[(4S)-4-[(4-[2-[(6R)-2-amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]-4-carboxybutyl](hydroxy)phosphoryl]methyl]pentanedioic acid
-
-
2-[[[(4S)-4-[(4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]benzoyl)amino]-4-carboxybutyl](hydroxy)phosphoryl]methyl]pentanedioic acid
-
-
3,3-Difluoroglutamic acid
-
i.e. beta,beta-difluoroglutamate, , the effect on polyglutamylation is dependent on its position relative to the point of L-Glu ligation. When beta,beta-difluoroglutamate is the acceptor amino acid, i.e. point of attachment. Ligation of Glu is enhanced. When beta,beta-difluoroglutamate is one residue distal to the acceptor amino acid, further elongation is blocked
5,10-dideaza-5,6,7,8-tetrahydrofolic acid
-
IC50 of 0.0000277 mM in the wild type cell line, IC50 of 0.000143 mM to 0.0035 mM in the antifolates-resistant sublines
5-fluorouracil
-
FPGS overexpression significantly enhances chemosensitivity to 5-fluorouracil, FPGS inhibition decreases chemosensitivity to 5-fluorouracil
iodoacetamide
-
2 mM, 30 to 85% loss of activity in 5 min, depending on the enzyme concentration
methotrexate-Glu
-
IC50 of 0.0000014 mM in the wild type cell line, IC50 of 0.000001 mM to 0.00095 mM in the antifolates-resistant sublines
methotrexate-phosphinate
-
competitive inhibition, IC50 of 0.000008 mM, at fixed substrate and recombinant enzyme concentrations. The most potent FPGS inhibitor based on methotrexate heterocycle. CCRF-CEM R2 subline does not respond to inhibition by this compound at 0.001 mM
methotrexate-phosphonate
-
IC50 0.00012 mM, at fixed substrate and recombinant enzyme concentrations
N-(4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]benzoyl)-L-gamma-glutamyl-5-[(2,4-dicarboxybutyl)(hydroxy)phosphoryl]-L-norvaline
-
-
N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid
-
IC50 of 0.0000032 mM in the wild type cell line, IC50 of 0.00032 mM to 0.007168 mM in the antifolates-resistant sublines
Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine
-
IC50 of 0.000001 mM in the wild type cell line, IC50 of 0.000006 mM to 0.0017 mM in the antifolates-resistant sublines
Non-gamma-glutamylatable antifolate analogs
-
aminopterin analogs are better inhibitors than their methotrexate counterparts
-
Ornithine-containing folate analogs
-
e.g. 2,4-diamino-pteroylornithine, 2-amino-4-oxo-5,8-dideazapteroyl-Orn
-
additional information
-
no inhibition by methotrexate in the CCRF-CEM R2 cell subline
-
additional information
-
no substrate: (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-mercaptoethanol
-
45 mM: 3.5fold enhancement of activity, 200 mM: 25% decrease in activity
3,3-difluoroglutamate
-
i.e. beta,beta-difluoroglutamate??, , the effect on polyglutamylation is dependent on its position relative to the point of L-Glu ligation. When beta,beta-difluoroglutamate is the acceptor amino acid, i.e. point of attachment. Ligation of Glu is enhanced. When beta,beta-difluoroglutamate is one residue distal to the acceptor amino acid, further elongation is blocked
pemetrexed
-
treatment of 211-H cells results in significantly higher expression of foloylpolyglutamate synthase and reduced folate carrier 1. Pemetrexed shows potent cytotoxicity in 211-H cells
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00087
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
0.00096
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.0016
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.00105
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.0145
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.00116
(6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
0.235
glutamic acid
-
pH 8.9, 37ºC, charcoal assay, wild type recombinant enzyme
0.126
N-(p(((2-amino-4-hydroxy-6-pteridinyl)methyl)-amino)benzoyl)glutamic acid
-
pH 8.7
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.157
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
0.179
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.144
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.417
(6R)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate-gamma-L-glutamate
-
-
0.092
(6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamate-gamma-L-glutamate
-
-
0.0000031
methotrexate-phosphinate
-
Kis value, with methrotrexate as variable substrate, for recombinant enzyme
0.000056
methotrexate-phosphinate
-
Kii value, with methotrexate as variable substrate, for recombinant enzyme
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000008
(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid
Homo sapiens
-
IC50 of 0.0000153 mM in the wild type cell line, IC50 of 0.000008 mM to 0.0016 mM in the antifolates-resistant sublines
0.0000012
(S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))-glutaric acid
Homo sapiens
-
IC50 of 0.0000009 mM in the wild type cell line, IC50 of 0.0000012 mM to 0.000539 mM in the antifolates-resistant sublines
0.000143
5,10-dideaza-5,6,7,8-tetrahydrofolic acid
Homo sapiens
-
IC50 of 0.0000277 mM in the wild type cell line, IC50 of 0.000143 mM to 0.0035 mM in the antifolates-resistant sublines
0.000001
methotrexate-Glu
Homo sapiens
-
IC50 of 0.0000014 mM in the wild type cell line, IC50 of 0.000001 mM to 0.00095 mM in the antifolates-resistant sublines
0.000008
methotrexate-phosphinate
Homo sapiens
-
competitive inhibition, IC50 of 0.000008 mM, at fixed substrate and recombinant enzyme concentrations. The most potent FPGS inhibitor based on methotrexate heterocycle. CCRF-CEM R2 subline does not respond to inhibition by this compound at 0.001 mM
0.00012
methotrexate-phosphonate
Homo sapiens
-
IC50 0.00012 mM, at fixed substrate and recombinant enzyme concentrations
0.00032
N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid
Homo sapiens
-
IC50 of 0.0000032 mM in the wild type cell line, IC50 of 0.00032 mM to 0.007168 mM in the antifolates-resistant sublines
0.000006
Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine
Homo sapiens
-
IC50 of 0.000001 mM in the wild type cell line, IC50 of 0.000006 mM to 0.0017 mM in the antifolates-resistant sublines
additional information
2-[[[(4S)-4-carboxy-4-[(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)amino]butyl](hydroxy)phosphoryl]methyl]pentanedioic acid
additional information
2-[[[(4S)-4-carboxy-4-[(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)amino]butyl](hydroxy)phosphoryl]methyl]pentanedioic acid
Homo sapiens
-
45 nM for species of low mobility, 3.5 nm for species of high mobility
additional information
