ID C1TC_HUMAN Reviewed; 935 AA. AC P11586; A0A024R652; A0A384N5Y3; B2R5Y2; G3V2B8; Q86VC9; Q9BVP5; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 02-JUN-2021, sequence version 4. DT 27-MAR-2024, entry version 247. DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic {ECO:0000305|PubMed:1881876}; DE Short=C1-THF synthase; DE AltName: Full=Epididymis secretory sperm binding protein {ECO:0000303|Ref.3}; DE Includes: DE RecName: Full=Methylenetetrahydrofolate dehydrogenase {ECO:0000305|PubMed:1881876}; DE EC=1.5.1.5 {ECO:0000269|PubMed:10828945, ECO:0000269|PubMed:18767138, ECO:0000269|PubMed:1881876}; DE Includes: DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase {ECO:0000305|PubMed:1881876}; DE EC=3.5.4.9 {ECO:0000269|PubMed:10828945, ECO:0000269|PubMed:1881876}; DE Includes: DE RecName: Full=Formyltetrahydrofolate synthetase {ECO:0000305|PubMed:1881876}; DE EC=6.3.4.3 {ECO:0000269|PubMed:18767138, ECO:0000269|PubMed:1881876}; DE Contains: DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed; GN Name=MTHFD1; Synonyms=MTHFC, MTHFD; 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 [MRNA], PROTEIN SEQUENCE OF 2-31, VARIANT ARG-134, AND RP SUBCELLULAR LOCATION. RC TISSUE=Liver; RX PubMed=3053686; DOI=10.1016/s0021-9258(18)37540-9; RA Hum D.W., Bell A.W., Rozen R., Mackenzie R.E.; RT "Primary structure of a human trifunctional enzyme. Isolation of a cDNA RT encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate RT cyclohydrolase-formyltetrahydrofolate synthetase."; RL J. Biol. Chem. 263:15946-15950(1988). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-134 AND GLN-653. RC TISSUE=Amygdala; 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 [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Li J.Y.; RL Submitted (SEP-2009) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS ARG-134 AND RP GLN-653. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-134; GLN-653 AND RP PHE-769. RC TISSUE=Brain, Eye, and Lymph; 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 [7] RP PROTEIN SEQUENCE OF 2-17. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [8] RP PROTEIN SEQUENCE OF 2-17; 251-264; 314-324; 355-362; 596-616 AND 722-733, RP CLEAVAGE OF INITIATOR METHIONINE, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Foreskin fibroblast, and Prostatic carcinoma; RA Bienvenut W.V., Gao M., Leug H., Campbell A., Ozanne B.W.; RL Submitted (JUL-2009) to UniProtKB. RN [9] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND DOMAIN. RX PubMed=1881876; DOI=10.1093/protein/4.4.493; RA Hum D.W., MacKenzie R.E.; RT "Expression of active domains of a human folate-dependent trifunctional RT enzyme in Escherichia coli."; RL Protein Eng. 4:493-500(1991). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.; RT "Proteomic characterization of the human centrosome by protein correlation RT profiling."; RL Nature 426:570-574(2003). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [14] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, 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 [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-318; SER-413 AND SER-490, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] {ECO:0007744|PDB:1A4I} RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-302 IN COMPLEX WITH NADP. RX PubMed=9519408; DOI=10.1016/s0969-2126(98)00019-7; RA Allaire M., Li Y., Mackenzie R.E., Cygler M.; RT "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase RT bifunctional enzyme at 1.5-A resolution."; RL Structure 6:173-182(1998). RN [18] {ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB, ECO:0007744|PDB:1DIG} RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-306 IN COMPLEX WITH NADP AND RP SUBSTRATE ANALOGS, FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBUNIT, ACTIVE RP SITE, AND MUTAGENESIS OF SER-49; TYR-52; LYS-56 AND CYS-147. RX PubMed=10828945; DOI=10.1021/bi992734y; RA Schmidt