MTHR_HUMAN
ID MTHR_HUMAN Reviewed; 656 AA.
AC P42898; B2R7A6; Q5SNW6; Q5SNW9; Q7Z6M6; Q8IU73; Q9UQR2;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 3.
DT 03-AUG-2022, entry version 205.
DE RecName: Full=Methylenetetrahydrofolate reductase {ECO:0000305};
DE EC=1.5.1.20 {ECO:0000269|PubMed:25736335};
GN Name=MTHFR {ECO:0000312|HGNC:HGNC:7436};
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] (ISOFORM 1).
RA Rozen R., Goyette P.;
RT "cDNA for human methylenetetrahydrofolate reductase.";
RL Patent number WO9533054, 07-DEC-1995.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9680386; DOI=10.1007/s003359900838;
RA Goyette P., Pai A., Milos R., Frosst P., Tran P., Chen Z., Chan M.,
RA Rozen R.;
RT "Gene structure of human and mouse methylenetetrahydrofolate reductase
RT (MTHFR).";
RL Mamm. Genome 9:652-656(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Homberger A., Linnebank M., Winter C., Rapp B., Koch H.G.;
RT "Revised translation initiation site of the human methylenetetrahydrofolate
RT reductase (MTHFR).";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-222.
RC TISSUE=Subthalamic nucleus;
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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-68; VAL-222; ARG-422;
RP ALA-429; CYS-519; GLN-594 AND MET-653.
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-594.
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-415 (ISOFORM 1), AND VARIANT HOMOCYSTINURIA
RP GLN-157.
RC TISSUE=Liver;
RX PubMed=7920641; DOI=10.1038/ng0694-195;
RA Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S.,
RA Matthews R.G., Rozen R.;
RT "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and
RT mutation identification.";
RL Nat. Genet. 7:195-200(1994).
RN [10]
RP ERRATUM OF PUBMED:7920641.
RX PubMed=7951330;
RA Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S.,
RA Matthews R.G., Rozen R.;
RL Nat. Genet. 7:551-551(1994).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-71 (ISOFORM 2), AND
RP ALTERNATIVE SPLICING.
RX PubMed=12370778; DOI=10.1007/s00335-002-2167-6;
RA Tran P., Leclerc D., Chan M., Pai A., Hiou-Tim F., Wu Q., Goyette P.,
RA Artigas C., Milos R., Rozen R.;
RT "Multiple transcription start sites and alternative splicing in the
RT methylenetetrahydrofolate reductase gene result in two enzyme isoforms.";
RL Mamm. Genome 13:483-492(2002).
RN [12]
RP INVOLVEMENT IN SCZD, AND VARIANT VAL-222.
RX PubMed=15729744; DOI=10.1002/ajmg.b.30170;
RA Lewis S.J., Zammit S., Gunnell D., Smith G.D.;
RT "A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk.";
RL Am. J. Med. Genet. B Neuropsychiatr. Genet. 135B:2-4(2005).
RN [13]
RP INVOLVEMENT IN SCZD, AND VARIANT VAL-222.
RX PubMed=18583979; DOI=10.1038/ng.171;
RA Allen N.C., Bagade S., McQueen M.B., Ioannidis J.P., Kavvoura F.K.,
RA Khoury M.J., Tanzi R.E., Bertram L.;
RT "Systematic meta-analyses and field synopsis of genetic association studies
RT in schizophrenia: the SzGene database.";
RL Nat. Genet. 40:827-834(2008).
RN [14]
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 [15]
RP VARIANTS MTHFRD GLN-52; MET-227; LEU-251; CYS-325; CYS-335 AND CYS-357, AND
RP SEQUENCE REVISION TO 177.
RX PubMed=7726158;
RA Goyette P., Frosst P., Rosenblatt D.S., Rozen R.;
RT "Seven novel mutations in the methylenetetrahydrofolate reductase gene and
RT genotype/phenotype correlations in severe methylenetetrahydrofolate
RT reductase deficiency.";
RL Am. J. Hum. Genet. 56:1052-1059(1995).
RN [16]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT VAL-222.
RX PubMed=7564788; DOI=10.1016/s0140-6736(95)91743-8;
RA van der Put N.M.J., Steegers-Theunissen R.P.M., Frosst P., Trijbels F.J.M.,
RA Eskes T.K.A.B., van den Heuvel L.P., Mariman E.C.M., den Heyer M.,
RA Rozen R., Blom H.J.;
RT "Mutated methylenetetrahydrofolate reductase as a risk factor for spina
RT bifida.";
RL Lancet 346:1070-1071(1995).
RN [17]
RP VARIANT VAL-222.
RX PubMed=7647779; DOI=10.1038/ng0595-111;
RA Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G.,
RA Boers G.J.H., den Heijer M., Kluijtmans L.A.J., van den Heuvel L.P.,
RA Rozen R.;
RT "A candidate genetic risk factor for vascular disease: a common mutation in
RT methylenetetrahydrofolate reductase.";
RL Nat. Genet. 10:111-113(1995).
RN [18]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT VAL-222.