2-[[[(4S)-4-[(4-[2-[(6R)-2-amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]-4-carboxybutyl](hydroxy)phosphoryl]methyl]pentanedioic acid
Homo sapiens
-
51 nM for species of low mobility, 1.7 nM for species of high mobility
additional information
2-[[[(4S)-4-[(4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]benzoyl)amino]-4-carboxybutyl](hydroxy)phosphoryl]methyl]pentanedioic acid
Homo sapiens
-
65 nM for species of low mobility, 6.5 nM for species of high mobility
additional information
N-(4-[[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino]benzoyl)-L-gamma-glutamyl-5-[(2,4-dicarboxybutyl)(hydroxy)phosphoryl]-L-norvaline
Homo sapiens
-
576 nM for species of low mobility, 98 nM for species of high mobility
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the specific activity of the extract derived from MTXR5 cell subline is 7.1fold lower than that obtained with the wild type cell line
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
leukemia line, wild type line and various antifolate-resistant sublines
-
T-lymphoblastic leukemia line, wild type cell line and its methrotrexate transport-deficient subline R2
additional information
FPGS expression analysis in human tissues, antifolate resistant sublines, overview
additional information
FPGS expression analysis in human tissues, antifolate resistant sublines, overview
additional information
quantitative real-time PCR enzyme expression analysis reveals significant differences in sex-specific mRNA expression, detailed overview
additional information
-
quantitative real-time PCR enzyme expression analysis reveals significant differences in sex-specific mRNA expression, detailed overview
additional information
FPGS expression analysis in human tissues, antifolate resistant sublines, overview
additional information
FPGS expression analysis in human tissues, antifolate resistant sublines, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
the mitochondrial isoform is an integral membrane protein
additional information
-
a single gene encodes both, mitochondrial and cytosolic isoforms of the enzyme
-
a single gene encodes both, mitochondrial and cytosolic isoforms of the enzyme
-
mFGPS is at least in part strongly associated with the inner mitochondrial membrane
additional information
human FPGS (hFPGS) has two major isoforms, the short isoform represents a cytosolic enzyme (cFPGS), while the longer isoform contains a mitochondrial leader sequence directing FPGS to mitochondria (mFPGS). The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%
-
additional information
human FPGS (hFPGS) has two major isoforms, the short isoform represents a cytosolic enzyme (cFPGS), while the longer isoform contains a mitochondrial leader sequence directing FPGS to mitochondria (mFPGS). The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%
-
additional information
-
distinct isoforms with different electrophoretic mobility
-
additional information
human FPGS (hFPGS) has two major isoforms, the short isoform represents a cytosolic enzyme (cFPGS), while the longer isoform contains a mitochondrial leader sequence (MLS) directing FPGS to mitochondria (mFPGS). The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%
-
additional information
human FPGS (hFPGS) has two major isoforms, the short isoform represents a cytosolic enzyme (cFPGS), while the longer isoform contains a mitochondrial leader sequence (MLS) directing FPGS to mitochondria (mFPGS). The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
subcellular compartmentalization of one-carbon metabolism in mammalian cells involving the enzyme, overview
physiological function
malfunction
metabolism
physiological function
additional information
malfunction
decreased FPGS activity is found to underlie intrinsic antifolate resistance in several human cells and tumor cell lines. Inherent methotrexate resistance in head and neck squamous carcinoma cells is attributed to a 3fold decrease in their cellular FPGS activity. Intrinsic resistance to MTX via reduced FPGS activity is also found in sarcoma patients. FPGS-deficient cells display parental sensitivity to methotrexate (MTX), detailed overview. Low MTX-polyglutamate levels are correlated with reduced response to MTX treatment in rheumatoid arthritis patients
malfunction
loss of FPGS activity results in decreased cellular levels of antifolates and consequently to polyglutamatable antifolates in acute lymphoblastic leukemia (ALL). Common genetic polymorphisms in the FPGS coding region including rs7039789, rs1544105, and rs10106 are significantly associated with increased ALL risk in Thai children
physiological function
enzyme FPGS may have a major role in regulating intracellular polyglutamation of methotrexate (MTX) in rheumatoid arthritis patients receiving low-dose weekly methotrexate therapy. MTX binds to the folate transporter, reduced folate carrier 1, gene SLC19A1, in order to enter target cells. Inside the cells, folylpolyglutamate synthetase (FPGS) converts MTX into MTX polyglutamates (MTXPGs), which show long-term persistence in target cells. Gamma-glutamyl hydrolase (GGH) is involved in removing glutamates from MTXPGs. After MTXPGs are converted back to MTX by GGH, the drug is removed from cells by adenosine triphosphate (ATP)-binding cassette transporters. Tetrahydrofolate is required for DNA synthesis and plays a vital role as an essential coenzyme in various aspects of amino acid metabolism, such as serine-glycine conversion and methionine synthesis. MTXPGs also inhibit aminoimidazole carboxamide ribonucleotide transformylase (ATIC), causing the intracellular accumulation of aminoimidazole carboxamide ribonucleotide, which in turn inhibits adenosine-metabolizing enzymes. Polymorphism of the SLC19A1, FPGS, and GGH genes play a vital role in intracellular metabolism of MTX, overview. Among the enzymes involved in intracellular conversion of MTX to MTXPGs, polymorphisms of the FPGS gene are determinants of the intracellular levels of MTXPGs
physiological function
folylpolyglutamate synthetase (FPGS) is an important enzyme in the folate metabolic pathway and plays a central role in intracellular accumulation of folate and antifolate in several mammalian cell types
physiological function
reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and gamma-glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. Significant differences between men and women are observed in RFC-1, FPGS, and GGH mRNA expression in the Japanese population. The mRNA expression of FPGS and GGH is greater in women than that in men, but the expression of RFC-1 is less in the former than the latter. The relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with rheumatoid arthritis
physiological function
the capacity of cells to accumulate folates several orders of magnitude above their extracellular concentration is predominantly attributable to the activity of the unique enzyme folylpoly-gamma-glutamate synthetase(FPGS). The enzyme is an ATP-dependent ligase which catalyzes the addition of a polyglutamate tail to reduced folates, one glutamate residue after the other (1-8 additional gluta-mate moieties). FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes, impact of polyglutamylation on intracellular folate homeostasis, overview. The average length of the polyglutamate tail is dependent upon the intracellular activity level of FPGS, the higher the protein level and activity, the longer the length of the polyglutamate congener which can be found within the cell. Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon unitsin the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intra-cellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In the cytosol, folates are crucial for the catalytic activity of the nucleotide biosynthesis enzymes 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and glycinamide ribonucleotide transformylase (GARTF) as well as for the remethylation of homocysteine to methionine by the enzyme methionine synthase (MS) and conversion of serine to glycine by serine hydroxymethyltransferase (SHMT) 1. In the nucleus, folates are crucial for the thymidylate biosynthesis enzyme, thymidylate synthase (TS). In mitochondria, folates are required for the biosynthesis of glycine by the enzyme SHMT-2, and for the synthesis of formyl-methionyl tRNA by the mitochondrial enzyme methionyl-tRNA formyltransferase (MTFMT). High FPGS levels, along with low GGH and MRP1 expression, correlate with higher accumulation of reduced folates in colorectal cancer patients administrated with leucovorin (folinic acid, 5-CHO-THF). Posttranscriptional mechanisms are involved in regulating FPGS activity. FPGS activity is correlated with cancer patient outcome
malfunction
-
a spectrum of FPGS splicing alterations occur in humans, including exon skipping and intron retention, all of which prove to frequently emerge in both pediatric and adult leukemia patient specimens. These splicing alterations result in loss of FPGS function. Pulse-exposure of leukemia cells to antifolates and other chemotherapeutics markedly enhance the prevalence of several FPGS splicing alterations in antifolate-resistant cells, but not in their parental antifolate-sensitive counterparts. An assortment of deleterious FPGS splicing alterations may constitute a mechanism of antifolate resistance in childhood acute lymphoblastic leukemia (ALL)
malfunction
-
analysis of the association of folylpolyglutamate synthetase (FPGS) polymorphism with the dynamic plasma concentration of methotrexate (MTX) in pediatric patients with acute lymphocytic leukemia (ALL), overview. FPGS rs1544105 alleles are demonstrated to be an indicator for poor prognosis
malfunction
decreased FPGS activity is found to underlie intrinsic antifolate resistance in several human cells and tumor cell lines. Inherent methotrexate resistance in head and neck squamous carcinoma cells is attributed to a 3fold decrease in their cellular FPGS activity. Intrinsic resistance to MTX via reduced FPGS activity is also found in sarcoma patients. FPGS-deficient cells display parental sensitivity to methotrexate (MTX), detailed overview. Low MTX-polyglutamate levels are correlated with reduced response to MTX treatment in rheumatoid arthritis patients
malfunction
-
FPGS modulation (overexpression or silencing) affects global and promoter CpG DNA methylation and expression of several genes involved in important biological pathways, molecular and cellular functions of genes associated with altered expression and promoter DNA methylation in the FPGS-modulated HCT116 and MDA-MB-435 cells, overview. FPGS-specific altered expression changes are regulated by promoter DNA methylation in MDA-MB-435 cells. In the MDA-MB-435 cells overexpressing FPGS, 41 hypermethylated and downregulated genes are primarily associated with drug metabolism, molecular transport, cell cycle, cell death and cellular assembly and organization, while 54 hypomethylated and upregulated genes are mainly involved in cellular movement, cell-to-cell signaling and interaction, cell death, posttranslational modification and cell signaling. In the FPGS-silenced MDA-MB-435 cells, 30 downregulated and 13 upregulated genes with an inverse association with promoter DNA methylation changes are related to cellular movement and cell cycle. In HCT-116 cells, 24 genes are upregulated in response to FPGS overexpression and downregulated in response to FPGS suppression, and these genes are associated with gene expression, cell-to-cell signaling and interaction, cell morphology, cellular assembly and organization and cell death. Twenty-one genes that are downregulated in response to FPGS overexpression and upregulated in response to FPGS suppression in HCT-116 cells, are involved in cell cycle, cellular compromise, lipid metabolism, small-molecule biochemistry, and vitamin and mineral metabolism
malfunction
-
the A22G polymorphism in the FPGS gene is associated with an increased risk of acute lymphoblastic leukemia (ALL) and plays a role in increasing the survival of patients with ALL, effects of folylpolyglutamate synthase A22G polymorphism on the risk and survival of patients with acute lymphoblastic leukemia, overview
metabolism
-
metabolizes methotrexate, a universal component of acute lymphoblastic leukemia, into long-chain poylglutamates, resulting in enhanced cytotoxicity from prolonged inhibition of dihydrofolate reductase and thymidylate synthetase
metabolism
subcellular compartmentalization of one-carbon metabolism in mammalian cells involving the enzyme, overview
physiological function
-
folylpolyglutamate synthase (FPGS) is the key enzyme that converts the chemotherapeutic agent, methotrexate (MTX), into MTX polyglutamate
physiological function
-