A., Wu H., MacKenzie R.E., Chen V.J., Bewly J.R., Ray J.E., RA Toth J.E., Cygler M.; RT "Structures of three inhibitor complexes provide insight into the reaction RT mechanism of the human methylenetetrahydrofolate RT dehydrogenase/cyclohydrolase."; RL Biochemistry 39:6325-6335(2000). RN [19] RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANTS HIS-293 AND GLN-653. RX PubMed=9611072; DOI=10.1111/j.1399-0004.1998.tb02658.x; RA Hol F.A., van der Put N.M.J., Geurds M.P.A., Heil S.G., Trijbels F.J.M., RA Hamel B.C.J., Mariman E.C.M., Blom H.J.; RT "Molecular genetic analysis of the gene encoding the trifunctional enzyme RT MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate- RT cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural RT tube defects."; RL Clin. Genet. 53:119-125(1998). RN [20] RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT GLN-653. RX PubMed=12384833; DOI=10.1086/344213; RA Brody L.C., Conley M., Cox C., Kirke P.N., McKeever M.P., Mills J.L., RA Molloy A.M., O'Leary V.B., Parle-McDermott A., Scott J.M., Swanson D.A.; RT "A polymorphism, R653Q, in the trifunctional enzyme RT methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate RT cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk RT factor for neural tube defects: report of the Birth Defects Research RT Group."; RL Am. J. Hum. Genet. 71:1207-1215(2002). RN [21] RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT GLN-653. RX PubMed=16552426; DOI=10.1038/sj.ejhg.5201603; RA Parle-McDermott A., Kirke P.N., Mills J.L., Molloy A.M., Cox C., RA O'Leary V.B., Pangilinan F., Conley M., Cleary L., Brody L.C., Scott J.M.; RT "Confirmation of the R653Q polymorphism of the trifunctional C1-synthase RT enzyme as a maternal risk for neural tube defects in the Irish RT population."; RL Eur. J. Hum. Genet. 14:768-772(2006). RN [22] RP ASSOCIATION WITH COLORECTAL CANCER SUSCEPTIBILITY. RX PubMed=17000706; DOI=10.1093/hmg/ddl401; RA Webb E.L., Rudd M.F., Sellick G.S., El Galta R., Bethke L., Wood W., RA Fletcher O., Penegar S., Withey L., Qureshi M., Johnson N., Tomlinson I., RA Gray R., Peto J., Houlston R.S.; RT "Search for low penetrance alleles for colorectal cancer through a scan of RT 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by RT kin-cohort analysis of 14 704 first-degree relatives."; RL Hum. Mol. Genet. 15:3263-3271(2006). RN [23] RP CHARACTERIZATION OF VARIANT GLN-653, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY. RX PubMed=18767138; DOI=10.1002/humu.20830; RA Christensen K.E., Rohlicek C.V., Andelfinger G.U., Michaud J., RA Bigras J.-L., Richter A., Mackenzie R.E., Rozen R.; RT "The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk RT for congenital heart defects."; RL Hum. Mutat. 30:212-220(2009). RN [24] RP INVOLVEMENT IN CIMAH, AND VARIANT CIMAH CYS-173. RX PubMed=21813566; DOI=10.1136/jmedgenet-2011-100286; RA Watkins D., Schwartzentruber J.A., Ganesh J., Orange J.S., Kaplan B.S., RA Nunez L.D., Majewski J., Rosenblatt D.S.; RT "Novel inborn error of folate metabolism: identification by exome capture RT and sequencing of mutations in the MTHFD1 gene in a single proband."; RL J. Med. Genet. 48:590-592(2011). RN [25] RP INVOLVEMENT IN CIMAH, VARIANTS CIMAH PHE-49; 225-GLU--PHE-935 DEL AND RP ILE-269, AND FUNCTION. RX PubMed=25633902; DOI=10.1007/s10545-015-9810-3; RA Burda P., Kuster A., Hjalmarson O., Suormala T., Buerer C., Lutz S., RA Roussey G., Christa L., Asin-Cayuela J., Kollberg G., Andersson B.A., RA Watkins D., Rosenblatt D.S., Fowler B., Holme E., Froese D.S., RA Baumgartner M.R.; RT "Characterization and review of MTHFD1 deficiency: four new patients, RT cellular delineation and response to folic and folinic acid treatment."; RL J. Inherit. Metab. Dis. 38:863-872(2015). RN [26] RP INVOLVEMENT IN CIMAH, AND VARIANT CIMAH PRO-51. RX PubMed=27707659; DOI=10.1016/j.jaip.2016.07.014; RA Ramakrishnan K.A., Pengelly R.J., Gao Y., Morgan M., Patel S.V., RA Davies E.G., Ennis S., Faust S.N., Williams A.P.; RT "Precision molecular diagnosis defines specific therapy in Combined RT Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 RT deficiency."; RL J. Allergy Clin. Immunol. Pract. 