RX PubMed=8826441;
RX DOI=10.1002/(sici)1096-8628(19960628)63:4<610::aid-ajmg15>3.0.co;2-l;
RA Ou C.Y., Stevenson R.E., Brown V.K., Schwartz C.E., Allen W.P.,
RA Khoury M.J., Rozen R., Oakley G.P. Jr., Adams M.J. Jr.;
RT "5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk
RT factor for neural tube defects.";
RL Am. J. Med. Genet. 63:610-614(1996).
RN [19]
RP VARIANTS MTHFRD PRO-51; PRO-323 AND CYS-377.
RX PubMed=8940272;
RA Goyette P., Christensen B., Rosenblatt D.S., Rozen R.;
RT "Severe and mild mutations in cis for the methylenetetrahydrofolate
RT reductase (MTHFR) gene, and description of five novel mutations in MTHFR.";
RL Am. J. Hum. Genet. 59:1268-1275(1996).
RN [20]
RP INVERSE ASSOCIATION OF VARIANT VAL-222 WITH COLORECTAL CANCER.
RX PubMed=8895734;
RA Chen J., Giovannucci E., Kelsey K., Rimm E.B., Stampfer M.J., Colditz G.A.,
RA Spiegelman D., Willett W.C., Hunter D.J.;
RT "A methylenetetrahydrofolate reductase polymorphism and the risk of
RT colorectal cancer.";
RL Cancer Res. 56:4862-4864(1996).
RN [21] {ECO:0007744|PDB:6FCX}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 37-644 IN COMPLEX WITH
RP S-ADENOSYLMETHIONINE AND FAD, FUNCTION, SUBUNIT, ACTIVITY REGULATION,
RP CATALYTIC ACTIVITY, COFACTOR, PHOSPHORYLATION AT SER-9; SER-10; SER-18;
RP SER-20; SER-21; SER-23; SER-25; SER-26; SER-29; SER-30; THR-34; TYR-90;
RP THR-94; SER-103; SER-394 AND THR-451, BIOPHYSICOCHEMICAL PROPERTIES,
RP MUTAGENESIS OF ALA-368 AND GLU-463, AND DOMAIN.
RX PubMed=29891918; DOI=10.1038/s41467-018-04735-2;
RA Froese D.S., Kopec J., Rembeza E., Bezerra G.A., Oberholzer A.E.,
RA Suormala T., Lutz S., Chalk R., Borkowska O., Baumgartner M.R., Yue W.W.;
RT "Structural basis for the regulation of human 5,10-
RT methylenetetrahydrofolate reductase by phosphorylation and S-
RT adenosylmethionine inhibition.";
RL Nat. Commun. 9:2261-2261(2018).
RN [22]
RP VARIANT VAL-222.
RX PubMed=9545406; DOI=10.1086/301836;
RA Schneider J.A., Rees D.C., Liu Y.-T., Clegg J.B.;
RT "Worldwide distribution of a common methylenetetrahydrofolate reductase
RT mutation.";
RL Am. J. Hum. Genet. 62:1258-1260(1998).
RN [23]
RP VARIANT ALA-429.
RX PubMed=9545395; DOI=10.1086/301825;
RA van der Put N.M.J., Gabreels F., Stevens E.M.B., Smeitink J.A.M.,
RA Trijbels F.J.M., Eskes T.K.A.B., van den Heuvel L.P., Blom H.J.;
RT "A second mutation in the methylenetetrahydrofolate reductase gene: an
RT additional risk factor for neural-tube defects?";
RL Am. J. Hum. Genet. 62:1044-1051(1998).
RN [24]
RP VARIANTS MTHFRD SER-324 AND GLY-339.
RX PubMed=9781030; DOI=10.1038/sj.ejhg.5200182;
RA Kluijtmans L.A.J., Wendel U., Stevens E.M.B., van den Heuvel L.P.W.J.,
RA Trijbels F.J.M., Blom H.J.;
RT "Identification of four novel mutations in severe methylenetetrahydrofolate
RT reductase deficiency.";
RL Eur. J. Hum. Genet. 6:257-265(1998).
RN [25]
RP VARIANT ALA-429.
RX PubMed=9719624; DOI=10.1006/mgme.1998.2714;
RA Weisberg I., Tran P., Christiensen B., Sibani S., Rozen R.;
RT "A second genetic polymorphism in methylenetetrahydrofolate reductase
RT (MTHFR) associated with decreased enzyme activity.";
RL Mol. Genet. Metab. 64:169-172(1998).
RN [26]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT VAL-222.
RX PubMed=10323741;
RX DOI=10.1002/(sici)1096-8628(19990521)84:2<151::aid-ajmg12>3.0.co;2-t;
RA Christensen B., Arbour L., Tran P., Leclerc D., Sabbaghian N., Platt R.,
RA Gilfix B.M., Rosenblatt D.S., Gravel R.A., Forbes P., Rozen R.;
RT "Genetic polymorphisms in methylenetetrahydrofolate reductase and
RT methionine synthase, folate levels in red blood cells, and risk of neural
RT tube defects.";
RL Am. J. Med. Genet. 84:151-157(1999).
RN [27]
RP VARIANTS VAL-222 AND ALA-429, AND ASSOCIATION WITH SUSCEPTIBILITY TO ACUTE
RP LEUKEMIA.