folylpolyglutamate synthase (FPGS) plays a critical role in intracellular folate homeostasis. FPGS-induced polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence FPGS modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression and aberrant DNA methylation is mechanistically linked cancer development. FPGS-mediated polyglutamylation-induced changes in total intracellular folate concentrations and in contents of polyglutamylated folates play an important role in DNA methylation as polyglutamylated folates are better substrates for methylenetetrahydrofolate reductase and methionine synthase, both of which are involved in the generation of S-adenosyl-L-methione. Role of FPGS modulation in DNA methylation and its associated downstream functional effects, overview
physiological function
the capacity of cells to accumulate folates several orders of magnitude above their extracellular concentration is predominantly attributable to the activity of the unique enzyme folylpoly-gamma-glutamate synthetase(FPGS). The enzyme is an ATP-dependent ligase which catalyzes the addition of a polyglutamate tail to reduced folates, one glutamate residue after the other (1-8 additional gluta-mate moieties). FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes, impact of polyglutamylation on intracellular folate homeostasis, overview. The average length of the polyglutamate tail is dependent upon the intracellular activity level of FPGS, the higher the protein level and activity, the longer the length of the polyglutamate congeners, which can be found within the cell. Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intra-cellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In the cytosol, folates are crucial for the catalytic activity of the nucleotide biosynthesis enzymes 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and glycinamide ribonucleotide transformylase (GARTF) as well as for the remethylation of homocysteine to methionine by the enzyme methionine synthase (MS) and conversion of serine to glycine by serine hydroxymethyltransferase (SHMT) 1. In the nucleus, folates are crucial for the thymidylate biosynthesis enzyme, thymidylate synthase (TS). In mitochondria, folates are required for the biosynthesis of glycine by the enzyme SHMT-2, and for the synthesis of formyl-methionyl tRNA by the mitochondrial enzyme methionyl-tRNA formyltransferase (MTFMT). High FPGS levels, along with low GGH and MRP1 expression, correlate with higher accumulation of reduced folates in colorectal cancer patients administrated with leucovorin (folinic acid, 5-CHO-THF). Posttranscriptional mechanisms are involved in regulating FPGS activity. FPGS activity is correlated with cancer patient outcome
physiological function
-
the cytotoxic activity of various antifolates is largely dependent on the activity of folylpolyglutamate synthetase (FPGS). The latter enzyme catalyzes the addition of multiple glutamate residues (i.e. polyglutamylation) to both folates and antifolates upon their entry into the cell. This unique metabolic conversion dramatically enhances the intracellular retention of antifolates including methotreaxate (MTX) as the polyglutamate forms of antifolates are no longer substrates of various efflux transporters. Polyglutamylation also decreases the Ki of MTX and other antifolates like pemetrexed to their target enzymes including dihydrofolate reductase and thymidylate synthase
additional information
3D-modeling analysis suggests that C388 is located at the entrance to the active site of this enzyme
additional information
3D-modeling analysis suggests that C388 is located at the entrance to the active site of this enzyme
additional information
amino acids D335, H338 and R377 participate in the alignment of glutamic acid in the active site
additional information
amino acids D335, H338 and R377 participate in the alignment of glutamic acid in the active site
additional information
-
structural and functional consequences of splicing alterations on FPGS protein, the relationship between FPGS splicing alterations and MTX resistance, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). FOLC_HUMAN
587
0
64609
Swiss-Prot
Mitochondrion (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
posttranscriptional mechanisms are involved in regulating FPGS activity
additional information
posttranscriptional mechanisms are involved in regulating FPGS activity
additional information
posttranscriptional mechanisms are involved in regulating FPGS activity
additional information
posttranscriptional mechanisms are involved in regulating FPGS activity
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C388F
MTXR5 resistant leukemia cells established by repeated cycles of 24 h-pulse exposures to methotrexate (MTX), harbor a C388F substitution resulting in a 91% loss of their cellular FPGS activity. Kinetic analysis reveals that the mutant protein retains parental affinity toward MTX, while the Km toward L-glutamate increases by 23fold. 3D-modeling analysis suggests that C388 is located at the entrance to the active site of this enzyme
A22G
-
a naturally occuring mutation, rs10760502 , phenotype, overview. The genotypes of the A22G polymorphism may be risk factors for acute lymphoblastic leukemia (ALL) and may play a role in the survival of patients with ALL
C346F
D335A
H338A
R377A D335A
site-directed mutagenesis, the substitution results in a 1500fold increase in the Km for glutamate, and a 20fold decrease in the Kcat
additional information
C346F
MTXR5 resistant leukemia cells, established by repeated cycles of 24 h-pulse exposures to methotrexate (MTX), harbor a C346F substitution resulting in a 91% loss of their cellular FPGS activity. Kinetic analysis reveals that the mutant protein retains parental affinity toward MTX, while the Km toward L-glutamate increases by 23fold. Substitution of active site residues D335, H338 and R377 results in an over 500fold decrease in the Vmax of the polyglutamylation reaction when compared to the wild-type hcFPGS protein
D335A
site-directed mutagenesis, the substitution leads to a catalytically dead FPGS with diminished binding of glutamate, ATP and the antifolate
H338A
site-directed mutagenesis, the mutation increases the Kmfor glutamic acid by 600fold foldwith negligible residual catalytic activity
additional information
