FOLC_HUMAN
ID FOLC_HUMAN Reviewed; 587 AA.
AC Q05932; B3KPW4; B7Z2Z3; F5H0K6; Q5JU19; Q5JU22; Q6P2P6;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 3.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Folylpolyglutamate synthase, mitochondrial;
DE EC=6.3.2.17;
DE AltName: Full=Folylpoly-gamma-glutamate synthetase;
DE Short=FPGS;
DE AltName: Full=Tetrahydrofolylpolyglutamate synthase;
DE Short=Tetrahydrofolate synthase;
DE Flags: Precursor;
GN Name=FPGS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4), AND VARIANT
RP VAL-22.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS VAL-22 AND
RP VAL-489.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-353, FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE
RP SPECIFICITY, SUBCELLULAR LOCATION, AND ALTERNATIVE SPLICING.
RC TISSUE=Fibroblast;
RX PubMed=8662720; DOI=10.1074/jbc.271.22.13077;
RA Chen L., Qi H., Korenberg J., Garrow T.A., Choi Y.J., Shane B.;
RT "Purification and properties of human cytosolic folylpoly-gamma-glutamate
RT synthetase and organization, localization, and differential splicing of its
RT gene.";
RL J. Biol. Chem. 271:13077-13087(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-107, ALTERNATIVE INITIATION, AND
RP VARIANT VAL-22.
RC TISSUE=Placenta;
RX PubMed=7721888; DOI=10.1074/jbc.270.16.9579;
RA Freemantle S.J., Taylor S.M., Krystal G., Moran R.G.;
RT "Upstream organization of and multiple transcripts from the human
RT folylpoly-gamma-glutamate synthetase gene.";
RL J. Biol. Chem. 270:9579-9584(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-587 (ISOFORM 1), AND CATALYTIC ACTIVITY.
RC TISSUE=Lymphocyte;
RX PubMed=1409616; DOI=10.1073/pnas.89.19.9151;
RA Garrow T.A., Admon A., Shane B.;
RT "Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate)
RT synthetase and determination of its primary structure.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:9151-9155(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 102-587.
RC TISSUE=Placenta;
RX PubMed=8521387;
RA Taylor S.M., Freemantle S.J., Moran R.G.;
RT "Structural organization of the human folypoly-gamma-glutamate synthetase
RT gene: evidence for a single genomic locus.";
RL Cancer Res. 55:6030-6034(1995).
RN [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8408018; DOI=10.1016/s0021-9258(20)80592-4;
RA Osborne C.B., Lowe K.E., Shane B.;
RT "Regulation of folate and one-carbon metabolism in mammalian cells. I.
RT Folate metabolism in Chinese hamster ovary cells expressing Escherichia
RT coli or human folylpoly-gamma-glutamate synthetase activity.";
RL J. Biol. Chem. 268:21657-21664(1993).
RN [9]
RP FUNCTION.
RX PubMed=8408019; DOI=10.1016/s0021-9258(20)80593-6;
RA Lowe K.E., Osborne C.B., Lin B.F., Kim J.S., Hsu J.C., Shane B.;
RT "Regulation of folate and one-carbon metabolism in mammalian cells. II.
RT Effect of folylpoly-gamma-glutamate synthetase substrate specificity and
RT level on folate metabolism and folylpoly-gamma-glutamate specificity of
RT metabolic cycles of one-carbon metabolism.";
RL J. Biol. Chem. 268:21665-21673(1993).
RN [10]
RP CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=8408020; DOI=10.1016/s0021-9258(20)80594-8;
RA Lin B.F., Huang R.F., Shane B.;
RT "Regulation of folate and one-carbon metabolism in mammalian cells. III.
RT Role of mitochondrial folylpoly-gamma-glutamate synthetase.";
RL J. Biol. Chem. 268:21674-21679(1993).
RN [11]
RP FUNCTION.
RX PubMed=8408021; DOI=10.1016/s0021-9258(20)80595-x;
RA Kim J.S., Lowe K.E., Shane B.;
RT "Regulation of folate and one-carbon metabolism in mammalian cells. IV.
RT Role of folylpoly-gamma-glutamate synthetase in methotrexate metabolism and
RT cytotoxicity.";
RL J. Biol. Chem. 268:21680-21685(1993).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=16169100; DOI=10.1016/j.bbamcr.2005.08.004;
RA Nair J.R., McGuire J.J.;
RT "Submitochondrial localization of the mitochondrial isoform of
RT folylpolyglutamate synthetase in CCRF-CEM human T-lymphoblastic leukemia
RT cells.";
RL Biochim. Biophys. Acta 1746:38-44(2005).
