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Folylpolyglutamate synthase, mitochondrial (EC 6.3.2.17) (Folylpoly-gamma-glutamate synthetase) (FPGS) (Tetrahydrofolylpolyglutamate synthase) (Tetrahydrofolate synthase)

 FOLC_HUMAN              Reviewed;         587 AA.
Q05932; B3KPW4; B7Z2Z3; F5H0K6; Q5JU19; Q5JU22; Q6P2P6;
01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
01-OCT-1996, sequence version 3.
25-OCT-2017, entry version 175.
RecName: Full=Folylpolyglutamate synthase, mitochondrial;
EC=6.3.2.17;
AltName: Full=Folylpoly-gamma-glutamate synthetase;
Short=FPGS;
AltName: Full=Tetrahydrofolylpolyglutamate synthase;
Short=Tetrahydrofolate synthase;
Flags: Precursor;
Name=FPGS;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4), AND VARIANT
VAL-22.
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS
VAL-22 AND VAL-489.
TISSUE=Lung;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-353, FUNCTION, CATALYTIC
ACTIVITY, COFACTOR, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
SUBSTRATE SPECIFICITY, SUBCELLULAR LOCATION, AND ALTERNATIVE SPLICING.
TISSUE=Fibroblast;
PubMed=8662720; DOI=10.1074/jbc.271.22.13077;
Chen L., Qi H., Korenberg J., Garrow T.A., Choi Y.J., Shane B.;
"Purification and properties of human cytosolic folylpoly-gamma-
glutamate synthetase and organization, localization, and differential
splicing of its gene.";
J. Biol. Chem. 271:13077-13087(1996).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-107, ALTERNATIVE INITIATION,
AND VARIANT VAL-22.
TISSUE=Placenta;
PubMed=7721888; DOI=10.1074/jbc.270.16.9579;
Freemantle S.J., Taylor S.M., Krystal G., Moran R.G.;
"Upstream organization of and multiple transcripts from the human
folylpoly-gamma-glutamate synthetase gene.";
J. Biol. Chem. 270:9579-9584(1995).
[6]
NUCLEOTIDE SEQUENCE [MRNA] OF 20-587 (ISOFORM 1), AND CATALYTIC
ACTIVITY.
TISSUE=Lymphocyte;
PubMed=1409616; DOI=10.1073/pnas.89.19.9151;
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. U.S.A. 89:9151-9155(1992).
[7]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 102-587.
TISSUE=Placenta;
PubMed=8521387;
Taylor S.M., Freemantle S.J., Moran R.G.;
"Structural organization of the human folypoly-gamma-glutamate
synthetase gene: evidence for a single genomic locus.";
Cancer Res. 55:6030-6034(1995).
[8]
FUNCTION, AND CATALYTIC ACTIVITY.
PubMed=8408018;
Osborne C.B., Lowe K.E., Shane B.;
"Regulation of folate and one-carbon metabolism in mammalian cells. I.
Folate metabolism in Chinese hamster ovary cells expressing
Escherichia coli or human folylpoly-gamma-glutamate synthetase
activity.";
J. Biol. Chem. 268:21657-21664(1993).
[9]
FUNCTION.
PubMed=8408019;
Lowe K.E., Osborne C.B., Lin B.F., Kim J.S., Hsu J.C., Shane B.;
"Regulation of folate and one-carbon metabolism in mammalian cells.
II. Effect of folylpoly-gamma-glutamate synthetase substrate
specificity and level on folate metabolism and folylpoly-gamma-
glutamate specificity of metabolic cycles of one-carbon metabolism.";
J. Biol. Chem. 268:21665-21673(1993).
[10]
CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
PubMed=8408020;
Lin B.F., Huang R.F., Shane B.;
"Regulation of folate and one-carbon metabolism in mammalian cells.
III. Role of mitochondrial folylpoly-gamma-glutamate synthetase.";
J. Biol. Chem. 268:21674-21679(1993).
[11]
FUNCTION.