RX PubMed=10536004; DOI=10.1073/pnas.96.22.12810;
RA Skibola C.F., Smith M.T., Kane E., Roman E., Rollinson S., Cartwright R.A.,
RA Morgan G.;
RT "Polymorphisms in the methylenetetrahydrofolate reductase gene are
RT associated with susceptibility to acute leukemia in adults.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:12810-12815(1999).
RN [28]
RP VARIANTS MTHFRD ASP-387; LEU-572 AND LYS-586.
RX PubMed=10679944;
RX DOI=10.1002/(sici)1098-1004(200003)15:3<280::aid-humu9>3.0.co;2-i;
RA Sibani S., Christensen B., O'Ferrall E., Saadi I., Hiou-Tim F.,
RA Rosenblatt D.S., Rozen R.;
RT "Characterization of six novel mutations in the methylenetetrahydrofolate
RT reductase (MTHFR) gene in patients with homocystinuria.";
RL Hum. Mutat. 15:280-287(2000).
RN [29]
RP ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO ISCHSTR.
RX PubMed=15534175; DOI=10.1001/archneur.61.11.1652;
RA Casas J.P., Hingorani A.D., Bautista L.E., Sharma P.;
RT "Meta-analysis of genetic studies in ischemic stroke: thirty-two genes
RT involving approximately 18,000 cases and 58,000 controls.";
RL Arch. Neurol. 61:1652-1661(2004).
RN [30]
RP VARIANT [LARGE SCALE ANALYSIS] ALA-470.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S.,
RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A.,
RA DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
RN [31]
RP VARIANTS MTHFRD LEU-218; SER-435 AND GLY-574, CHARACTERIZATION OF VARIANT
RP MTHFRD LEU-218, CHARACTERIZATION OF VARIANT VAL-222, AND COFACTOR.
RX PubMed=20236116; DOI=10.1111/j.1399-0004.2010.01391.x;
RA Urreizti R., Moya-Garcia A.A., Pino-Angeles A., Cozar M., Langkilde A.,
RA Fanhoe U., Esteves C., Arribas J., Vilaseca M.A., Perez-Duenas B.,
RA Pineda M., Gonzalez V., Artuch R., Baldellou A., Vilarinho L., Fowler B.,
RA Ribes A., Sanchez-Jimenez F., Grinberg D., Balcells S.;
RT "Molecular characterization of five patients with homocystinuria due to
RT severe methylenetetrahydrofolate reductase deficiency.";
RL Clin. Genet. 78:441-448(2010).
RN [32]
RP VARIANT MTHFRD SER-435.
RX PubMed=25818041; DOI=10.1111/epi.12954;
RA Mercimek-Mahmutoglu S., Patel J., Cordeiro D., Hewson S., Callen D.,
RA Donner E.J., Hahn C.D., Kannu P., Kobayashi J., Minassian B.A., Moharir M.,
RA Siriwardena K., Weiss S.K., Weksberg R., Snead O.C. III;
RT "Diagnostic yield of genetic testing in epileptic encephalopathy in
RT childhood.";
RL Epilepsia 56:707-716(2015).
RN [33]
RP VARIANTS MTHFRD GLN-46; TRP-46; GLN-52; SER-59; GLY-68; TRP-82; THR-113;
RP TYR-127; ASN-129; ARG-130; PRO-147; VAL-149; MET-153; GLN-157; THR-175;
RP GLN-183; VAL-195; ASP-196; LYS-215 DEL; LEU-225; ILE-226 DEL; PHE-253;
RP SER-254; VAL-255; ASN-256; VAL-257; HIS-335; THR-338; GLY-339; SER-348;
RP TYR-354; HIS-363; GLU-372; CYS-377; HIS-377; ASP-387; SER-421; ASP-506;
RP PHE-536; LEU-572; GLY-574; GLY-575; PRO-598 AND PRO-628, CHARACTERIZATION
RP OF VARIANTS MTHFRD GLN-46; TRP-46; GLN-52; SER-59; GLY-68; TRP-82; THR-113;
RP TYR-127; ASN-129; ARG-130; PRO-147; VAL-149; MET-153; GLN-157; THR-175;
RP GLN-183; VAL-195; ASP-196; LYS-215 DEL; LEU-225; ILE-226 DEL; PHE-253;
RP SER-254; VAL-255; ASN-256; VAL-257; HIS-335; THR-338; GLY-339; SER-348;
RP TYR-354; HIS-363; GLU-372; CYS-377; HIS-377; ASP-387; SER-421; ASP-506;
RP PHE-536; LEU-572; GLY-574; GLY-575; PRO-598 AND PRO-628, FUNCTION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=25736335; DOI=10.1002/humu.22779;
RA Burda P., Schaefer A., Suormala T., Rummel T., Buerer C., Heuberger D.,
RA Frapolli M., Giunta C., Sokolova J., Vlaskova H., Kozich V., Koch H.G.,
RA Fowler B., Froese D.S., Baumgartner M.R.;
RT "Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency:
RT molecular genetic and enzymatic characterization of 76 patients.";
RL Hum. Mutat. 36:611-621(2015).