aberrant FPGS preRNA splicing, FPGS preRNA splicing, five sublines, isolated by 24 h-pulse exposure of CCRF-CEM cells to MTX or 7OH-MTX, as well as ALL patients' specimens display aberrant splicing of the FPGS mRNA, comprised of both intron retention and exon skipping. FPGS mutations in antifolate selected tumor cell lines are identified in antifolate-resistant sublines of the human T-ALL cell line CCRF-CEM. The resistant sublines, MTXR5, CEM-p, MTAR1.5, ZD1694 C-9 andMTA C-3, all harboring point mutations in the FPGS open reading frame, are selected with different polyglutamatable (i.e. classical) antifolates using diverse selection methods. These drug-resistant sublines are all crossresistant to classical antifolates (e.g. raltitrexed/ZD1694/tomudex) while retaining sensitivity to non-polyglutamatable antifolates (e.g. plevitrexed/ZD9331/vamidex), compared to their parental counterparts, hence exhibiting a major loss of FPGS activity
additional information
aberrant FPGS preRNA splicing, FPGS preRNA splicing, five sublines, isolated by 24 h-pulse exposure of CCRF-CEM cells to MTX or 7OH-MTX, as well as ALL patients' specimens display aberrant splicing of the FPGS mRNA, comprised of both intron retention and exon skipping. FPGS mutations in antifolate selected tumor cell lines are identified in antifolate-resistant sublines of the human T-ALL cell line CCRF-CEM. The resistant sublines, MTXR5, CEM-p, MTAR1.5, ZD1694 C-9 andMTA C-3, all harboring point mutations in the FPGS open reading frame, are selected with different polyglutamatable (i.e. classical) antifolates using diverse selection methods. These drug-resistant sublines are all crossresistant to classical antifolates (e.g. raltitrexed/ZD1694/tomudex) while retaining sensitivity to non-polyglutamatable antifolates (e.g. plevitrexed/ZD9331/vamidex), compared to their parental counterparts, hence exhibiting a major loss of FPGS activity
additional information
enzyme genotyping, 3 genotypes for 3 SNPs of FPGS, the methotrexate polyglutamates MTXPG3-5/1-2 ratio shows significant differences among these 3 genotypes for 3 different SNPs of FPGS
additional information
-
enzyme genotyping, 3 genotypes for 3 SNPs of FPGS, the methotrexate polyglutamates MTXPG3-5/1-2 ratio shows significant differences among these 3 genotypes for 3 different SNPs of FPGS
additional information
-
siRNA transfected into DLD-1 cells to downregulate folylpolyglutamate synthase reduces the basal level of reduced folate, the folate level after leucovorin treatment, and the enhancement of 5-fluoro-2'-deoxyuridine-induced cytotoxicity elicited by leucovorin. Folylpolyglutamate synthase and gamma-glutamyl hydrolase expression levels in tumors are determinants of the efficacy of leucovorin in enhancing the antitumor activity of 5-fluorouracil
additional information
aberrant FPGS preRNA splicing, FPGS preRNA splicing, five sublines, isolated by 24 h-pulse exposure of CCRF-CEM cells to MTX or 7OH-MTX, as well as ALL patients' specimens display aberrant splicing of the FPGS mRNA, comprised of both intron retention and exon skipping. FPGS mutations in antifolate selected tumor cell lines are identified in antifolate-resistant sublines of the human T-ALL cell line CCRF-CEM. The resistant sublines, MTXR5, CEM-p, MTAR1.5, ZD1694 C-9 andMTA C-3, all harboring point mutations in the FPGS open reading frame, are selected with different polyglutamatable (i.e. classical) antifolates using diverse selection methods. These drug-resistant sublines are all crossresistant to classical antifolates (e.g. raltitrexed/ZD1694/tomudex) while retaining sensitivity to non-polyglutamatable antifolates (e.g. plevitrexed/ZD9331/vamidex), compared to their parental counterparts, hence exhibiting a majorloss of FPGS activity
additional information
aberrant FPGS preRNA splicing, FPGS preRNA splicing, five sublines, isolated by 24 h-pulse exposure of CCRF-CEM cells to MTX or 7OH-MTX, as well as ALL patients' specimens display aberrant splicing of the FPGS mRNA, comprised of both intron retention and exon skipping. FPGS mutations in antifolate selected tumor cell lines are identified in antifolate-resistant sublines of the human T-ALL cell line CCRF-CEM. The resistant sublines, MTXR5, CEM-p, MTAR1.5, ZD1694 C-9 andMTA C-3, all harboring point mutations in the FPGS open reading frame, are selected with different polyglutamatable (i.e. classical) antifolates using diverse selection methods. These drug-resistant sublines are all crossresistant to classical antifolates (e.g. raltitrexed/ZD1694/tomudex) while retaining sensitivity to non-polyglutamatable antifolates (e.g. plevitrexed/ZD9331/vamidex), compared to their parental counterparts, hence exhibiting a majorloss of FPGS activity
additional information
-
FPGS overexpression and suppression in colon and breast cancers cells, HCT-116 and MDA-MB-435 cell lines, FPGS inhibition is developed by transfecting HCT-116 cells and MDA-MB-435 cells with the antisense FPGS cDNA and the FPGS-targeted small interfering RNA (siRNA), respectively. FPGS overexpression is associated with significantly lower (by 18%) global DNA methylation than controls in HCT-116 cells, but is associated with significantly higher (by 13%) global DNA methylation than controls in MDA-MB-435 cells. FPGS suppression is associated with significantly higher (by 12%) global DNA methylation than controls in HCT-116 cells, but has no effect in MDA-MB-435 cells. In MDA-MB-435 cells, 2239 differentially methylated genes (1161 hypermethylated and 1078 hypomethylated) occur in response to FPGS overexpression and 2024 differentially methylated genes (1150 hypermethylated and 874 hypomethylated) occur in response to FPGS suppression. Differentially methylated genes are involved in molecular transport and cell death in both the FPGS-overexpressed and silenced MDA-MB-435 cells
additional information
-
genotyping of FPGS rs1544105 polymorphism in 57 ALL patients and 31 age and sex-matched children, overall survival is analyzed by Kaplan-Meier method. No differences are observed between patients and controls regarding the distribution frequency of genotype and alleles of rs1544105. Patients carrying AA genotype have a significantly higher plasma concentration of methotrexate after 24 h than those carrying GG or GA (P<0.05) and no differences are found after 44 h. Kaplan-Meier survival analysis shows a longer median survival time in patients with AA than other genotypes with significant difference in overall survival
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
2-mercaptoethanol enhances stabilization provided by ATP. ATP stabilizes against heat inactivation
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20ºC, 0.05% n-octylglucoside, DTT 2 mM, 50% glycerol, stable for 9 months. Replenishment of DTT every 2 months is necesary.