PubMed=8408021;
Kim J.S., Lowe K.E., Shane B.;
"Regulation of folate and one-carbon metabolism in mammalian cells.
IV. Role of folylpoly-gamma-glutamate synthetase in methotrexate
metabolism and cytotoxicity.";
J. Biol. Chem. 268:21680-21685(1993).
[12]
SUBCELLULAR LOCATION.
PubMed=16169100; DOI=10.1016/j.bbamcr.2005.08.004;
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).
[13]
CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND VARIANTS
LEU-13; CYS-466; VAL-489 AND PHE-499.
PubMed=17875718; DOI=10.1158/0008-5472.CAN-07-0156;
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).
[14]
CATALYTIC ACTIVITY, AND REACTION MECHANISM.
PubMed=18672898; DOI=10.1021/bi800406w;
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).
[15]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-43, CLEAVAGE OF TRANSIT
PEPTIDE [LARGE SCALE ANALYSIS] AFTER SER-42, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22814378; DOI=10.1073/pnas.1210303109;
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
Aldabe R.;
"N-terminal acetylome analyses and functional insights of the N-
terminal acetyltransferase NatB.";
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
[16]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-539, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
-!- FUNCTION: Catalyzes conversion of folates to polyglutamate
derivatives allowing concentration of folate compounds in the cell
and the intracellular retention of these cofactors, which are
important substrates for most of the folate-dependent enzymes that
are involved in one-carbon transfer reactions involved in purine,
pyrimidine and amino acid synthesis. Unsubstituted reduced folates
are the preferred substrates. Metabolizes methotrexate (MTX) to
polyglutamates. {ECO:0000269|PubMed:8408018,
ECO:0000269|PubMed:8408019, ECO:0000269|PubMed:8408021,
ECO:0000269|PubMed:8662720}.
-!- CATALYTIC ACTIVITY: ATP + tetrahydropteroyl-(gamma-Glu)(n) + L-
glutamate = ADP + phosphate + tetrahydropteroyl-(gamma-Glu)(n+1).
{ECO:0000269|PubMed:1409616, ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:18672898, ECO:0000269|PubMed:8408018,
ECO:0000269|PubMed:8408020, ECO:0000269|PubMed:8662720}.
-!- COFACTOR:
Name=K(+); Xref=ChEBI:CHEBI:29103;
Evidence={ECO:0000269|PubMed:8662720};
Name=NH4(+); Xref=ChEBI:CHEBI:28938;
Evidence={ECO:0000269|PubMed:8662720};
Note=A monovalent cation. K(+) is most effective, followed by
NH4(+) and Rb(+). Na(+), Li(+) and Cs(+) are ineffective.
{ECO:0000269|PubMed:8662720};
-!- ENZYME REGULATION: Activated by 10 mM sodium bicarbonate.