4:1160.E10-1166.E10(2016). CC -!- FUNCTION: Trifunctional enzyme that catalyzes the interconversion of CC three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10- CC methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and CC (6S)-10-formyltetrahydrofolate (PubMed:1881876, PubMed:10828945, CC PubMed:18767138). These derivatives of tetrahydrofolate are CC differentially required in nucleotide and amino acid biosynthesis, CC (6S)-10-formyltetrahydrofolate being required for purine biosynthesis CC while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine CC and methionine biosynthesis for instance (PubMed:25633902, CC PubMed:18767138). {ECO:0000269|PubMed:10828945, CC ECO:0000269|PubMed:18767138, ECO:0000269|PubMed:1881876, CC ECO:0000269|PubMed:25633902}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)- CC 5,10-methenyltetrahydrofolate + NADPH; Xref=Rhea:RHEA:22812, CC ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; EC=1.5.1.5; Evidence={ECO:0000269|PubMed:10828945, CC ECO:0000269|PubMed:18767138, ECO:0000269|PubMed:1881876}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22813; CC Evidence={ECO:0000305|PubMed:1881876}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-5,10-methenyltetrahydrofolate + H2O = (6R)-10- CC formyltetrahydrofolate + H(+); Xref=Rhea:RHEA:23700, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57455, CC ChEBI:CHEBI:195366; EC=3.5.4.9; CC Evidence={ECO:0000269|PubMed:10828945, ECO:0000269|PubMed:1881876}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + ATP + formate = (6R)-10- CC formyltetrahydrofolate + ADP + phosphate; Xref=Rhea:RHEA:20221, CC ChEBI:CHEBI:15740, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:57453, ChEBI:CHEBI:195366, ChEBI:CHEBI:456216; CC EC=6.3.4.3; Evidence={ECO:0000269|PubMed:18767138, CC ECO:0000269|PubMed:1881876}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=30.3 uM for ATP {ECO:0000269|PubMed:10828945}; CC KM=364 uM for (6S)-5,6,7,8-tetrahydrofolate CC {ECO:0000269|PubMed:10828945}; CC KM=36.7 mM for formate {ECO:0000269|PubMed:10828945}; CC Vmax=13.2 umol/min/mg enzyme for the methylenetetrahydrofolate CC dehydrogenase activity {ECO:0000269|PubMed:10828945}; CC Vmax=23 umol/min/mg enzyme for the formyltetrahydrofolate synthetase CC activity {ECO:0000269|PubMed:10828945}; CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion. CC {ECO:0000269|PubMed:10828945, ECO:0000269|PubMed:18767138, CC ECO:0000269|PubMed:1881876}. CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:10828945}. CC -!- INTERACTION: CC P11586; Q9WMX2; Xeno; NbExp=3; IntAct=EBI-709638, EBI-710918; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:3053686}. CC -!- TISSUE SPECIFICITY: Ubiquitous. CC -!- DOMAIN: The N-terminal methylenetetrahydrofolate dehydrogenase and CC methenyltetrahydrofolate cyclohydrolase (D/C) domain carries both the CC methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate CC cyclohydrolase activities. {ECO:0000269|PubMed:1881876}. CC -!- DOMAIN: The larger C-terminal formyltetrahydrofolate synthetase domain CC carries a third formyltetrahydrofolate synthetase activity. CC {ECO:0000269|PubMed:1881876}. CC -!- DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: CC The most common NTDs are open spina bifida (myelomeningocele) and CC anencephaly. {ECO:0000269|PubMed:12384833, ECO:0000269|PubMed:16552426, CC ECO:0000269|PubMed:9611072}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease CC characterized by malignant lesions arising from the inner wall of the CC large intestine (the colon) and the rectum. Genetic alterations are CC often associated with progression from premalignant lesion (adenoma) to CC invasive adenocarcinoma. Risk factors for cancer of the colon and CC rectum include colon polyps, long-standing ulcerative colitis, and CC genetic family history. {ECO:0000269|PubMed:17000706}. Note=Disease CC susceptibility may be associated with variants affecting the gene CC represented in this entry. Susceptibility to colorectal cancer may be CC associated with the missense variant p.Arg134Lys, which has been CC observed in about 16% of the human population. The sequence shown in CC this entry represents the minor allele, as it is reported in the CC reference genome. {ECO:0000269|PubMed:17000706}. CC -!- DISEASE: Combined immunodeficiency and megaloblastic anemia with or CC without hyperhomocysteinemia (CIMAH) [MIM:617780]: An autosomal CC recessive disorder due to an inborn error of folate metabolism. CC Variable clinical manifestations include hemolytic uremic syndrome, CC macrocytosis, epilepsy, hearing loss, retinopathy, mild intellectual CC disability, and lymphopenia. {ECO:0000269|PubMed:21813566, CC ECO:0000269|PubMed:25633902, ECO:0000269|PubMed:27707659}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: In the N-terminal section; belongs to the tetrahydrofolate CC dehydrogenase/cyclohydrolase family. {ECO:0000305}. CC -!- SIMILARITY: In the C-terminal section; belongs to the CC formate--tetrahydrofolate ligase family. {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; J04031; AAA59574.1; -; mRNA. DR EMBL; AK312361; BAG35279.1; -; mRNA. DR EMBL; GQ891332; ADO22194.1; -; mRNA. DR EMBL; AL122035; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471061; EAW80857.1; -; Genomic_DNA. DR EMBL; CH471061; EAW80858.1; -; Genomic_DNA. DR EMBL; BC001014; AAH01014.2; -; mRNA. DR EMBL; BC009806; AAH09806.1; -; mRNA. DR EMBL; BC050420; AAH50420.1; -; mRNA. DR CCDS; CCDS9763.1; -. DR PIR; A31903; A31903. DR RefSeq; NP_005947.3; NM_005956.3. DR PDB; 1A4I; X-ray; 1.50 A; A/B=1-301. DR PDB; 1DIA; X-ray; 2.20 A; A/B=1-306. DR PDB; 1DIB; X-ray; 2.70 A; A/B=1-306. DR PDB; 1DIG; X-ray; 2.20 A; A/B=1-306. DR PDB; 6ECP; X-ray; 2.20 A; A/B=1-306. DR PDB; 6ECQ; X-ray; 2.70 A; A/B=1-296. DR PDB; 6ECR; X-ray; 2.20 A; A/B=1-296. DR PDBsum; 1A4I; -. DR PDBsum; 1DIA; -. DR PDBsum; 1DIB; -. DR PDBsum; 1DIG; -. DR PDBsum; 6ECP; -. DR PDBsum; 6ECQ; -. DR PDBsum; 6ECR; -. DR AlphaFoldDB; P11586; -. DR SMR; P11586; -. DR BioGRID; 110622; 249. DR DIP; DIP-33682N; -. DR IntAct; P11586; 59. DR MINT; P11586; -. DR STRING; 9606.ENSP00000498336; -. DR BindingDB; P11586; -. DR ChEMBL; CHEMBL2541; -. DR DrugBank; DB04322; LY249543. DR DrugBank; DB02358; LY374571. DR DrugBank; DB00157; NADH. DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate. DR DrugBank; DB00116; Tetrahydrofolic acid. DR GlyGen; P11586; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P11586; -. DR MetOSite; P11586; -. DR PhosphoSitePlus; P11586; -. DR SwissPalm; P11586; -. DR BioMuta; MTHFD1; -. DR DMDM; 115206; -. DR REPRODUCTION-2DPAGE; IPI00218342; -. DR CPTAC; CPTAC-407; -. DR CPTAC; CPTAC-408; -. DR EPD; P11586; -. DR jPOST; P11586; -. DR MassIVE; P11586; -. DR MaxQB; P11586; -. DR PaxDb; 9606-ENSP00000216605; -. DR PeptideAtlas; P11586; -. DR ProteomicsDB; 32586; -. DR ProteomicsDB; 52794; -. DR Pumba; P11586; -. DR ABCD; P11586; 1 sequenced antibody. DR Antibodypedia; 52; 190 antibodies from 30 providers. DR DNASU; 4522; -. DR Ensembl; ENST00000651537.1; ENSP00000498511.1; ENSG00000100714.18. DR Ensembl; ENST00000652337.1; ENSP00000498336.1; ENSG00000100714.18. DR GeneID; 4522; -. DR KEGG; hsa:4522; -. DR MANE-Select; ENST00000652337.1; ENSP00000498336.1; NM_005956.4; NP_005947.3. DR UCSC; uc001xhb.4; human. DR AGR; HGNC:7432; -. DR CTD; 4522; -. DR DisGeNET; 4522; -. DR GeneCards; MTHFD1; -. DR HGNC; HGNC:7432; MTHFD1. DR HPA; ENSG00000100714; Tissue enriched (liver). DR MalaCards; MTHFD1; -. DR MIM; 114500; phenotype. DR MIM; 172460; gene+phenotype. DR MIM; 601634; phenotype. DR