RN [13]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND VARIANTS LEU-13;
RP CYS-466; VAL-489 AND PHE-499.
RX PubMed=17875718; DOI=10.1158/0008-5472.can-07-0156;
RA Leil T.A., Endo C., Adjei A.A., Dy G.K., Salavaggione O.E., Reid J.R.,
RA Ames M.M., Adjei A.A.;
RT "Identification and characterization of genetic variation in the
RT folylpolyglutamate synthase gene.";
RL Cancer Res. 67:8772-8782(2007).
RN [14]
RP CATALYTIC ACTIVITY, AND REACTION MECHANISM.
RX PubMed=18672898; DOI=10.1021/bi800406w;
RA Tomsho J.W., Moran R.G., Coward J.K.;
RT "Concentration-dependent processivity of multiple glutamate ligations
RT catalyzed by folylpoly-gamma-glutamate synthetase.";
RL Biochemistry 47:9040-9050(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-43, CLEAVAGE OF TRANSIT PEPTIDE
RP [LARGE SCALE ANALYSIS] AFTER SER-42, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-539, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
CC -!- FUNCTION: Catalyzes conversion of folates to polyglutamate derivatives
CC allowing concentration of folate compounds in the cell and the
CC intracellular retention of these cofactors, which are important
CC substrates for most of the folate-dependent enzymes that are involved
CC in one-carbon transfer reactions involved in purine, pyrimidine and
CC amino acid synthesis. Unsubstituted reduced folates are the preferred
CC substrates. Metabolizes methotrexate (MTX) to polyglutamates.
CC {ECO:0000269|PubMed:8408018, ECO:0000269|PubMed:8408019,
CC ECO:0000269|PubMed:8408021, ECO:0000269|PubMed:8662720}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + ATP + L-
CC glutamate = (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n+1) + ADP +
CC H(+) + phosphate; Xref=Rhea:RHEA:10580, Rhea:RHEA-COMP:14738,
CC Rhea:RHEA-COMP:14740, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:141005,
CC ChEBI:CHEBI:456216; EC=6.3.2.17;
CC Evidence={ECO:0000269|PubMed:1409616, ECO:0000269|PubMed:17875718,
CC ECO:0000269|PubMed:18672898, ECO:0000269|PubMed:8408018,
CC ECO:0000269|PubMed:8408020, ECO:0000269|PubMed:8662720};
CC -!- COFACTOR:
CC Name=K(+); Xref=ChEBI:CHEBI:29103;
CC Evidence={ECO:0000269|PubMed:8662720};
CC Name=NH4(+); Xref=ChEBI:CHEBI:28938;
CC Evidence={ECO:0000269|PubMed:8662720};
CC Note=A monovalent cation. K(+) is most effective, followed by NH4(+)
CC and Rb(+). Na(+), Li(+) and Cs(+) are ineffective.
CC {ECO:0000269|PubMed:8662720};
CC -!- ACTIVITY REGULATION: Activated by 10 mM sodium bicarbonate.
CC {ECO:0000269|PubMed:8662720}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=201 uM for L-glutamate (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=200 uM for MgATP (isoform 2 at 37 degrees Celsius in the presence
CC of 1 mM ATP and 2 mM L-glutamate) {ECO:0000269|PubMed:17875718,
CC ECO:0000269|PubMed:8662720};
CC KM=59 uM for pteroylglutamic acid (PteGlu) (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=16 uM for PteGlu(2) (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=20 uM for PteGlu(3) (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=12 uM for PteGlu(4) (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=64 uM for PteGlu(5) (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=0.81 uM for H(2)PteGlu (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=47 uM for H(2)PteGlu(2) (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=1.6 uM for (6ambo)-tetrahydropteroylpoly-gamma-glutamate
CC (H(4)PteGlu) (isoform 2 at 37 degrees Celsius in the presence of 1 mM
CC ATP and 2 mM L-glutamate) {ECO:0000269|PubMed:17875718,
CC ECO:0000269|PubMed:8662720};
CC KM=4.4 uM for (6S)-H(4)PteGlu (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=3.3 uM for (6S)-H(4)PteGlu(2) (isoform 2 at 37 degrees Celsius in
CC the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=1.4 uM for (6S)-H(4)PteGlu(3) (isoform 2 at 37 degrees Celsius in
CC the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=1.6 uM for (6S)-H(4)PteGlu(4) (isoform 2 at 37 degrees Celsius in
CC the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=1.4 uM for (6S)-H(4)PteGlu(5) (isoform 2 at 37 degrees Celsius in
