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 27-MAR-2024, entry version 213. 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; 39. 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 SwissPalm; Q05932; -. DR BioMuta; FPGS; -. DR DMDM; 1706884; -. DR EPD; Q05932; -. DR jPOST; Q05932; -. DR MassIVE; Q05932; -. DR MaxQB; Q05932; -. DR PaxDb; 9606-ENSP00000362344; -. DR PeptideAtlas; Q05932; -. DR ProteomicsDB; 58358; -. [Q05932-1] DR ProteomicsDB; 58359; -. [Q05932-2] DR ProteomicsDB; 58360; -. [Q05932-3] DR ProteomicsDB; 58361; -. [Q05932-4] DR Pumba; Q05932; -. DR Antibodypedia; 30819; 189 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 AGR; HGNC:3824; -. 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; ESLDCCM; -. DR OrthoDB; 7073at2759; -. DR PhylomeDB; Q05932; -. DR TreeFam; TF313956; -. DR BioCyc; MetaCyc:HS06237-MONOMER; -. 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; 275 hits in 1165 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 148 other cell types or tissues. DR ExpressionAtlas; Q05932; baseline and differential. 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:0008283; P:cell population proliferation; IMP:BHF-UCL. DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome. 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; 3.90.190.20; Mur ligase, C-terminal domain; 1. DR Gene3D; 3.40.1190.10; Mur-like, catalytic domain; 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 NCBIfam; TIGR01499; folC; 1. DR PANTHER; PTHR11136:SF5; FOLYLPOLYGLUTAMATE SYNTHASE, MITOCHONDRIAL; 1. DR PANTHER; PTHR11136; FOLYLPOLYGLUTAMATE SYNTHASE-RELATED; 1. DR PIRSF; PIRSF038895; FPGS; 1. DR SUPFAM; SSF53623; MurD-like peptide ligases, catalytic domain; 1. DR SUPFAM; SSF53244; MurD-like peptide ligases, peptide-binding domain; 1. DR PROSITE; PS01011; FOLYLPOLYGLU_SYNT_1; 1. DR PROSITE; PS01012; FOLYLPOLYGLU_SYNT_2; 1. DR Genevisible; Q05932; HS. 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 FT 5-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 //