-
0ºC, leupeptin, MgATP2- 2 mM and 2-mercaptoethanol 50 mM or DTT 2 mM, limited stability. More stable with DTT in place of 2-mercaptoethanol.
-
37ºC, Tris buffer, without thiols, with or without MgATP2- 5 mM, highly unstable, half-life of 6-7.3 min. Addition of 2-mercaptoethanol increases half-life of the enzyme to 11-21 min. Addition of 0.3 mg/ml BSA, stabilizes for 2 hours.
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate fractionation and chromatography on BioGel A-0.5M, recombinant enzyme
-
ammonium sulfate fractionation, chromatography on Sephacryl S-100 and DEAE-Sephacel columns
-
ammonium sulfate fractionation, chromatography on Sephacryl S-100HR and DEAE-Sephacel ion exchange column, 25fold purification
-
crude total cell extracts are obtained by sonication followed by centrifugation
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene fpgs, determination of genotypes and mRNA expression levels in 190 female and male unrelated healthy Japanese people, quantitative real-time PCR enzyme expression analysis reveals significant differences in sex-specific mRNA expression, detailed overview
gene FPGS, DNA and amino acid sequence analysis, promoter determination and analysis, overview, recombinnat expression in murine knockout cell line AUXB1
gene FPGS, genotyping of 134 children suffering acute lymphoblastic leukemia (ALL), overview
gene FPGS, DNA and amino acid sequence analysis, promoter determination and analysis, overview, recombinnat expression in murine knockout cell line AUXB1
gene FPGS, DNA and amino acid sequence determination and analysis of splicing variants, quantitative RT- and real-time-PCR analyses of FPGS enzyme expression and splicing patterns. FPGS splicing alterations are abundant in blasts of acute lymphoblastic leukemia (ALL) patients, overview
-
gene FPGS, gene-specific promoter CpG DNA methylation analysis and global DNA methylation analysis, recombinant FPGS overexpression in HCT-116 and MDA-MB-435 cells, quantitative RT-PCR enzyme expression analysis
-
gene FPGS, genotyping of FPGS rs1544105 polymorphism in 57 ALL patients and 31 age and sex-matched children
-
HCT-116 cells stable transfected with the sense or antisense FPGS cDNA. Compared with cells expressing endogenous FPGS, those overexpressing FPGS have significantly faster growth rates and higher concentrations of total folate and long-chain folate polyglutamates while antisense FPGS inhibition produces opposite results. FPGS overexpression significantly enhances, whereas FPGS inhibition decreases chemosensitivity to 5-fluorouracil. No significant difference in chemosensitivity to methotrexate is observed
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
2- to 5fold increased mRNA expression after treatment with sodium butyrate or suberoylanilide hydroxamic acid
-
both TEL-AML1 and E2A-PBX1 down-regulate FPGS gene transcription through association with this multiprotein complex, and this complex also influences FPGS expression throughout lymphoblast cell cycle progression
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
pharmacology
-
polymorphism of FPGS rs1544105 might be used as an effective approach for prediction of the treatment outcome of methotrexate (MTX)
medicine
-
pemetrexed shows potent cytotoxicity in 211-H cells compared to A-549 cells and H-1299 cells, accompanied by significantly higher expression of foloylpolyglutamate synthase and reduced folate carrier 1. Simulltaneous exposure of pemtrexed and gemcitabine is antagonistic in all cell lines tested, while strong synergism is observed in 211-H cells when pemetrexed precedes gemcitabine
medicine
-
reduced folate carrier-1 and folylpolyglutamate synthase gene expression levels are significantly correlated in patients lacking p16 promoter hypermethylation in mucosa, but not at all correlated in patients having hypermethylation in mucosa. p16 Hypermethylation in mucosa of colorectal cancer patients is an independent prognostic parameter for cancer-specific survival as well as an independent predictor of disease-free survival
medicine
-
siRNA transfected into DLD-1 cells to downregulate folylpolyglutamate synthase reduces the basal level of reduced folate, the folate level after leucovorin treatment, and the enhancement of 5-fluoro-2'-deoxyuridine-induced cytotoxicity elicited by leucovorin. Folylpolyglutamate synthase and gamma-glutamyl hydrolase expression levels in tumors are determinants of the efficacy of leucovorin in enhancing the antitumor activity of 5-fluorouracil
medicine
-
FPGS rs1544105 alleles are demonstrated to be an indicator for poor prognosis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Clarke, L.; Waxman, D.J.