CC the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=3.7 uM for (6R)-10-formyl-H(4)PteGlu (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=2.7 uM for (6R)-10-formyl-H(4)PteGlu(2) (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=105 uM for (6S)-5-formyl-H(4)PteGlu (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=13 uM for (6S)-5-formyl-H(4)PteGlu(2) (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=48 uM for (6S)-5-methyl-H(4)PteGlu (isoform 2 at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=4.4 uM for aminopterin (isoform 2 at 37 degrees Celsius in the
CC presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:17875718, ECO:0000269|PubMed:8662720};
CC KM=55.5 uM for methotrexate (isoform 2, at 37 degrees Celsius in the
CC presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718};
CC KM=52.6 uM for methotrexate (isoform 1, at 37 degrees Celsius in the
CC presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718};
CC KM=71 uM for methotrexate (Glu-1) (isoform 2, at 37 degrees Celsius
CC in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:8662720};
CC KM=50 uM for methotrexate (Glu-2) (isoform 2, at 37 degrees Celsius
CC in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:8662720};
CC KM=148 uM for methotrexate (Glu-3) (isoform 2, at 37 degrees Celsius
CC in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:8662720};
CC KM=5.3 uM for 5-deazaacyclotetrahydrofolate (isoform 2, at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:8662720};
CC KM=2.8 uM for 2-methyl-5,8-dideazaisofolate (isoform 2, at 37 degrees
CC Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)
CC {ECO:0000269|PubMed:8662720};
CC KM=1702 uM for glutamic acid (isoform 2, at 37 degrees Celsius in the
CC presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718};
CC KM=2068 uM for glutamic acid (isoform 1, at 37 degrees Celsius in the
CC presence of 10 mM ATP and pH 8.5) {ECO:0000269|PubMed:17875718};
CC Vmax=0.34 umol/h/mg enzyme with methotrexate as substrate (isoform 2,
CC at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)
CC {ECO:0000269|PubMed:17875718};
CC Vmax=0.05 umol/h/mg enzyme with methotrexate as substrate (isoform 1,
CC at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)
CC {ECO:0000269|PubMed:17875718};
CC Vmax=1.26 umol/h/mg enzyme with glutamic acid as substrate (isoform
CC 2, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)
CC {ECO:0000269|PubMed:17875718};
CC Vmax=0.25 umol/h/mg enzyme with glutamic acid as substrate (isoform
CC 1, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)
CC {ECO:0000269|PubMed:17875718};
CC pH dependence:
CC Optimum pH is 9.6 (isoform 2). {ECO:0000269|PubMed:17875718,
CC ECO:0000269|PubMed:8662720};
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolylpolyglutamate
CC biosynthesis.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:16169100}. Mitochondrion matrix
CC {ECO:0000269|PubMed:16169100, ECO:0000269|PubMed:8408020,
CC ECO:0000269|PubMed:8662720}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000269|PubMed:8662720}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=4;
CC Name=1; Synonyms=Mitochondrial;
CC IsoId=Q05932-1; Sequence=Displayed;
CC Name=2; Synonyms=Cytoplasmic;
CC IsoId=Q05932-2; Sequence=VSP_018733;
CC Name=3;
CC IsoId=Q05932-3; Sequence=VSP_018733, VSP_041959;
CC Name=4;
CC IsoId=Q05932-4; Sequence=VSP_041960;
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative initiation at Met-
CC 43 of isoform 1. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing of isoform
CC 1. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Produced by alternative splicing of isoform
CC 1. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the folylpolyglutamate synthase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA35852.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AK056920; BAG51826.1; -; mRNA.
DR EMBL; AK295309; BAH12029.1; -; mRNA.
DR EMBL; AL162586; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC064393; AAH64393.1; -; mRNA.
DR EMBL; AH006037; AAC13871.1; -; Genomic_DNA.
DR EMBL; M98045; AAA35852.1; ALT_INIT; mRNA.
DR EMBL; U14939; AAA85815.1; -; Genomic_DNA.
DR EMBL; AH003340; AAA87568.1; -; Genomic_DNA.
DR CCDS; CCDS35148.1; -. [Q05932-1]
DR CCDS; CCDS35149.1; -. [Q05932-3]
DR CCDS; CCDS75905.1; -. [Q05932-4]
DR PIR; A46281; A46281.