{ECO:0000269|PubMed:8662720}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=201 uM for L-glutamate (isoform 2 at 37 degrees Celsius in
the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=200 uM for MgATP (isoform 2 at 37 degrees Celsius in the
presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=59 uM for pteroylglutamic acid (PteGlu) (isoform 2 at 37
degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=16 uM for PteGlu(2) (isoform 2 at 37 degrees Celsius in the
presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=20 uM for PteGlu(3) (isoform 2 at 37 degrees Celsius in the
presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=12 uM for PteGlu(4) (isoform 2 at 37 degrees Celsius in the
presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=64 uM for PteGlu(5) (isoform 2 at 37 degrees Celsius in the
presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=0.81 uM for H(2)PteGlu (isoform 2 at 37 degrees Celsius in
the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=47 uM for H(2)PteGlu(2) (isoform 2 at 37 degrees Celsius in
the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=1.6 uM for (6ambo)-tetrahydropteroylpoly-gamma-glutamate
(H(4)PteGlu) (isoform 2 at 37 degrees Celsius in the presence of
1 mM ATP and 2 mM L-glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=4.4 uM for (6S)-H(4)PteGlu (isoform 2 at 37 degrees Celsius
in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=3.3 uM for (6S)-H(4)PteGlu(2) (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=1.4 uM for (6S)-H(4)PteGlu(3) (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=1.6 uM for (6S)-H(4)PteGlu(4) (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=1.4 uM for (6S)-H(4)PteGlu(5) (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=3.7 uM for (6R)-10-formyl-H(4)PteGlu (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=2.7 uM for (6R)-10-formyl-H(4)PteGlu(2) (isoform 2 at 37
degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=105 uM for (6S)-5-formyl-H(4)PteGlu (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=13 uM for (6S)-5-formyl-H(4)PteGlu(2) (isoform 2 at 37
degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=48 uM for (6S)-5-methyl-H(4)PteGlu (isoform 2 at 37 degrees
Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=4.4 uM for aminopterin (isoform 2 at 37 degrees Celsius in
the presence of 1 mM ATP and 2 mM L-glutamate)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=55.5 uM for methotrexate (isoform 2, PubMed:17875718, at 37
degrees Celsius in the presence of 10 mM ATP and pH 8.5)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=52.6 uM for methotrexate (isoform 1, PubMed:17875718, at 37
degrees Celsius in the presence of 10 mM ATP and pH 8.5)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=71 uM for methotrexate (Glu-1) (isoform 2, PubMed:8662720, at
37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=50 uM for methotrexate (Glu-2) (isoform 2, PubMed:8662720, at
37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=148 uM for methotrexate (Glu-3) (isoform 2, PubMed:8662720,
at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=5.3 uM for 5-deazaacyclotetrahydrofolate (isoform 2, at 37
degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=2.8 uM for 2-methyl-5,8-dideazaisofolate (isoform 2, at 37
degrees Celsius in the presence of 1 mM ATP and 2 mM L-
glutamate) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
KM=1702 uM for glutamic acid (isoform 2, PubMed:17875718, at 37
degrees Celsius in the presence of 10 mM ATP and pH 8.5)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
KM=2068 uM for glutamic acid (isoform 1, PubMed:17875718, at 37
degrees Celsius in the presence of 10 mM ATP and pH 8.5)
{ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
Vmax=0.34 umol/h/mg enzyme with methotrexate as substrate
(isoform 2, PubMed:17875718, at 37 degrees Celsius in the
presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
Vmax=0.05 umol/h/mg enzyme with methotrexate as substrate
(isoform 1, PubMed:17875718, at 37 degrees Celsius in the
presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
Vmax=1.26 umol/h/mg enzyme with glutamic acid as substrate
(isoform 2, PubMed:17875718, at 37 degrees Celsius in the
presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
Vmax=0.25 umol/h/mg enzyme with glutamic acid as substrate
(isoform 1, PubMed:17875718, at 37 degrees Celsius in the
presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
pH dependence:
Optimum pH is 9.6 (isoform 2). {ECO:0000269|PubMed:17875718,
ECO:0000269|PubMed:8662720};
-!- PATHWAY: Cofactor biosynthesis; tetrahydrofolylpolyglutamate
biosynthesis.
-!- SUBUNIT: Monomer.
-!- SUBCELLULAR LOCATION: Isoform 1: Mitochondrion inner membrane
{ECO:0000269|PubMed:16169100}. Mitochondrion matrix
{ECO:0000269|PubMed:16169100, ECO:0000269|PubMed:8408020,
ECO:0000269|PubMed:8662720}.