Human liver folylpolyglutamate synthetase: biochemical characterization and interactions with folates and folate antagonists
Arch. Biochem. Biophys.
256
585-596
1987
Oryctolagus cuniculus, Homo sapiens
Clarke, L.; Rosowsky, A.; Waxman, D.J.
Inhibition of human liver folylpolyglutamate synthetase by non-gamma-glutamylatable antifolate analogs
Mol. Pharmacol.
31
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1987
Homo sapiens
Bolanowska, W.E.; Russell, C.A.; McGuire, J.J.
Activation of mammalian folylpolyglutamate synthetase by sodium bicarbonate
Arch. Biochem. Biophys.
281
198-203
1990
Homo sapiens, Rattus norvegicus
Garrow, T.A.; Admon, A.; Shane, B.
Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate)synthetase and determination of its primary structure
Proc. Natl. Acad. Sci. USA
89
9151-9155
1992
Homo sapiens
McGuire, J.J.; Bolanowska, W.E.; Piper, J.R.
Structural specificity of inhibition of human folylpolyglutamate synthetase by ornithine-containing folate analogs
Biochem. Pharmacol.
37
3931-3939
1988
Homo sapiens
Atkinson, I.; Garrow, T.; Brenner, A.; Shane, B.
Human cytosolic folylpoly-gamma-glutamate synthase
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281
134-140
1997
Homo sapiens
Imeson, H.C.; Cossins, E.A.
Folylpolyglutamate synthase from higher plants
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281
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Homo sapiens, Pisum sativum
Garrow, T.A.; Shane, B.
Purification and general properties of human folylpolyglutamate synthetase
Chem. Biol. Pteridines Folates (J. E. Ayling et al eds. ) Plenum Press New York
659-662
1993
Homo sapiens
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
-
McGuire, J.J.; Hart, B.P.; Haile, W.H.; Rhee, M.S.; Galivan, J.; Coward, J.K.
DL-beta,beta-Difluoroglutamic acid mediates position-dependent enhancement or termination of pteroylpoly(glutamate)synthesis catalyzed by folylpolyglutamate synthetase
Arch. Biochem. Biophys.
321
319-328
1995
Homo sapiens, Rattus norvegicus
Qi, H.; Atkinson, I.; Xiao, S.; Choi, Y.J.; Tobimatsu, T.; Shane, B.
Folylpoly-gamma-glutamate synthetase: generation of isozymes and the role in one carbon metabolism and antifolate cytotoxicity
Adv. Enzyme Regul.
39
263-273
1999
Homo sapiens
McGuire, J.J.; Haile, W.H.; Valiaeva, N.; Bartley, D.; Guo, J.; Coward, J.K.
Potent inhibition of human folylpolyglutamate synthetase by a phosphinic acid mimic of the tetrahedral reaction intermediate
Biochem. Pharmacol.
65
315-318
2003
Homo sapiens
Rots, M.G.; Pieters, R.; Peters, G.J.; Noordhuis, P.; van Zantwijk, C.H.; Kaspers, G.J.; Hahlen, K.; Creutzig, U.; Veerman, A.J.; Jansen, G.
Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia
Blood
93
1677-1683
1999
Homo sapiens
Liani, E.; Rothem, L.; Bunni, M.A.; Smith, C.A.; Jansen, G.; Assaraf, Y.G.
Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines
Int. J. Cancer
103
587-599
2003
Homo sapiens, Mus musculus
Sanghani, S.P.; Sanghani, P.C.; Moran, R.G.
Identification of three key active site residues in the C-terminal domain of human recombinant folylpoly-gamma-glutamate synthetase by site-directed mutagenesis
J. Biol. Chem.
274
27018-27027
1999
Homo sapiens
McGuire, J.J.; Russell, C.A.; Balinska, M.
Human cytosolic and mitochondrial folylpolyglutamate synthetase are electrophoretically distinct. Expression in antifolate-sensitive and -resistant human cell lines
J. Biol. Chem.
275
13012-13016
2000
Homo sapiens
Sanghani, P.C.; Moran, R.G.
Purification and characteristics of recombinant human folylpoly-gamma-glutamate synthetase expressed at high levels in insect cells
Protein Expr. Purif.
18
36-45
2000
Homo sapiens
Nair, J.R.; McGuire, J.J.
Submitochondrial localization of the mitochondrial isoform of folylpolyglutamate synthetase in CCRF-CEM human T-lymphoblastic leukemia cells
Biochim. Biophys. Acta
1746
38-44
2005
Homo sapiens
Sohn, K.J.; Smirnakis, F.; Moskovitz, D.N.; Novakovic, P.; Yates, Z.; Lucock, M.; Croxford, R.; Kim, Y.I.
Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate
Gut
53
1825-1831
2004
Homo sapiens
Tomsho, J.W.; McGuire, J.J.; Coward, J.K.
Synthesis of (6R)- and (6S)-5,10-dideazatetrahydrofolate oligo-gamma-glutamates: kinetics of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase
Org. Biomol. Chem.
3
3388-3398
2005
Homo sapiens
Sakamoto, E.; Tsukioka, S.; Oie, S.; Kobunai, T.; Tsujimoto, H.; Sakamoto, K.; Okayama, Y.; Sugimoto, Y.; Oka, T.; Fukushima, M.; Oka, T.
Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity
Biochem. Biophys. Res. Commun.