CC -!- FUNCTION: Catalyzes the conversion of 5,10-methylenetetrahydrofolate to
CC 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation
CC to methionine (PubMed:29891918). Represents a key regulatory connection
CC between the folate and methionine cycles (Probable).
CC {ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:29891918,
CC ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-
CC methylene-5,6,7,8-tetrahydrofolate + H(+) + NADPH;
CC Xref=Rhea:RHEA:19817, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.5.1.20;
CC Evidence={ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:29891918};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19819;
CC Evidence={ECO:0000305|PubMed:29891918};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NAD(+) = (6R)-5,10-
CC methylene-5,6,7,8-tetrahydrofolate + H(+) + NADH;
CC Xref=Rhea:RHEA:19821, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.5.1.20;
CC Evidence={ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:29891918};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19823;
CC Evidence={ECO:0000305|PubMed:29891918};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:20236116, ECO:0000269|PubMed:29891918};
CC -!- ACTIVITY REGULATION: Allosterically regulated by S-adenosylmethionine
CC (SAM). {ECO:0000269|PubMed:29891918}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=22.4 uM for (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate
CC {ECO:0000269|PubMed:29891918};
CC KM=35.5 uM for NADPH {ECO:0000269|PubMed:29891918};
CC KM=3760 uM for NADH {ECO:0000269|PubMed:29891918};
CC Note=kcat is 40.7 sec(-1). {ECO:0000269|PubMed:29891918};
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000305|PubMed:29891918}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:29891918}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P42898-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P42898-2; Sequence=VSP_053744;
CC -!- DOMAIN: Contains a serine-rich phosphorylation region at the N-terminal
CC and an eukaryote-only S-adenosylmethionine (SAM)-binding domain at the
CC C-terminal. Through asymmetric homodimerization, the two regions are
CC positioned next to each other and N-terminal phosphorylation increases
CC sensitivity to SAM binding and inhibition.
CC {ECO:0000269|PubMed:29891918}.
CC -!- PTM: Phosphorylation of an N-terminal serine-rich phosphorylation
CC region increases sensitivity to S-adenosylmethionine and inhibition.
CC {ECO:0000269|PubMed:29891918}.
CC -!- POLYMORPHISM: Genetic variation in MTHFR influences susceptibility to
CC occlusive vascular disease, neural tube defects (NTD), colon cancer and
CC acute leukemia.
CC -!- DISEASE: Homocystinuria due to deficiency of N(5,10)-
CC methylenetetrahydrofolate reductase activity (MTHFRD) [MIM:236250]: An
CC autosomal recessive inborn error of folate metabolism. Clinical
CC severity is variable, ranging from severe neurologic features to
CC absence of symptoms. Clinical features include homocysteinuria,
CC homocysteinemia, developmental delay, severe intellectual disability,
CC perinatal death, psychiatric disturbances, and later-onset
CC neurodegenerative disorders. {ECO:0000269|PubMed:10679944,
CC ECO:0000269|PubMed:20236116, ECO:0000269|PubMed:25736335,
CC ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:7726158,
CC ECO:0000269|PubMed:8940272, ECO:0000269|PubMed:9781030}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute
CC neurologic event leading to death of neural tissue of the brain and
CC resulting in loss of motor, sensory and/or cognitive function. Ischemic
CC strokes, resulting from vascular occlusion, is considered to be a
CC highly complex disease consisting of a group of heterogeneous disorders
CC with multiple genetic and environmental risk factors.
CC {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
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:10323741, ECO:0000269|PubMed:7564788,
CC ECO:0000269|PubMed:8826441}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- DISEASE: Schizophrenia (SCZD) [MIM:181500]: A complex, multifactorial
CC psychotic disorder or group of disorders characterized by disturbances
CC in the form and content of thought (e.g. delusions, hallucinations), in
CC mood (e.g. inappropriate affect), in sense of self and relationship to
CC the external world (e.g. loss of ego boundaries, withdrawal), and in
CC behavior (e.g bizarre or apparently purposeless behavior). Although it
CC affects emotions, it is distinguished from mood disorders in which such
CC disturbances are primary. Similarly, there may be mild impairment of
CC cognitive function, and it is distinguished from the dementias in which
CC disturbed cognitive function is considered primary. Some patients
CC manifest schizophrenic as well as bipolar disorder symptoms and are
CC often given the diagnosis of schizoaffective disorder.
CC {ECO:0000269|PubMed:15729744, ECO:0000269|PubMed:18583979}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MTHFRID41448ch1p36.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mthfr/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Methylenetetrahydrofolate reductase
CC entry;
CC URL="https://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase";
CC ---------------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U09806; AAA74440.2; -; mRNA.
DR EMBL; AF105987; AAD17965.1; -; Genomic_DNA.
DR EMBL; AF105977; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105978; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105979; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105980; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105981; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105982; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105983; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105984; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105985; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AF105986; AAD17965.1; JOINED; Genomic_DNA.
DR EMBL; AJ237672; CAB41971.1; -; mRNA.
DR EMBL; AK312907; BAG35753.1; -; mRNA.
DR EMBL; AY338232; AAP88033.1; -; Genomic_DNA.
DR EMBL; AL953897; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471130; EAW71709.1; -; Genomic_DNA.