-!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm
{ECO:0000269|PubMed:8662720}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing, Alternative initiation; Named isoforms=4;
Name=1; Synonyms=Mitochondrial;
IsoId=Q05932-1; Sequence=Displayed;
Name=2; Synonyms=Cytoplasmic;
IsoId=Q05932-2; Sequence=VSP_018733;
Note=Produced by alternative initiation at Met-43 of isoform 1.;
Name=3;
IsoId=Q05932-3; Sequence=VSP_018733, VSP_041959;
Note=Produced by alternative splicing of isoform 1.;
Name=4;
IsoId=Q05932-4; Sequence=VSP_041960;
Note=Produced by alternative splicing of isoform 1.;
-!- SIMILARITY: Belongs to the folylpolyglutamate synthase family.
{ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=AAA35852.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
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EMBL; AK056920; BAG51826.1; -; mRNA.
EMBL; AK295309; BAH12029.1; -; mRNA.
EMBL; AL162586; CAI39770.1; -; Genomic_DNA.
EMBL; AL162586; CAI39773.1; -; Genomic_DNA.
EMBL; BC064393; AAH64393.1; -; mRNA.
EMBL; AH006037; AAC13871.1; -; Genomic_DNA.
EMBL; M98045; AAA35852.1; ALT_INIT; mRNA.
EMBL; U14939; AAA85815.1; -; Genomic_DNA.
EMBL; AH003340; AAA87568.1; -; Genomic_DNA.
CCDS; CCDS35148.1; -. [Q05932-1]
CCDS; CCDS35149.1; -. [Q05932-3]
CCDS; CCDS75905.1; -. [Q05932-4]
PIR; A46281; A46281.
RefSeq; NP_001018088.1; NM_001018078.2. [Q05932-3]
RefSeq; NP_001275732.1; NM_001288803.1. [Q05932-4]
RefSeq; NP_004948.4; NM_004957.5. [Q05932-1]
UniGene; Hs.335084; -.
ProteinModelPortal; Q05932; -.
BioGrid; 108639; 7.
IntAct; Q05932; 1.
STRING; 9606.ENSP00000362344; -.
BindingDB; Q05932; -.
ChEMBL; CHEMBL3171; -.
DrugBank; DB00142; L-Glutamic Acid.
DrugBank; DB00563; Methotrexate.
DrugBank; DB06813; Pralatrexate.
DrugBank; DB00293; Raltitrexed.
iPTMnet; Q05932; -.
PhosphoSitePlus; Q05932; -.
BioMuta; FPGS; -.
DMDM; 1706884; -.
EPD; Q05932; -.
MaxQB; Q05932; -.
PaxDb; Q05932; -.
PeptideAtlas; Q05932; -.
PRIDE; Q05932; -.
DNASU; 2356; -.
Ensembl; ENST00000373225; ENSP00000362322; ENSG00000136877. [Q05932-3]
Ensembl; ENST00000373247; ENSP00000362344; ENSG00000136877. [Q05932-1]
Ensembl; ENST00000393706; ENSP00000377309; ENSG00000136877. [Q05932-4]
GeneID; 2356; -.
KEGG; hsa:2356; -.
UCSC; uc004bsg.3; human. [Q05932-1]
CTD; 2356; -.
DisGeNET; 2356; -.
EuPathDB; HostDB:ENSG00000136877.14; -.
GeneCards; FPGS; -.
HGNC; HGNC:3824; FPGS.
HPA; HPA050488; -.
MIM; 136510; gene+phenotype.
neXtProt; NX_Q05932; -.
OpenTargets; ENSG00000136877; -.
PharmGKB; PA167; -.
eggNOG; KOG2525; Eukaryota.
eggNOG; COG0285; LUCA.
GeneTree; ENSGT00390000016526; -.
HOGENOM; HOG000181278; -.
HOVERGEN; HBG003086; -.
InParanoid; Q05932; -.
KO; K01930; -.
OMA; GIYKEGV; -.
OrthoDB; EOG091G0DO0; -.
PhylomeDB; Q05932; -.
TreeFam; TF313956; -.
BioCyc; MetaCyc:HS06237-MONOMER; -.
Reactome; R-HSA-196757; Metabolism of folate and pterines.
UniPathway; UPA00850; -.
ChiTaRS; FPGS; human.
GeneWiki; FPGS; -.
GenomeRNAi; 2356; -.
PRO; PR:Q05932; -.
Proteomes; UP000005640; Chromosome 9.
Bgee; ENSG00000136877; -.
CleanEx; HS_FPGS; -.
ExpressionAtlas; Q05932; baseline and differential.
Genevisible; Q05932; HS.
GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0004326; F:tetrahydrofolylpolyglutamate synthase activity; IDA:BHF-UCL.
GO; GO:0031100; P:animal organ regeneration; IEA:Ensembl.
GO; GO:0007420; P:brain development; IEA:Ensembl.
GO; GO:0008283; P:cell proliferation; IMP:BHF-UCL.
GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
GO; GO:0006760; P:folic acid-containing compound metabolic process; IDA:BHF-UCL.
GO; GO:0006536; P:glutamate metabolic process; IDA:BHF-UCL.
GO; GO:0001889; P:liver development; IEA:Ensembl.
GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc.
GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
GO; GO:0046901; P:tetrahydrofolylpolyglutamate biosynthetic process; IDA:BHF-UCL.
Gene3D; 3.40.1190.10; -; 1.
Gene3D; 3.90.190.20; -; 1.
InterPro; IPR001645; Folylpolyglutamate_synth.
InterPro; IPR018109; Folylpolyglutamate_synth_CS.
InterPro; IPR023600; Folylpolyglutamate_synth_euk.
InterPro; IPR036565; Mur-like_cat_sf.
InterPro; IPR036615; Mur_ligase_C_dom_sf.
PANTHER; PTHR11136; PTHR11136; 1.
PANTHER; PTHR11136:SF5; PTHR11136:SF5; 1.
PIRSF; PIRSF038895; FPGS; 1.
SUPFAM; SSF53244; SSF53244; 1.
SUPFAM; SSF53623; SSF53623; 1.
TIGRFAMs; TIGR01499; folC; 1.
PROSITE; PS01011; FOLYLPOLYGLU_SYNT_1; 1.
PROSITE; PS01012; FOLYLPOLYGLU_SYNT_2; 1.
1: Evidence at protein level;
Acetylation; Alternative initiation; Alternative splicing;
ATP-binding; Complete proteome; Cytoplasm; Ligase; Magnesium;
Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane;
Nucleotide-binding; One-carbon metabolism; Phosphoprotein;
Polymorphism; Reference proteome; Transit peptide.
TRANSIT 1 42 Mitochondrion.
{ECO:0000244|PubMed:22814378}.
CHAIN 43 587 Folylpolyglutamate synthase,
mitochondrial.
/FTId=PRO_0000010097.
NP_BIND 106 109 ATP. {ECO:0000250|UniProtKB:P08192}.
METAL 130 130 Magnesium 1.
{ECO:0000250|UniProtKB:P08192}.
METAL 200 200 Magnesium 1.
{ECO:0000250|UniProtKB:P08192}.
METAL 228 228 Magnesium 2.
{ECO:0000250|UniProtKB:P08192}.
BINDING 363 363 ATP. {ECO:0000250|UniProtKB:P08192}.
BINDING 377 377 ATP. {ECO:0000250|UniProtKB:P08192}.
MOD_RES 43 43 N-acetylmethionine.
{ECO:0000244|PubMed:22814378}.
MOD_RES 539 539 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
VAR_SEQ 1 42 Missing (in isoform 2 and isoform 3).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_018733.
VAR_SEQ 43 50 Missing (in isoform 3).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_041959.
VAR_SEQ 168 193 Missing (in isoform 4).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_041960.
VARIANT 13 13 F -> L (in dbSNP:rs759336102).
{ECO:0000269|PubMed:17875718}.
/FTId=VAR_066016.
VARIANT 22 22 I -> V (in dbSNP:rs10760502).
{ECO:0000269|PubMed:14702039,
ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:7721888}.
/FTId=VAR_059305.
VARIANT 437 437 V -> D (in dbSNP:rs12686275).
/FTId=VAR_043929.
VARIANT 466 466 R -> C (expression is reduced by 1.86-
fold; Vmax with methotrexate as substrate
is significantly reduced resulting in
significantly decreased intrinsic
clearance of methotrexate; Km of glutamic
acid is increased 3.5-fold and apparent
Vmax of it is reduced 3.4-fold; reaction
velocity at 100 nmol/L of pemetrexed is
significantly reduced and folic acid
dose-response curve is shifted to the
right which corresponds to 4.32-fold
increase in the EC(50) for folic acid;
IC(50) of methotrexate is 1.84-fold
higher and accumulation of a lower ratio
of long-chain methotrexate polyglutamates
to short-chain polyglutamates is
detected; all results are for isoform 2
variant in comparison to the wild-type of
it; dbSNP:rs35789560).
{ECO:0000269|PubMed:17875718}.
/FTId=VAR_066017.
VARIANT 489 489 A -> V (in dbSNP:rs17855900).
{ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:17875718}.
/FTId=VAR_043930.
VARIANT 499 499 S -> F (expression reduced by 2.11-fold;
Vmax with methotrexate as substrate is
significantly reduced resulting in
significantly decreased intrinsic
clearance of methotrexate; apparent Vmax
for glutamic acid is reduced 5-fold;
reaction velocity at 100 nmol/L of
pemetrexed is significantly reduced and
folic acid dose-response curve is shifted
to the right which corresponds to 4.28-
fold increase in the EC(50) for folic
acid; IC(50) of methotrexate is 1.64-fold
higher and accumulation of a lower ratio
of long-chain methotrexate polyglutamates
to short-chain polyglutamates is
detected; all results are for isoform 2
variant in comparison to the wild-type of
it; dbSNP:rs200314440).
{ECO:0000269|PubMed:17875718}.
/FTId=VAR_066018.
VARIANT 528 528 S -> T (in dbSNP:rs34354111).
/FTId=VAR_043931.
CONFLICT 101 101 V -> A (in Ref. 1; BAG51826).
{ECO:0000305}.
SEQUENCE 587 AA; 64609 MW; 5AF81409F5F77E5C CRC64;
MSRARSHLRA ALFLAAASAR GITTQVAARR GLSAWPVPQE PSMEYQDAVR MLNTLQTNAG
YLEQVKRQRG DPQTQLEAME LYLARSGLQV EDLDRLNIIH VTGTKGKGST CAFTECILRS
YGLKTGFFSS PHLVQVRERI RINGQPISPE LFTKYFWRLY HRLEETKDGS CVSMPPYFRF
LTLMAFHVFL QEKVDLAVVE VGIGGAYDCT NIIRKPVVCG VSSLGIDHTS LLGDTVEKIA
WQKGGIFKQG VPAFTVLQPE GPLAVLRDRA QQISCPLYLC PMLEALEEGG PPLTLGLEGE
HQRSNAALAL QLAHCWLQRQ DRHGAGEPKA SRPGLLWQLP LAPVFQPTSH MRLGLRNTEW
PGRTQVLRRG PLTWYLDGAH TASSAQACVR WFRQALQGRE RPSGGPEVRV LLFNATGDRD
PAALLKLLQP CQFDYAVFCP NLTEVSSTGN ADQQNFTVTL DQVLLRCLEH QQHWNHLDEE
QASPDLWSAP SPEPGGSASL LLAPHPPHTC SASSLVFSCI SHALQWISQG RDPIFQPPSP
PKGLLTHPVA HSGASILREA AAIHVLVTGS LHLVGGVLKL LEPALSQ


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