365
801-807
2007
Homo sapiens
Leclerc, G.J.; Leclerc, G.M.; Kinser, T.T.; Barredo, J.C.
Analysis of folylpoly-gamma-glutamate synthetase gene expression in human B-precursor ALL and T-lineage ALL cells
BMC Cancer
6
132
2006
Homo sapiens
Leil, T.A.; Endo, C.; Adjei, A.A.; Dy, G.K.; Salavaggione, O.E.; Reid, J.R.; Ames, M.M.; Adjei, A.A.
Identification and characterization of genetic variation in the folylpolyglutamate synthase gene
Cancer Res.
67
8772-8782
2007
Homo sapiens
Leclerc, G.J.; York, T.A.; Hsieh-Kinser, T.; Barredo, J.C.
Molecular basis for decreased folylpoly-gamma-glutamate synthetase expression in a methotrexate resistant CCRF-CEM mutant cell line
Leuk. Res.
31
293-299
2007
Homo sapiens
Tomsho, J.W.; Moran, R.G.; Coward, J.K.
Concentration-dependent processivity of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase
Biochemistry
47
9040-9050
2008
Homo sapiens
Nagai, S.; Takenaka, K.; Sonobe, M.; Wada, H.; Tanaka, F.
Schedule-dependent synergistic effect of pemetrexed combined with gemcitabine against malignant pleural mesothelioma and non-small cell lung cancer cell lines
Chemotherapy
54
166-175
2008
Homo sapiens
Wettergren, Y.; Odin, E.; Nilsson, S.; Carlsson, G.; Gustavsson, B.
p161NK4a gene promoter hypermethylation in mucosa as a prognostic factor for patients with colorectal cancer
Mol. Med.
14
412-421
2008
Homo sapiens
-
McGuire, J.J.; Bartley, D.M.; Tomsho, J.W.; Haile, W.H.; Coward, J.K.
Inhibition of human folylpolyglutamate synthetase by diastereomeric phosphinic acid mimics of the tetrahedral intermediate
Arch. Biochem. Biophys.
488
140-145
2009
Homo sapiens
Izbicka, E.; Diaz, A.; Streeper, R.; Wick, M.; Campos, D.; Steffen, R.; Saunders, M.
Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers
Cancer Chemother. Pharmacol.
64
993-999
2009
Homo sapiens
Nannizzi, S.; Veal, G.J.; Giovannetti, E.; Mey, V.; Ricciardi, S.; Ottley, C.J.; Del Tacca, M.; Danesi, R.
Cellular and molecular mechanisms for the synergistic cytotoxicity elicited by oxaliplatin and pemetrexed in colon cancer cell lines
Cancer Chemother. Pharmacol.
66
547 - 558
2009
Homo sapiens
Leclerc, G.J.; Mou, C.; Leclerc, G.M.; Mian, A.M.; Barredo, J.C.
Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy
Leukemia
24
552-562
2010
Homo sapiens
Leclerc, G.J.; Sanderson, C.; Hunger, S.; Devidas, M.; Barredo, J.C.
Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia
Leuk. Res.
34
1601-1609
2010
Homo sapiens
Piwkham, D.; Siriboonpiputtana, T.; Beuten, J.; Pakakasama, S.; Gelfond, J.A.; Paisooksantivatana, K.; Tomlinson, G.E.; Rerkamnuaychoke, B.
Mutation screening and association study of the folylpolyglutamate synthetase (FPGS) gene with susceptibility to childhood acute lymphoblastic leukemia
Asian Pac. J. Cancer Prev.
16
4727-4732
2015
Homo sapiens (Q05932), Homo sapiens
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)
Wojtuszkiewicz, A.; Raz, S.; Stark, M.; Assaraf, Y.G.; Jansen, G.; Peters, G.J.; Sonneveld, E.; Kaspers, G.J.; Cloos, J.
Folylpolyglutamate synthetase splicing alterations in acute lymphoblastic leukemia are provoked by methotrexate and other chemotherapeutics and mediate chemoresistance
Int. J. Cancer
138
1645-1656
2016
Homo sapiens
Hashiguchi, M.; Tanaka, T.; Shimizu, M.; Tsuru, T.; Chiyoda, T.; Miyawaki, K.; Irie, S.; Takeuchi, O.; Hakamata, J.; Mochizuki, M.
Sex differences in mRNA expression of reduced folate carrier-1, folypolyformyl glutamate synthase, and gamma-glutamyl hydrolase in a healthy Japanese population
J. Clin. Pharm.
56
1563-1569
2016
Homo sapiens (Q05932), Homo sapiens
Kim, S.E.; Hinoue, T.; Kim, M.S.; Sohn, K.J.; Cho, R.C.; Weisenberger, D.J.; Laird, P.W.; Kim, Y.I.
Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells
J. Nutr. Biochem.
29
27-35
2016
Homo sapiens
Huang, Z.; Tong, H.F.; Li, Y.; Qian, J.C.; Wang, J.X.; Wang, Z.; Ruan, J.C.
Effect of the polymorphism of folylpolyglutamate synthetase on treatment of high-dose methotrexate in pediatric patients with acute lymphocytic leukemia
Med. Sci. Monit.
22
4967-4973
2016
Homo sapiens
Gomez-Gomez, Y.; Organista-Nava, J.; Rangel-Rodriguez, C.A.; Illades-Aguiar, B.; Moreno-Godinez, M.E.; Alarcon-Romero, L.D.; Leyva-Vazquez, M.A.
Effect of folylpolyglutamate synthase A22G polymorphism on the risk and survival of patients with acute lymphoblastic leukemia
Oncol. Lett.
8
731-735
2014
Homo sapiens
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