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Information on EC 6.3.2.17 - tetrahydrofolate synthase and Organism(s) Cricetulus griseus and UniProt Accession Q924L9
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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: Cricetulus griseus
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
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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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FPGS
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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Folylpolyglutamate synthetase
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FPGS
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
carboxylic acid amide formation
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carboxamide formation
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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
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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
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
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-
-
?
additional information
?
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monoglutamyl form and polyglutamyl forms of 5,6,7,8-tetrahydropteroate are the preferred substrates
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-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
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-
-
?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
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-
-
?
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 + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
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-
-
?
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
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
folylpoly-gamma-glutamate synthetase resides in both the cytoplasm and mitochondria
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additional information
-
two mRNAs for the fpgs gene direct isoforms of FPGS to the cytosol and to mitochondria in mouse and human tissues
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additional information
two mRNAs for the fpgs gene direct isoforms of FPGS to the cytosol and to mitochondria in mouse and human tissues
-
additional information
-
two mRNAs for the fpgs gene direct isoforms of FPGS to the cytosol and to mitochondria
-
additional information
two mRNAs for the fpgs gene direct isoforms of FPGS to the cytosol and to mitochondria
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
the lack of FPGS activity in catalytically inactive AUXB1 mutant cells results in intracellular folate pools in AUXB1 cells that are composed predominantly of folate monoglutamates which are rapidly exported out of cells (i.e. via the ATP-driven exporters and the bidirectional anion exchanger RFC). In turn, the cells retain only 10% of the intracellular folate pool presentin parental CHO cells, and lose 50% of their folate pools as fast as 2 h after transfer to a folate-depleted medium. AUXB1 cells have lower intracellular concentrations of folatescompared to the growth medium. FPGS-null AUXB1 cells have very little intracellular folate concentrations, albeit they can grow in the absence of purines or thymidine provided, their growth medium is supplemented with high folate concentrations. But they fail to grow in the absence of glycine at any folate medium concentration, suggesting the complete deficiency of mitochondrial folatesin these cells. AUXB1 cells transfected with Escherichia coli FPGS can only yield a triglutamate folate tail in AUXB1 cells. Both eFPGS and human cytosolic FPGS (hcFPGS) can rescue nucleoside auxotrophy of AUXB1 cells. Transfection of AUXB1 cells with hcFPGS complements growth in methionine-free medium, while cytosolic eFPGS does not
physiological function
physiological function
folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the addition of multiple glutamates to tetrahydrofolate derivatives, the enzyme is localized in the cytosol and mitochondria and folylpolyglutamates are synthezised in both compartments. Folylpolyglutamates cannot traverse mitochondrial membranes in either direction. Subcellular isoforms of FPGS are required to establish and maintain subcellular folate compartmentalization and function. Mitochondrial folates are a separate metabolic pool not in equilibrium with cytosol. Roles of cytosolic and mitochondrial FPGS in cell growth and survival, overview
physiological function
folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the addition of multiple glutamates to tetrahydrofolate derivatives, the enzyme is localized in the cytosol and mitochondria, and folylpolyglutamates are synthezised in both compartments. Folylpolyglutamates cannot traverse mitochondrial membranes in either direction. Subcellular isoforms of FPGS are required to establish and maintain subcellular folate compartmentalization and function. Mitochondrial folates are a separate metabolic pool not in equilibrium with cytosol. Mitochondrial FPGS is required because folate polyglutamates are not substrates for transport across the mitochondrial membrane in either direction and that polyglutamation not only traps folates in the cytosol, but also in the mitochondrial matrix. Roles of cytosolic and mitochondrial FPGS in cell growth and survival, overview
physiological function
FPGS catalyzes the addition of a long polyglutamate chain to folates andantifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. 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 ribonu-cleotide (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). Cytosolic folates are mostly present as penta-to hexaglutamates, while mitochondrial folates have longer polyglutamate tails with hepta- and octaglutamate moieties in hamsters
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_CRIGR
587
0
65093
Swiss-Prot
Mitochondrion (Reliability: 2)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A173S/Q536E
cell line V79 compared to wild-type CHO-K1 cells, also with silent polymorphisms at codons 94 and 187
additional information
additional information
-
C to T transition at nucleotide 1294 generating a premature stop at codon 432 in AUXB1 mutant cell line. The M7.2 cell line has superphysiologic levels of FPGS protein in both the mitochondria and cytosol
additional information
C to T transition at nucleotide 1294 generating a premature stop at codon 432 in AUXB1 mutant cell line. The M7.2 cell line has superphysiologic levels of FPGS protein in both the mitochondria and cytosol
additional information
generation of a FPGS-null Chinese hamster ovary (CHO) cell line AUXB1. The cells are isolated as auxotrophs for glycine, adenosine and thymidine. AUXB1 cells are hemizygous for the FPGS gene and harbor a nonsense mutation at position 432 which renders the enzyme catalytically dead. AUXB1 cells are transfected with human FPGS cDNA presenting high FPGS activity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene FPGS, sequence comparisons, genotyping, sequence of FPGS cDNAs from hamster cells auxotrophic for thymidine, purine, and glycine, FPGS mitochondrial isoform expression in CHO, AUXB1, and AUXB1 cells stably transfected with cDNA for fpgs under a viral promoter. Enzyme expression in the mutant cells can complement the mutants which no longer require supplementation with purines, thymidine, or glycine for survival, the mFPGStet cell line is made by transfecting the fpgs cDNA that produces only mitochondrial FPGS protein under doxycycline control, cytosolic folates are observed in both cFPGStet and mFPGStet cells in the presence of doxycyclin
gene FPGS, sequence comparisons, genotyping, sequence of FPGS cDNAs from hamster cells auxotrophic for thymidine, purine, and glycine, FPGS cytosolic isoform expression in CHO, AUXB1, and AUXB1 cells stably transfected with cDNA for fpgs under a viral promoter, the cFPGStet cell line is made by transfecting the fpgs cDNA that produces only cytosolic FPGS protein under doxycycline control, cytosolic folates are observed in both cFPGStet and mFPGStet cells in the presence of doxycyclin
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Shane, B.; Cichowicz, D.J.
Folylpoly-gamma-glutamate synthetases: properties and regulation
Adv. Exp. Med. Biol.
163
149-165
1983
Bacteria, Cricetulus griseus, Corynebacterium sp., Enterococcus faecalis, Lacticaseibacillus casei
Cook, J.D.; Cichowicz, D.J.; George, S.; Lawler, A.; Shane, B.
Mammalian folylpoly-gamma-glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis
Biochemistry
26
530-539
1987
Cricetulus griseus, Sus scrofa
Moran, R.G.; Colman, P.D.
Measurement of folylpolyglutamate synthetase in mammalian tissues
Anal. Biochem.
140
326-342
1984
Cricetulus griseus, Mus musculus, Rattus norvegicus
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
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)
Lawrence, S.A.; Titus, S.A.; Ferguson, J.; Heineman, A.L.; Taylor, S.M.; Moran, R.G.
Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates
J. Biol. Chem.
289
29386-29396
2014
Cricetulus griseus, Cricetulus griseus (Q924L9)
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