DR EMBL; BC053509; AAH53509.1; -; mRNA.
DR EMBL; AY046562; AAL17648.1; -; mRNA.
DR EMBL; AF398930; AAN40865.1; -; Genomic_DNA.
DR CCDS; CCDS137.1; -. [P42898-1]
DR CCDS; CCDS81262.1; -. [P42898-2]
DR PIR; S46454; S46454.
DR RefSeq; NP_001317287.1; NM_001330358.1. [P42898-2]
DR RefSeq; NP_005948.3; NM_005957.4. [P42898-1]
DR RefSeq; XP_005263517.1; XM_005263460.4. [P42898-1]
DR RefSeq; XP_005263519.1; XM_005263462.4. [P42898-1]
DR PDB; 6FCX; X-ray; 2.50 A; A/B=37-644.
DR PDBsum; 6FCX; -.
DR AlphaFoldDB; P42898; -.
DR SMR; P42898; -.
DR BioGRID; 110624; 44.
DR IntAct; P42898; 23.
DR MINT; P42898; -.
DR STRING; 9606.ENSP00000365777; -.
DR DrugBank; DB00542; Benazepril.
DR DrugBank; DB00115; Cyanocobalamin.
DR DrugBank; DB00544; Fluorouracil.
DR DrugBank; DB00158; Folic acid.
DR DrugBank; DB00170; Menadione.
DR DrugBank; DB00134; Methionine.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB00140; Riboflavin.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR iPTMnet; P42898; -.
DR PhosphoSitePlus; P42898; -.
DR BioMuta; MTHFR; -.
DR DMDM; 56405339; -.
DR EPD; P42898; -.
DR jPOST; P42898; -.
DR MassIVE; P42898; -.
DR MaxQB; P42898; -.
DR PaxDb; P42898; -.
DR PeptideAtlas; P42898; -.
DR PRIDE; P42898; -.
DR ProteomicsDB; 55566; -. [P42898-1]
DR Antibodypedia; 28242; 415 antibodies from 38 providers.
DR DNASU; 4524; -.
DR Ensembl; ENST00000376583.7; ENSP00000365767.3; ENSG00000177000.13. [P42898-2]
DR Ensembl; ENST00000376585.6; ENSP00000365770.1; ENSG00000177000.13. [P42898-2]
DR Ensembl; ENST00000376590.9; ENSP00000365775.3; ENSG00000177000.13. [P42898-1]
DR Ensembl; ENST00000376592.6; ENSP00000365777.1; ENSG00000177000.13. [P42898-1]
DR GeneID; 4524; -.
DR KEGG; hsa:4524; -.
DR MANE-Select; ENST00000376590.9; ENSP00000365775.3; NM_005957.5; NP_005948.3.
DR UCSC; uc001atc.3; human. [P42898-1]
DR CTD; 4524; -.
DR DisGeNET; 4524; -.
DR GeneCards; MTHFR; -.
DR HGNC; HGNC:7436; MTHFR.
DR HPA; ENSG00000177000; Low tissue specificity.
DR MalaCards; MTHFR; -.
DR MIM; 181500; phenotype.
DR MIM; 236250; phenotype.
DR MIM; 601367; phenotype.
DR MIM; 601634; phenotype.
DR MIM; 603174; phenotype.
DR MIM; 607093; gene.
DR neXtProt; NX_P42898; -.
DR OpenTargets; ENSG00000177000; -.
DR Orphanet; 268392; Cervical spina bifida aperta.
DR Orphanet; 268762; Cervical spina bifida cystica.
DR Orphanet; 268397; Cervicothoracic spina bifida aperta.
DR Orphanet; 268766; Cervicothoracic spina bifida cystica.
DR Orphanet; 395; Homocystinuria due to methylene tetrahydrofolate reductase deficiency.
DR Orphanet; 563609; Isolated anencephaly.
DR Orphanet; 563612; Isolated exencephaly.
DR Orphanet; 268388; Lumbosacral spina bifida aperta.
DR Orphanet; 268758; Lumbosacral spina bifida cystica.
DR Orphanet; 565785; Methotrexate dose selection.
DR Orphanet; 64738; NON RARE IN EUROPE: Non rare thrombophilia.
DR Orphanet; 268384; Thoracolumbosacral spina bifida aperta.
DR Orphanet; 268752; Thoracolumbosacral spina bifida cystica.
DR Orphanet; 268377; Total spina bifida aperta.
DR Orphanet; 268748; Total spina bifida cystica.
DR Orphanet; 268740; Upper thoracic spina bifida aperta.
DR Orphanet; 268770; Upper thoracic spina bifida cystica.
DR PharmGKB; PA245; -.
DR VEuPathDB; HostDB:ENSG00000177000; -.
DR eggNOG; KOG0564; Eukaryota.
DR GeneTree; ENSGT00390000012490; -.
DR HOGENOM; CLU_025841_2_0_1; -.
DR InParanoid; P42898; -.
DR OMA; HPVHGWG; -.
DR OrthoDB; 338303at2759; -.
DR PhylomeDB; P42898; -.
DR TreeFam; TF105665; -.
DR BioCyc; MetaCyc:HS11117-MON; -.
DR BRENDA; 1.5.1.20; 2681.