MIM; 617780; phenotype. DR neXtProt; NX_P11586; -. DR OpenTargets; ENSG00000100714; -. DR PharmGKB; PA31236; -. DR VEuPathDB; HostDB:ENSG00000100714; -. DR eggNOG; KOG4230; Eukaryota. DR GeneTree; ENSGT00940000154746; -. DR HOGENOM; CLU_034045_3_0_1; -. DR InParanoid; P11586; -. DR OMA; QPIMFRR; -. DR OrthoDB; 651667at2759; -. DR PhylomeDB; P11586; -. DR TreeFam; TF300623; -. DR BioCyc; MetaCyc:HS02138-MONOMER; -. DR BRENDA; 1.5.1.5; 2681. DR BRENDA; 3.5.4.9; 2681. DR BRENDA; 6.3.3.2; 2681. DR BRENDA; 6.3.4.3; 2681. DR PathwayCommons; P11586; -. DR Reactome; R-HSA-196757; Metabolism of folate and pterines. DR SignaLink; P11586; -. DR SIGNOR; P11586; -. DR UniPathway; UPA00193; -. DR BioGRID-ORCS; 4522; 222 hits in 1179 CRISPR screens. DR ChiTaRS; MTHFD1; human. DR EvolutionaryTrace; P11586; -. DR GeneWiki; MTHFD1; -. DR GenomeRNAi; 4522; -. DR Pharos; P11586; Tchem. DR PRO; PR:P11586; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P11586; Protein. DR Bgee; ENSG00000100714; Expressed in right lobe of liver and 202 other cell types or tissues. DR ExpressionAtlas; P11586; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; TAS:ProtInc. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; IDA:UniProtKB. DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IDA:UniProtKB. DR GO; GO:0004487; F:methylenetetrahydrofolate dehydrogenase (NAD+) activity; ISS:BHF-UCL. DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IDA:UniProtKB. DR GO; GO:0004486; F:methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity; IDA:BHF-UCL. DR GO; GO:0009257; P:10-formyltetrahydrofolate biosynthetic process; IDA:BHF-UCL. DR GO; GO:0048702; P:embryonic neurocranium morphogenesis; ISS:BHF-UCL. DR GO; GO:0048703; P:embryonic viscerocranium morphogenesis; ISS:BHF-UCL. DR GO; GO:0007507; P:heart development; ISS:BHF-UCL. DR GO; GO:0009086; P:methionine biosynthetic process; IMP:BHF-UCL. DR GO; GO:0006555; P:methionine metabolic process; ISS:BHF-UCL. DR GO; GO:0001843; P:neural tube closure; ISS:BHF-UCL. DR GO; GO:0001780; P:neutrophil homeostasis; IEA:Ensembl. DR GO; GO:0006730; P:one-carbon metabolic process; IMP:BHF-UCL. DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IMP:UniProtKB. DR GO; GO:0009152; P:purine ribonucleotide biosynthetic process; IEA:Ensembl. DR GO; GO:0009070; P:serine family amino acid biosynthetic process; IMP:BHF-UCL. DR GO; GO:0009069; P:serine family amino acid metabolic process; ISS:BHF-UCL. DR GO; GO:0061053; P:somite development; ISS:BHF-UCL. DR GO; GO:0035999; P:tetrahydrofolate interconversion; IDA:UniProtKB. DR GO; GO:0019346; P:transsulfuration; IEA:Ensembl. DR CDD; cd00477; FTHFS; 1. DR CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 1. DR Gene3D; 1.10.8.770; -; 1. DR Gene3D; 3.10.410.10; Formyltetrahydrofolate synthetase, domain 3; 1. DR Gene3D; 3.40.50.10860; Leucine Dehydrogenase, chain A, domain 1; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR HAMAP; MF_01543; FTHFS; 1. DR HAMAP; MF_01576; THF_DHG_CYH; 1. DR InterPro; IPR046346; Aminoacid_DH-like_N_sf. DR InterPro; IPR000559; Formate_THF_ligase. DR InterPro; IPR020628; Formate_THF_ligase_CS. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR000672; THF_DH/CycHdrlase. DR InterPro; IPR020630; THF_DH/CycHdrlase_cat_dom. DR InterPro; IPR020867; THF_DH/CycHdrlase_CS. DR InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom. DR PANTHER; PTHR48099:SF1; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC; 1. DR PANTHER; PTHR48099; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 1. DR Pfam; PF01268; FTHFS; 1. DR Pfam; PF00763; THF_DHG_CYH; 1. DR Pfam; PF02882; THF_DHG_CYH_C; 1. DR PRINTS; PR00085; THFDHDRGNASE. DR SUPFAM; SSF53223; Aminoacid dehydrogenase-like, N-terminal domain; 1. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS00721; FTHFS_1; 1. DR PROSITE; PS00722; FTHFS_2; 1. DR PROSITE; PS00766; THF_DHG_CYH_1; 1. DR PROSITE; PS00767; THF_DHG_CYH_2; 1. DR SWISS-2DPAGE; P11586; -. DR Genevisible; P11586; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; ATP-binding; Cytoplasm; KW Direct protein sequencing; Disease variant; Hydrolase; Ligase; KW Multifunctional enzyme; NADP; Nucleotide-binding; One-carbon metabolism; KW Oxidoreductase; Phosphoprotein; Reference proteome. FT CHAIN 1..935 FT /note="C-1-tetrahydrofolate synthase, cytoplasmic" FT /id="PRO_0000423280" FT INIT_MET 1 FT /note="Removed; alternate" FT /evidence="ECO:0000269|PubMed:12665801, FT ECO:0000269|PubMed:3053686, ECO:0000269|Ref.8" FT CHAIN 2..935 FT /note="C-1-tetrahydrofolate synthase, cytoplasmic, N- FT terminally processed" FT /id="PRO_0000199321" FT REGION 2..291 FT /note="Methylenetetrahydrofolate dehydrogenase and FT methenyltetrahydrofolate cyclohydrolase (D/C) domain" FT /evidence="ECO:0000269|PubMed:1881876" FT REGION 310..935 FT /note="Formyltetrahydrofolate synthetase domain" FT /evidence="ECO:0000269|PubMed:1881876" FT ACT_SITE 56 FT /evidence="ECO:0000269|PubMed:10828945" FT BINDING 52..56 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:10828945, FT ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB" FT BINDING 99..101 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:10828945, FT ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB" FT BINDING 172..174 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000269|PubMed:10828945, FT ECO:0000269|PubMed:9519408, ECO:0007744|PDB:1A4I, FT ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB, FT ECO:0007744|PDB:1DIG" FT BINDING 197 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000269|PubMed:10828945, FT ECO:0000269|PubMed:9519408, ECO:0007744|PDB:1A4I, FT ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB, FT ECO:0007744|PDB:1DIG" FT BINDING 272..276 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:10828945, FT ECO:0007744|PDB:1DIA, ECO:0007744|PDB:1DIB" FT BINDING 380..387 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378" FT MOD_RES 318 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 413 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 490 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT VARIANT 49 FT /note="S -> F (in CIMAH; dbSNP:rs370444838)" FT /evidence="ECO:0000269|PubMed:25633902" FT /id="VAR_074075" FT VARIANT 51 FT /note="L -> P (in CIMAH; dbSNP:rs1555336810)" FT /evidence="ECO:0000269|PubMed:27707659" FT /id="VAR_080873" FT VARIANT 134 FT /note="K -> R (in dbSNP:rs1950902)" FT /id="VAR_016232" FT VARIANT 162 FT /note="P -> L (in dbSNP:rs4902283)" FT /id="VAR_055458" FT VARIANT 173 FT /note="R -> C (in CIMAH; dbSNP:rs141210410)" FT /evidence="ECO:0000269|PubMed:21813566" FT /id="VAR_074076" FT VARIANT 225..935 FT /note="Missing (in CIMAH)" FT /evidence="ECO:0000269|PubMed:25633902" FT /id="VAR_080874" FT VARIANT 269 FT /note="T -> I (in CIMAH; dbSNP:rs771978838)" FT /evidence="ECO:0000269|PubMed:25633902" FT /id="VAR_074077" FT VARIANT 293 FT /note="R -> H (probable risk factor for NTDFS; FT dbSNP:rs34181110)" FT /id="VAR_010241" FT VARIANT 653 FT /note="R -> Q (probable risk factor for NTDFS; decreased FT enzyme stability; no effect on methylenetetrahydrofolate FT dehydrogenase (NADP+) activity; no effect on FT formyltetrahydrofolate synthetase activity; FT dbSNP:rs2236225)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:18767138, FT ECO:0000269|PubMed:9611072, ECO:0000269|Ref.5" FT /id="VAR_010251" FT VARIANT 761 FT /note="T -> M (in dbSNP:rs10813)" FT /id="VAR_032789" FT VARIANT 769 FT /note="L -> F (in dbSNP:rs17857382)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_032790" FT MUTAGEN 49 FT /note="S->A: No effect on methylenetetrahydrofolate FT dehydrogenase (NADP+) activity. No effect on FT methenyltetrahydrofolate cyclohydrolase activity. Decreased FT affinity for NADP." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 49 FT /note="S->Q: Reduced methylenetetrahydrofolate FT dehydrogenase (NADP+) activity by 75%. Reduced FT methenyltetrahydrofolate cyclohydrolase activity by 99%. No FT effect on affinity for NADP and FT 5,10-methenyltetrahydrofolate." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 52 FT /note="Y->A,S: Reduced methylenetetrahydrofolate FT dehydrogenase (NADP+) activity by 99%. Reduced FT methenyltetrahydrofolate cyclohydrolase activity by 70%. No FT effect on affinity for NADP and FT 5,10-methenyltetrahydrofolate." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 52 FT /note="Y->F: Slightly reduced methylenetetrahydrofolate FT dehydrogenase (NADP+) activity. Slightly reduced FT methenyltetrahydrofolate cyclohydrolase activity. Decreased FT affinity for NADP and for 5,10-methenyltetrahydrofolate." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 56 FT /note="K->A,I,S,T: Decreased methylenetetrahydrofolate FT dehydrogenase (NADP+) activity over 90%. Loss of FT methenyltetrahydrofolate cyclohydrolase activity." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 56 FT /note="K->E,M,Q: Moderate decrease of FT methylenetetrahydrofolate dehydrogenase (NADP+) activity. FT Loss of methenyltetrahydrofolate cyclohydrolase activity. FT Strongly decreased affinity for NADP. Increased affinity FT for 5,10-methenyltetrahydrofolate." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 56 FT /note="K->R: Reduced methylenetetrahydrofolate FT dehydrogenase (NADP+) activity. Reduced FT methenyltetrahydrofolate cyclohydrolase activity by 99%. No FT effect on affinity for NADP and FT 5,10-methenyltetrahydrofolate." FT /evidence="ECO:0000269|PubMed:10828945" FT MUTAGEN 147 FT /note="C->Q: Reduced methylenetetrahydrofolate FT dehydrogenase (NADP+) activity by 50%. Reduced FT methenyltetrahydrofolate cyclohydrolase activity by 87%." FT /evidence="ECO:0000269|PubMed:10828945" FT HELIX 9..30 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 37..44 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 47..63 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 66..72 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 78..90 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 96..99 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 111..116 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 120..122 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 129..136 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 147..157 FT /evidence="ECO:0007829|PDB:1A4I" FT TURN 158..160 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 167..171 FT /evidence="ECO:0007829|PDB:1A4I" FT TURN 175..177 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 178..187 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 191..195 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 202..206 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 210..214 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 224..226 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 232..235 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 258..261 FT /evidence="ECO:0007829|PDB:1A4I" FT TURN 262..264 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:1A4I" FT STRAND 271..274 FT /evidence="ECO:0007829|PDB:1A4I" FT HELIX 275..295 FT /evidence="ECO:0007829|PDB:1A4I" SQ SEQUENCE 935 AA; 101531 MW; B834DB504BC1869A CRC64; MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN LYINVKLKAA EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP EKDVDGLTSI NAGKLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP MHDLLLWNNA TVTTCHSKTA HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LYQNVFACVR QPSQGPTFGI KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV PSVNGVRRFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP KAYIQENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTESELDLI SRLSREHGAF DAVKCTHWAE GGKGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE LLPEAQHKAE VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF //