Literature summary for 6.3.2.17 extracted from

Raz, S.; Stark, M.; Assaraf, Y.G.
Folylpoly-gamma-glutamate synthetase A key determinant of folate homeostasis and antifolate resistance in cancer (2016), Drug Resist. Updat., 28, 43-64 .

Search for more literature for 6.3.2.17

Cloned(Commentary)

Cloned (Comment)	Organism
gene FPGS, DNA and amino acid sequence analysis, promoter determination and analysis, overview, recombinnat expression in murine knockout cell line AUXB1	Homo sapiens
gene fpgS, DNA and amino acid sequence determination and analysis	Lacticaseibacillus casei

Protein Variants

Protein Variants	Comment	Organism
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	Homo sapiens
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	Homo sapiens
D335A	site-directed mutagenesis, the substitution leads to a catalytically dead FPGS with diminished binding of glutamate, ATP and the antifolate	Homo sapiens
H338A	site-directed mutagenesis, the mutation increases the Kmfor glutamic acid by 600fold foldwith negligible residual catalytic activity	Homo sapiens
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	Homo sapiens
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	Homo sapiens
additional information	FPGS promoter methylation leads to reduced transcription in rats following three months of alcohol consumption. This reduction in FPGS activity results in decreased levels of total as well as polyglutamated folates in different tissues	Rattus norvegicus
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	Cricetulus griseus
R377A D335A	site-directed mutagenesis, the substitution results in a 1500fold increase in the Km for glutamate, and a 20fold decrease in the Kcat	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
cytoplasm	-	Lacticaseibacillus casei	5737	-
cytoplasm	-	Rattus norvegicus	5737	-
cytoplasm	-	Homo sapiens	5737	-
mitochondrial inner membrane	the mitochondrial isoform is an integral membrane protein	Homo sapiens	5743	-
mitochondrion	-	Rattus norvegicus	5739	-
mitochondrion	-	Cricetulus griseus	5739	-
mitochondrion	-	Mus musculus	5739	-
additional information	folylpoly-gamma-glutamate synthetase resides in both the cytoplasm and mitochondria	Cricetulus griseus	-	-
additional information	folylpoly-gamma-glutamate synthetase resides in both the cytoplasm and mitochondria. The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%	Rattus norvegicus	-	-
additional information	folylpoly-gamma-glutamate synthetase resides in both the cytoplasm and mitochondria. The cytosolic fraction contains between 65-75% of total cellular FPGS and the mitochondria 25-35%	Mus musculus	-	-
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%	Homo sapiens	-	-
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%	Homo sapiens	-	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Lacticaseibacillus casei
Mg2+	required	Escherichia coli
Mg2+	required	Rattus norvegicus
Mg2+	required	Cricetulus griseus
Mg2+	required	Mus musculus
Mg2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Lacticaseibacillus casei	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Escherichia coli	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Rattus norvegicus	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Cricetulus griseus	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Mus musculus	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	Homo sapiens	-	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?

Organism

Organism	UniProt	Comment	Textmining
Cricetulus griseus	Q924L9	-	-
Escherichia coli	P08192	-	-
Homo sapiens	Q05932	-	-
Homo sapiens	Q96LE3	-	-
Lacticaseibacillus casei	P15925	-	-
Mus musculus	P48760	-	-
Rattus norvegicus	M0R401	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
additional information	posttranscriptional mechanisms are involved in regulating FPGS activity	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
AML-193 cell	-	Homo sapiens	-
bone marrow	-	Homo sapiens	-
CCRF-CEM cell	-	Homo sapiens	-
CEM cell	-	Homo sapiens	-
CHO cell	-	Cricetulus griseus	-
head and neck squamous carcinoma cell	-	Homo sapiens	-
Hep-G2 cell	-	Homo sapiens	-
HL-60 cell	-	Homo sapiens	-
K-562 cell	-	Homo sapiens	-
liver	-	Homo sapiens	-
MOLT-3 cell	-	Homo sapiens	-
additional information	FPGS expression analysis in human tissues, antifolate resistant sublines, overview	Homo sapiens	-
NALM-6 cell	-	Homo sapiens	-
peripheral blood mononuclear cell	-	Homo sapiens	-
skeletal muscle	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Lacticaseibacillus casei	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Escherichia coli	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Rattus norvegicus	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Cricetulus griseus	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Mus musculus	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate	-	Homo sapiens	ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1	-	?

Synonyms

Synonyms	Comment	Organism
cFPGS	-	Homo sapiens
DHFS/FPGS	-	Escherichia coli
dihydrofolate synthase/folylpolyglutamate synthase	-	Escherichia coli
eFPGS	-	Escherichia coli
Folylpoly-gamma-glutamate synthetase	-	Lacticaseibacillus casei
Folylpoly-gamma-glutamate synthetase	-	Escherichia coli
Folylpoly-gamma-glutamate synthetase	-	Rattus norvegicus
Folylpoly-gamma-glutamate synthetase	-	Cricetulus griseus
Folylpoly-gamma-glutamate synthetase	-	Mus musculus
Folylpoly-gamma-glutamate synthetase	-	Homo sapiens
FPGS	-	Lacticaseibacillus casei
FPGS	-	Escherichia coli
FPGS	-	Rattus norvegicus
FPGS	-	Cricetulus griseus
FPGS	-	Mus musculus
FPGS	-	Homo sapiens
mFPGS	-	Homo sapiens
More	cf. EC 6.3.2.12	Escherichia coli

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Lacticaseibacillus casei
ATP	-	Escherichia coli
ATP	-	Rattus norvegicus
ATP	-	Cricetulus griseus
ATP	-	Mus musculus
ATP	-	Homo sapiens

Expression

Organism	Comment	Expression
Homo sapiens	mechanisms of FPGS downregulation, overview	down
Homo sapiens	mechanisms of FPGSd ownregulation, overview	down

General Information

General Information	Comment	Organism
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	Homo sapiens
malfunction	knockout of the FPGS gene in mice results in embryonic lethality. Decreased translation of the FPGS mRNA is demonstrated in edatrexate (EDX)-resistant L-1210 cells obtained from mice treated with EDX. While 7 EDX-resistant clones display FPGS-based EDX resistance, only one leukemia cell line which displays the greatest loss of FPGS activity, exhibits reduced translation of FPGS mRNA upon in vitro translation experiments. Insufficient FPGS translation is not a common mechanism of loss of FPGS activity	Mus musculus
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	Cricetulus griseus
metabolism	subcellular compartmentalization of one-carbon metabolism in mammalian cells involving the enzyme, overview	Rattus norvegicus
metabolism	subcellular compartmentalization of one-carbon metabolism in mammalian cells involving the enzyme, overview	Mus musculus
metabolism	subcellular compartmentalization of one-carbon metabolism in mammalian cells involving the enzyme, overview	Homo sapiens
additional information	3D-modeling analysis suggests that C388 is located at the entrance to the active site of this enzyme	Homo sapiens
additional information	amino acids D335, H338 and R377 participate in the alignment of glutamic acid in the active site	Homo sapiens
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	Cricetulus griseus
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 glutamate 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 swhich 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, intracellular 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)	Rattus norvegicus
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 swhich 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, intracellular 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)	Mus musculus
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	Homo sapiens
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	Homo sapiens

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Release 2023.1 (January 2023)