DR BRENDA; 1.5.1.53; 2681.
DR PathwayCommons; P42898; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SABIO-RK; P42898; -.
DR SignaLink; P42898; -.
DR SIGNOR; P42898; -.
DR UniPathway; UPA00193; -.
DR BioGRID-ORCS; 4524; 10 hits in 1074 CRISPR screens.
DR ChiTaRS; MTHFR; human.
DR GeneWiki; Methylenetetrahydrofolate_reductase; -.
DR GenomeRNAi; 4524; -.
DR Pharos; P42898; Tbio.
DR PRO; PR:P42898; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P42898; protein.
DR Bgee; ENSG00000177000; Expressed in corpus epididymis and 175 other tissues.
DR ExpressionAtlas; P42898; baseline and differential.
DR Genevisible; P42898; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0045202; C:synapse; IEA:Ensembl.
DR GO; GO:0071949; F:FAD binding; IBA:GO_Central.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:BHF-UCL.
DR GO; GO:0004489; F:methylenetetrahydrofolate reductase (NAD(P)H) activity; IDA:UniProtKB.
DR GO; GO:0106312; F:methylenetetrahydrofolate reductase NADH activity; IEA:RHEA.
DR GO; GO:0106313; F:methylenetetrahydrofolate reductase NADPH activity; IEA:RHEA.
DR GO; GO:0072341; F:modified amino acid binding; IDA:UniProtKB.
DR GO; GO:0050661; F:NADP binding; IEA:Ensembl.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:BHF-UCL.
DR GO; GO:0070828; P:heterochromatin organization; IDA:BHF-UCL.
DR GO; GO:0050667; P:homocysteine metabolic process; IDA:UniProtKB.
DR GO; GO:0009086; P:methionine biosynthetic process; IBA:GO_Central.
DR GO; GO:0006555; P:methionine metabolic process; IGI:BHF-UCL.
DR GO; GO:0001843; P:neural tube closure; IMP:BHF-UCL.
DR GO; GO:0031060; P:regulation of histone methylation; IDA:BHF-UCL.
DR GO; GO:0043200; P:response to amino acid; IEA:Ensembl.
DR GO; GO:0051593; P:response to folic acid; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IEA:Ensembl.
DR GO; GO:0033274; P:response to vitamin B2; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0046500; P:S-adenosylmethionine metabolic process; IEA:Ensembl.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IDA:UniProtKB.
DR CDD; cd00537; MTHFR; 1.
DR InterPro; IPR029041; FAD-linked_oxidoreductase-like.
DR InterPro; IPR004621; Fadh2_euk.
DR InterPro; IPR003171; Mehydrof_redctse-like.
DR Pfam; PF02219; MTHFR; 1.
DR SUPFAM; SSF51730; SSF51730; 1.
DR TIGRFAMs; TIGR00677; fadh2_euk; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing; Disease variant;
KW FAD; Flavoprotein; NADP; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Schizophrenia.
FT CHAIN 1..656
FT /note="Methylenetetrahydrofolate reductase"
FT /id="PRO_0000190245"
FT REGION 1..44
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..33
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 63
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 63..68
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 94..95
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 94..95
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 127
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 157..159
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 159
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 174..175
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 197
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 201..204
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 210
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 217
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 228
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 321
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 325
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 456
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 461..464
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 481..485
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 560
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29891918"
FT BINDING 573
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 9
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 18
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 20
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 21
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 23
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 26
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 29
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 30
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 34
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 90
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 94
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 103
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT MOD_RES 451
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29891918"
FT VAR_SEQ 1
FT /note="M -> MDHRKARVLPAGHYCPSLGIWASQVGSVRSSVPPSISRNPAM (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:12370778"
FT /id="VSP_053744"
FT VARIANT 46
FT /note="R -> Q (in MTHFRD; reduces methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs776483190)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074111"
FT VARIANT 46
FT /note="R -> W (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs138189536)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074112"
FT VARIANT 51
FT /note="R -> P (in MTHFRD; dbSNP:rs201618781)"
FT /evidence="ECO:0000269|PubMed:8940272"
FT /id="VAR_009530"
FT VARIANT 52
FT /note="R -> Q (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs754980119)"
FT /evidence="ECO:0000269|PubMed:25736335,
FT ECO:0000269|PubMed:7726158"
FT /id="VAR_004319"
FT VARIANT 59
FT /note="W -> S (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs786204007)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074113"
FT VARIANT 68
FT /note="R -> G (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs763539350)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074114"
FT VARIANT 68
FT /note="R -> Q (in dbSNP:rs2066472)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_014881"
FT VARIANT 82
FT /note="R -> W (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs786204009)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074115"
FT VARIANT 113
FT /note="A -> T (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs147257424)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074116"
FT VARIANT 127
FT /note="H -> Y (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs769381688)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074117"
FT VARIANT 129
FT /note="T -> N (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074118"
FT VARIANT 130
FT /note="C -> R (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs786204012)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074119"
FT VARIANT 147
FT /note="Q -> P (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs786204013)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074120"
FT VARIANT 149
FT /note="G -> V (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074121"
FT VARIANT 153
FT /note="I -> M (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs767890671)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074122"
FT VARIANT 157
FT /note="R -> Q (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs121434295)"
FT /evidence="ECO:0000269|PubMed:25736335,
FT ECO:0000269|PubMed:7920641"
FT /id="VAR_004320"
FT VARIANT 175
FT /note="A -> T (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs1182635980)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074123"
FT VARIANT 183
FT /note="R -> Q (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs574132670)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074124"
FT VARIANT 195
FT /note="A -> V (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs760161369)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074125"
FT VARIANT 196
FT /note="G -> D (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204014)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074126"
FT VARIANT 215
FT /note="Missing (in MTHFRD; loss of
FT methylenetetrahydrofolate reductase activity)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074127"
FT VARIANT 218
FT /note="V -> L (in MTHFRD; decreased affinity for FAD
FT cofactor)"
FT /evidence="ECO:0000269|PubMed:20236116"
FT /id="VAR_074128"
FT VARIANT 222
FT /note="A -> V (at homozygosity reduces the risk for
FT colorectal cancer in individuals with adequate folate
FT status; decreased risk for adult acute leukemia; increased
FT risk for NTDFS; increased risk for schizophrenia;
FT thermolabile; decreased affinity for FAD cofactor; 50%
FT reduced activity; dbSNP:rs1801133)"
FT /evidence="ECO:0000269|PubMed:10536004,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15729744,
FT ECO:0000269|PubMed:18583979, ECO:0000269|PubMed:20236116,
FT ECO:0000269|PubMed:7647779, ECO:0000269|PubMed:9545406,
FT ECO:0000269|Ref.5"
FT /id="VAR_009528"
FT VARIANT 225
FT /note="I -> L (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs200100285)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074129"
FT VARIANT 226
FT /note="Missing (in MTHFRD; reduced
FT methylenetetrahydrofolate reductase activity; reduced
FT affinity for NADPH)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074130"
FT VARIANT 227
FT /note="T -> M (in MTHFRD; dbSNP:rs748571395)"
FT /evidence="ECO:0000269|PubMed:7726158"
FT /id="VAR_004321"
FT VARIANT 251
FT /note="P -> L (in MTHFRD)"
FT /evidence="ECO:0000269|PubMed:7726158"
FT /id="VAR_004322"
FT VARIANT 253
FT /note="V -> F (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074131"
FT VARIANT 254
FT /note="P -> S (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs786204017)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074132"
FT VARIANT 255
FT /note="G -> V (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs786204018)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074133"
FT VARIANT 256
FT /note="I -> N (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs373398993)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074134"
FT VARIANT 257
FT /note="F -> V (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs786204019)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074135"
FT VARIANT 323
FT /note="L -> P (in MTHFRD; dbSNP:rs121434297)"
FT /evidence="ECO:0000269|PubMed:8940272"
FT /id="VAR_009531"
FT VARIANT 324
FT /note="N -> S (in MTHFRD; dbSNP:rs267606887)"
FT /evidence="ECO:0000269|PubMed:9781030"
FT /id="VAR_009532"
FT VARIANT 325
FT /note="R -> C (in MTHFRD; dbSNP:rs371085894)"
FT /evidence="ECO:0000269|PubMed:7726158"
FT /id="VAR_004323"
FT VARIANT 335
FT /note="R -> C (in MTHFRD; dbSNP:rs748289202)"
FT /evidence="ECO:0000269|PubMed:7726158"
FT /id="VAR_004324"
FT VARIANT 335
FT /note="R -> H (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; no effect on affinity for NADPH;
FT dbSNP:rs543016186)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074136"
FT VARIANT 338
FT /note="M -> T (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs368321176)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074137"
FT VARIANT 339
FT /note="W -> G (in MTHFRD; loss of methylenetetrahydrofolate
FT reductase activity; dbSNP:rs267606886)"
FT /evidence="ECO:0000269|PubMed:25736335,
FT ECO:0000269|PubMed:9781030"
FT /id="VAR_009533"
FT VARIANT 348
FT /note="P -> S (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204021)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074138"
FT VARIANT 354
FT /note="H -> Y (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204022)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074139"
FT VARIANT 357
FT /note="R -> C (in MTHFRD; dbSNP:rs779993607)"
FT /evidence="ECO:0000269|PubMed:7726158"
FT /id="VAR_004325"
FT VARIANT 363
FT /note="R -> H (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204023)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074140"
FT VARIANT 372
FT /note="K -> E (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204024)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074141"
FT VARIANT 377
FT /note="R -> C (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs121434296)"
FT /evidence="ECO:0000269|PubMed:25736335,
FT ECO:0000269|PubMed:8940272"
FT /id="VAR_009534"
FT VARIANT 377
FT /note="R -> H (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs750323424)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074142"
FT VARIANT 387
FT /note="G -> D (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs1430872491)"
FT /evidence="ECO:0000269|PubMed:10679944,
FT ECO:0000269|PubMed:25736335"
FT /id="VAR_009535"
FT VARIANT 421
FT /note="W -> S (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs200137991)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074143"
FT VARIANT 422
FT /note="G -> R (in dbSNP:rs45571736)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_018857"
FT VARIANT 429
FT /note="E -> A (decreased risk for adult acute leukemia;
FT thermolabile; decreased activity; dbSNP:rs1801131)"
FT /evidence="ECO:0000269|PubMed:10536004,
FT ECO:0000269|PubMed:9545395, ECO:0000269|PubMed:9719624,
FT ECO:0000269|Ref.5"
FT /id="VAR_014882"
FT VARIANT 435
FT /note="F -> S (in MTHFRD; dbSNP:rs754015864)"
FT /evidence="ECO:0000269|PubMed:20236116,
FT ECO:0000269|PubMed:25818041"
FT /id="VAR_074144"
FT VARIANT 470
FT /note="E -> A"
FT /evidence="ECO:0000269|PubMed:18987736"
FT /id="VAR_054158"
FT VARIANT 506
FT /note="Y -> D (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204026)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074145"
FT VARIANT 519
FT /note="R -> C (in dbSNP:rs45496998)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_018858"
FT VARIANT 519
FT /note="R -> H (in dbSNP:rs45449298)"
FT /id="VAR_050293"
FT VARIANT 536
FT /note="V -> F (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204028)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074146"
FT VARIANT 566
FT /note="G -> E (in dbSNP:rs2274974)"
FT /id="VAR_050294"
FT VARIANT 572
FT /note="P -> L (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs144508139)"
FT /evidence="ECO:0000269|PubMed:10679944,
FT ECO:0000269|PubMed:25736335"
FT /id="VAR_009536"
FT VARIANT 574
FT /note="V -> G (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH)"
FT /evidence="ECO:0000269|PubMed:20236116,
FT ECO:0000269|PubMed:25736335"
FT /id="VAR_074147"
FT VARIANT 575
FT /note="V -> G (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204031)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074148"
FT VARIANT 586
FT /note="E -> K (in MTHFRD; dbSNP:rs983672500)"
FT /evidence="ECO:0000269|PubMed:10679944"
FT /id="VAR_009537"
FT VARIANT 594
FT /note="R -> Q (in dbSNP:rs2274976)"
FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.5"
FT /id="VAR_018859"
FT VARIANT 598
FT /note="L -> P (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204034)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074149"
FT VARIANT 628
FT /note="L -> P (in MTHFRD; reduced methylenetetrahydrofolate
FT reductase activity; reduced affinity for NADPH;
FT dbSNP:rs786204037)"
FT /evidence="ECO:0000269|PubMed:25736335"
FT /id="VAR_074150"
FT VARIANT 653
FT /note="T -> M (in dbSNP:rs35737219)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_018860"
FT MUTAGEN 368
FT /note="A->G,L: No effect on S-adenosylmethionine-binding."
FT /evidence="ECO:0000269|PubMed:29891918"
FT MUTAGEN 463
FT /note="E->D,Q: Loss of S-adenosylmethionine-binding."
FT /evidence="ECO:0000269|PubMed:29891918"
FT HELIX 45..55
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 59..64
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 70..84
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 89..93
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 97..99
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 103..105
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 109..118
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 124..129
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 135..147
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 152..156
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 175..186
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 189..196
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 207..221
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 224..227
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 233..246
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 263..272
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 278..284
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 285..287
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 291..310
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 317..321
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 327..336
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 346..349
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 355..357
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 365..367
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 371..378
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 405..407
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 414..421
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 428..440
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 462..466
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 468..476
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 480..485
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 488..492
FT /evidence="ECO:0007829|PDB:6FCX"
FT TURN 496..498
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 506..509
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 511..517
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 519..529
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 530..532
FT /evidence="ECO:0007829|PDB:6FCX"
FT TURN 533..535
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 536..542
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 547..549
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 552..554
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 557..563
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 570..575
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 577..593
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 596..598
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 604..615
FT /evidence="ECO:0007829|PDB:6FCX"
FT STRAND 617..623
FT /evidence="ECO:0007829|PDB:6FCX"
FT HELIX 632..643
FT /evidence="ECO:0007829|PDB:6FCX"
SQ SEQUENCE 656 AA; 74597 MW; F16E774833D054B8 CRC64;
MVNEARGNSS LNPCLEGSAS SGSESSKDSS RCSTPGLDPE RHERLREKMR RRLESGDKWF
SLEFFPPRTA EGAVNLISRF DRMAAGGPLY IDVTWHPAGD PGSDKETSSM MIASTAVNYC
GLETILHMTC CRQRLEEITG HLHKAKQLGL KNIMALRGDP IGDQWEEEEG GFNYAVDLVK
HIRSEFGDYF DICVAGYPKG HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV
KACTDMGITC PIVPGIFPIQ GYHSLRQLVK LSKLEVPQEI KDVIEPIKDN DAAIRNYGIE
LAVSLCQELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA LSAHPKRREE
DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL KDYYLFYLKS KSPKEELLKM
WGEELTSEES VFEVFVLYLS GEPNRNGHKV TCLPWNDEPL AAETSLLKEE LLRVNRQGIL
TINSQPNING KPSSDPIVGW GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL
VNVKGENITN APELQPNAVT WGIFPGREII QPTVVDPVSF MFWKDEAFAL WIERWGKLYE
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDTL ELLNRPTQNA RETEAP
