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 27-MAR-2024, entry version 214. DE RecName: Full=Methylenetetrahydrofolate reductase (NADPH) {ECO:0000305}; DE EC=1.5.1.53 {ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:29891918}; 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=1.5.1.53; 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 -!- 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="https://atlasgeneticsoncology.org/gene/41448/MTHFR"; 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 --------------------------------------------------------------------------- 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; 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. DR RefSeq; XP_005263519.1; XM_005263462.4. [P42898-1] DR PDB; 6FCX; X-ray; 2.50 A; A/B=37-644. DR PDB; 8QA4; EM; 2.80 A; A/B=1-656. DR PDB; 8QA5; EM; 3.14 A; A/B=1-656. DR PDB; 8QA6; EM; 2.91 A; A/B=1-656. DR PDBsum; 6FCX; -. DR PDBsum; 8QA4; -. DR PDBsum; 8QA5; -. DR PDBsum; 8QA6; -. DR AlphaFoldDB; P42898; -. DR EMDB; EMD-18298; -. DR EMDB; EMD-18299; -. DR EMDB; EMD-18300; -. DR SMR; P42898; -. DR BioGRID; 110624; 47. DR IntAct; P42898; 24. DR MINT; P42898; -. DR STRING; 9606.ENSP00000365770; -. 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; 9606-ENSP00000365777; -. DR PeptideAtlas; P42898; -. DR ProteomicsDB; 55566; -. [P42898-1] DR Pumba; P42898; -. DR Antibodypedia; 28242; 468 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 AGR; HGNC:7436; -. 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; 395; Homocystinuria due to methylene tetrahydrofolate reductase deficiency. DR Orphanet; 563609; Isolated anencephaly. DR Orphanet; 563612; Isolated exencephaly. DR Orphanet; 64738; NON RARE IN EUROPE: Non rare thrombophilia. 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; VARTSQW; -. DR OrthoDB; 1381745at2759; -. DR PhylomeDB; P42898; -. DR TreeFam; TF105665; -. DR BioCyc; MetaCyc:HS11117-MONOMER; -. 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; 12 hits in 1154 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 177 other cell types or tissues. DR ExpressionAtlas; P42898; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. 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: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: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 Gene3D; 3.20.20.220; -; 1. DR InterPro; IPR029041; FAD-linked_oxidoreductase-like. DR InterPro; IPR004621; Fadh2_euk. DR InterPro; IPR003171; Mehydrof_redctse-like. DR NCBIfam; TIGR00677; fadh2_euk; 1. DR PANTHER; PTHR45754; METHYLENETETRAHYDROFOLATE REDUCTASE; 1. DR PANTHER; PTHR45754:SF3; METHYLENETETRAHYDROFOLATE REDUCTASE; 1. DR Pfam; PF02219; MTHFR; 1. DR SUPFAM; SSF51730; FAD-linked oxidoreductase; 1. DR Genevisible; P42898; HS. 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 (NADPH)" 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 //