DR RefSeq; NP_001018088.1; NM_001018078.2. [Q05932-3]
DR RefSeq; NP_001275732.1; NM_001288803.1. [Q05932-4]
DR RefSeq; NP_004948.4; NM_004957.5. [Q05932-1]
DR AlphaFoldDB; Q05932; -.
DR SMR; Q05932; -.
DR BioGRID; 108639; 32.
DR IntAct; Q05932; 9.
DR STRING; 9606.ENSP00000362344; -.
DR BindingDB; Q05932; -.
DR ChEMBL; CHEMBL3171; -.
DR DrugBank; DB00142; Glutamic acid.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB06813; Pralatrexate.
DR DrugBank; DB00293; Raltitrexed.
DR DrugCentral; Q05932; -.
DR iPTMnet; Q05932; -.
DR PhosphoSitePlus; Q05932; -.
DR BioMuta; FPGS; -.
DR DMDM; 1706884; -.
DR EPD; Q05932; -.
DR jPOST; Q05932; -.
DR MassIVE; Q05932; -.
DR MaxQB; Q05932; -.
DR PaxDb; Q05932; -.
DR PeptideAtlas; Q05932; -.
DR PRIDE; Q05932; -.
DR ProteomicsDB; 58358; -. [Q05932-1]
DR ProteomicsDB; 58359; -. [Q05932-2]
DR ProteomicsDB; 58360; -. [Q05932-3]
DR ProteomicsDB; 58361; -. [Q05932-4]
DR Antibodypedia; 30819; 166 antibodies from 23 providers.
DR DNASU; 2356; -.
DR Ensembl; ENST00000373225.7; ENSP00000362322.3; ENSG00000136877.15. [Q05932-3]
DR Ensembl; ENST00000373247.7; ENSP00000362344.2; ENSG00000136877.15. [Q05932-1]
DR Ensembl; ENST00000393706.6; ENSP00000377309.2; ENSG00000136877.15. [Q05932-4]
DR GeneID; 2356; -.
DR KEGG; hsa:2356; -.
DR MANE-Select; ENST00000373247.7; ENSP00000362344.2; NM_004957.6; NP_004948.4.
DR UCSC; uc004bsg.3; human. [Q05932-1]
DR CTD; 2356; -.
DR DisGeNET; 2356; -.
DR GeneCards; FPGS; -.
DR HGNC; HGNC:3824; FPGS.
DR HPA; ENSG00000136877; Low tissue specificity.
DR MIM; 136510; gene+phenotype.
DR neXtProt; NX_Q05932; -.
DR OpenTargets; ENSG00000136877; -.
DR PharmGKB; PA167; -.
DR VEuPathDB; HostDB:ENSG00000136877; -.
DR eggNOG; KOG2525; Eukaryota.
DR GeneTree; ENSGT00390000016526; -.
DR HOGENOM; CLU_015869_0_2_1; -.
DR InParanoid; Q05932; -.
DR OMA; FFFEVWD; -.
DR OrthoDB; 840266at2759; -.
DR PhylomeDB; Q05932; -.
DR TreeFam; TF313956; -.
DR BioCyc; MetaCyc:HS06237-MON; -.
DR BRENDA; 6.3.2.17; 2681.
DR PathwayCommons; Q05932; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SignaLink; Q05932; -.
DR UniPathway; UPA00850; -.
DR BioGRID-ORCS; 2356; 264 hits in 1084 CRISPR screens.
DR ChiTaRS; FPGS; human.
DR GeneWiki; FPGS; -.
DR GenomeRNAi; 2356; -.
DR Pharos; Q05932; Tchem.
DR PRO; PR:Q05932; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q05932; protein.
DR Bgee; ENSG00000136877; Expressed in left ovary and 146 other tissues.
DR ExpressionAtlas; Q05932; baseline and differential.
DR Genevisible; Q05932; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004326; F:tetrahydrofolylpolyglutamate synthase activity; IDA:BHF-UCL.
DR GO; GO:0031100; P:animal organ regeneration; IEA:Ensembl.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0009396; P:folic acid-containing compound biosynthetic process; IBA:GO_Central.
DR GO; GO:0006760; P:folic acid-containing compound metabolic process; IDA:BHF-UCL.
DR GO; GO:0006536; P:glutamate metabolic process; IDA:BHF-UCL.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0046901; P:tetrahydrofolylpolyglutamate biosynthetic process; IDA:BHF-UCL.
DR Gene3D; 3.40.1190.10; -; 1.
DR Gene3D; 3.90.190.20; -; 1.
DR InterPro; IPR001645; Folylpolyglutamate_synth.
DR InterPro; IPR018109; Folylpolyglutamate_synth_CS.
DR InterPro; IPR023600; Folylpolyglutamate_synth_euk.
DR InterPro; IPR036565; Mur-like_cat_sf.
DR InterPro; IPR036615; Mur_ligase_C_dom_sf.
DR PANTHER; PTHR11136; PTHR11136; 1.
DR PANTHER; PTHR11136:SF5; PTHR11136:SF5; 1.
DR PIRSF; PIRSF038895; FPGS; 1.
DR SUPFAM; SSF53244; SSF53244; 1.
DR SUPFAM; SSF53623; SSF53623; 1.
DR TIGRFAMs; TIGR01499; folC; 1.
DR PROSITE; PS01011; FOLYLPOLYGLU_SYNT_1; 1.
DR PROSITE; PS01012; FOLYLPOLYGLU_SYNT_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative initiation; Alternative splicing; ATP-binding;
KW Cytoplasm; Ligase; Magnesium; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; Nucleotide-binding; One-carbon metabolism;
KW Phosphoprotein; Reference proteome; Transit peptide.
FT TRANSIT 1..42
FT /note="Mitochondrion"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 43..587
FT /note="Folylpolyglutamate synthase, mitochondrial"
FT /id="PRO_0000010097"
FT BINDING 106..109
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT BINDING 130
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT BINDING 200
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT BINDING 228
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT BINDING 363
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT BINDING 377
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P08192"
FT MOD_RES 43
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 539
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..42
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_018733"
FT VAR_SEQ 43..50
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_041959"
FT VAR_SEQ 168..193
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_041960"
FT VARIANT 13
FT /note="F -> L (in dbSNP:rs1034635821 and
FT dbSNP:rs759336102)"
FT /evidence="ECO:0000269|PubMed:17875718"
FT /id="VAR_066016"
FT VARIANT 22
FT /note="I -> V (in dbSNP:rs10760502)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:7721888"
FT /id="VAR_059305"
FT VARIANT 437
FT /note="V -> D (in dbSNP:rs12686275)"
FT /id="VAR_043929"
FT VARIANT 466
FT /note="R -> C (expression is reduced by 1.86-fold; Vmax
FT with methotrexate as substrate is significantly reduced
FT resulting in significantly decreased intrinsic clearance of
FT methotrexate; Km of glutamic acid is increased 3.5-fold and
FT apparent Vmax of it is reduced 3.4-fold; reaction velocity
FT at 100 nmol/L of pemetrexed is significantly reduced and
FT folic acid dose-response curve is shifted to the right
FT which corresponds to 4.32-fold increase in the EC(50) for
FT folic acid; IC(50) of methotrexate is 1.84-fold higher and
FT accumulation of a lower ratio of long-chain methotrexate
FT polyglutamates to short-chain polyglutamates is detected;
FT all results are for isoform 2 variant in comparison to the
FT wild-type of it; dbSNP:rs35789560)"
FT /evidence="ECO:0000269|PubMed:17875718"
FT /id="VAR_066017"
FT VARIANT 489
FT /note="A -> V (in dbSNP:rs17855900)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17875718"
FT /id="VAR_043930"
FT VARIANT 499
FT /note="S -> F (expression reduced by 2.11-fold; Vmax with
FT methotrexate as substrate is significantly reduced
FT resulting in significantly decreased intrinsic clearance of
FT methotrexate; apparent Vmax for glutamic acid is reduced 5-
FT fold; reaction velocity at 100 nmol/L of pemetrexed is
FT significantly reduced and folic acid dose-response curve is
FT shifted to the right which corresponds to 4.28-fold
FT increase in the EC(50) for folic acid; IC(50) of
FT methotrexate is 1.64-fold higher and accumulation of a
FT lower ratio of long-chain methotrexate polyglutamates to
FT short-chain polyglutamates is detected; all results are for
FT isoform 2 variant in comparison to the wild-type of it;
FT dbSNP:rs200314440)"
FT /evidence="ECO:0000269|PubMed:17875718"
FT /id="VAR_066018"
FT VARIANT 528
FT /note="S -> T (in dbSNP:rs34354111)"
FT /id="VAR_043931"
FT CONFLICT 101
FT /note="V -> A (in Ref. 1; BAG51826)"
FT /evidence="ECO:0000305"
SQ 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
