[1]	NUCLEOTIDE SEQUENCE [MRNA] OF 1-415, AND VARIANT HOMOCYSTINURIA GLN-157. TISSUE=Liver; DOI=10.1038/ng0694-195; PubMed=7920641 [NCBI, ExPASy, EBI, Israel, Japan] Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S., Matthews R.G., Rozen R.; "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification."; Nat. Genet. 7:195-200(1994).
[2]	ERRATUM. PubMed=7951330 [NCBI, ExPASy, EBI, Israel, Japan] Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S., Matthews R.G., Rozen R.; Nat. Genet. 7:551-551(1994).
[3]	NUCLEOTIDE SEQUENCE [MRNA]. Rozen R., Goyette P.; "cDNA for human methylenetetrahydrofolate reductase."; Patent number WO9533054, 07-DEC-1995.
[4]	NUCLEOTIDE SEQUENCE [GENOMIC DNA]. DOI=10.1007/s003359900838; PubMed=9680386 [NCBI, ExPASy, EBI, Israel, Japan] Goyette P., Pai A., Milos R., Frosst P., Tran P., Chen Z., Chan M., Rozen R.; "Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)."; Mamm. Genome 9:652-656(1998).
[5]	NUCLEOTIDE SEQUENCE. Homberger A., Linnebank M., Winter C., Rapp B., Koch H.G.; "Revised translation initiation site of the human methylenetetrahydrofolate reductase (MTHFR)."; Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
[6]	NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-68; VAL-222; ARG-422; ALA-429; CYS-519; GLN-594 AND MET-653. Rieder M.J., Livingston R.J., Daniels M.R., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.; "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)."; Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
[7]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLN-594. TISSUE=Lung; DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[8]	VARIANTS MTHFRD GLN-52; MET-227; LEU-251; CYS-325; CYS-335 AND CYS-357, AND SEQUENCE REVISION TO 177. PubMed=7726158 [NCBI, ExPASy, EBI, Israel, Japan] Goyette P., Frosst P., Rosenblatt D.S., Rozen R.; "Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency."; Am. J. Hum. Genet. 56:1052-1059(1995).
[9]	ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD. DOI=10.1016/S0140-6736(95)91743-8; PubMed=7564788 [NCBI, ExPASy, EBI, Israel, Japan] van der Put N.M.J., Steegers-Theunissen R.P.M., Frosst P., Trijbels F.J.M., Eskes T.K.A.B., van den Heuvel L.P., Mariman E.C.M., den Heyer M., Rozen R., Blom H.J.; "Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida."; Lancet 346:1070-1071(1995).
[10]	VARIANT VAL-222. DOI=10.1038/ng0595-111; PubMed=7647779 [NCBI, ExPASy, EBI, Israel, Japan] Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., Boers G.J.H., den Heijer M., Kluijtmans L.A.J., van den Heuvel L.P., Rozen R.; "A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase."; Nat. Genet. 10:111-113(1995).
[11]	ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD. DOI=10.1002/(SICI)1096-8628(19960628)63:4<610::AID-AJMG15>3.0.CO;2-L; PubMed=8826441 [NCBI, ExPASy, EBI, Israel, Japan] Ou C.Y., Stevenson R.E., Brown V.K., Schwartz C.E., Allen W.P., Khoury M.J., Rozen R., Oakley G.P. Jr., Adams M.J. Jr.; "5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects."; Am. J. Med. Genet. 63:610-614(1996).
[12]	VARIANTS MTHFRD PRO-51; PRO-323 AND CYS-377. PubMed=8940272 [NCBI, ExPASy, EBI, Israel, Japan] Goyette P., Christensen B., Rosenblatt D.S., Rozen R.; "Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR."; Am. J. Hum. Genet. 59:1268-1275(1996).
[13]	INVERSE ASSOCIATION OF VARIANT VAL-222 WITH COLORECTAL CANCER. PubMed=8895734 [NCBI, ExPASy, EBI, Israel, Japan] Chen J., Giovannucci E., Kelsey K., Rimm E.B., Stampfer M.J., Colditz G.A., Spiegelman D., Willett W.C., Hunter D.J.; "A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer."; Cancer Res. 56:4862-4864(1996).
[14]	VARIANT VAL-222. DOI=10.1086/301836; PubMed=9545406 [NCBI, ExPASy, EBI, Israel, Japan] Schneider J.A., Rees D.C., Liu Y.-T., Clegg J.B.; "Worldwide distribution of a common methylenetetrahydrofolate reductase mutation."; Am. J. Hum. Genet. 62:1258-1260(1998).
[15]	VARIANT ALA-429. DOI=10.1086/301825; PubMed=9545395 [NCBI, ExPASy, EBI, Israel, Japan] van der Put N.M.J., Gabreels F., Stevens E.M.B., Smeitink J.A.M., Trijbels F.J.M., Eskes T.K.A.B., van den Heuvel L.P., Blom H.J.; "A second mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?"; Am. J. Hum. Genet. 62:1044-1051(1998).
[16]	VARIANTS MTHFRD SER-324 AND GLY-339. DOI=10.1038/sj.ejhg.5200182; PubMed=9781030 [NCBI, ExPASy, EBI, Israel, Japan] Kluijtmans L.A.J., Wendel U., Stevens E.M.B., van den Heuvel L.P.W.J., Trijbels F.J.M., Blom H.J.; "Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency."; Eur. J. Hum. Genet. 6:257-265(1998).
[17]	VARIANT ALA-429. DOI=10.1006/mgme.1998.2714; PubMed=9719624 [NCBI, ExPASy, EBI, Israel, Japan] Weisberg I., Tran P., Christiensen B., Sibani S., Rozen R.; "A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity."; Mol. Genet. Metab. 64:169-172(1998).
[18]	ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD. DOI=10.1002/(SICI)1096-8628(19990521)84:2<151::AID-AJMG12>3.0.CO;2-T; PubMed=10323741 [NCBI, ExPASy, EBI, Israel, Japan] Christensen B., Arbour L., Tran P., Leclerc D., Sabbaghian N., Platt R., Gilfix B.M., Rosenblatt D.S., Gravel R.A., Forbes P., Rozen R.; "Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects."; Am. J. Med. Genet. 84:151-157(1999).
[19]	VARIANTS VAL-222 AND ALA-429, AND ASSOCIATION WITH SUSCEPTIBILITY TO ACUTE LEUKEMIA. DOI=10.1073/pnas.96.22.12810; PubMed=10536004 [NCBI, ExPASy, EBI, Israel, Japan] Skibola C.F., Smith M.T., Kane E., Roman E., Rollinson S., Cartwright R.A., Morgan G.; "Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults."; Proc. Natl. Acad. Sci. U.S.A. 96:12810-12815(1999).
[20]	VARIANTS MTHFRD ASP-387; LEU-572 AND LYS-586. DOI=10.1002/(SICI)1098-1004(200003)15:3<280::AID-HUMU9>3.3.CO;2-9; PubMed=10679944 [NCBI, ExPASy, EBI, Israel, Japan] Sibani S., Christensen B., O'Ferrall E., Saadi I., Hiou-Tim F., Rosenblatt D.S., Rozen R.; "Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria."; Hum. Mutat. 15:280-287(2000).
[21]	ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO ISCHEMIC STROKE. DOI=10.1001/archneur.61.11.1652; PubMed=15534175 [NCBI, ExPASy, EBI, Israel, Japan] Casas J.P., Hingorani A.D., Bautista L.E., Sharma P.; "Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls."; Arch. Neurol. 61:1652-1661(2004).

Comments

FUNCTION: Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
CATALYTIC ACTIVITY: 5-methyltetrahydrofolate + NAD(P)⁺ = 5,10-methylenetetrahydrofolate + NAD(P)H.
COFACTOR: FAD.
ENZYME REGULATION: Allosterically regulated by S-adenosylmethionine.
PATHWAY: One-carbon metabolism; tetrahydrofolate pathway .
SUBUNIT: Homodimer.
INTERACTION:
O95777:LSM8; NbExp=1; IntAct=EBI-372435, EBI-347779;
POLYMORPHISM: Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.
DISEASE: Defects in MTHFR are the cause of methylenetetrahydrofolate reductase deficiency (MTHFRD) [MIM:236250]. MTHFRD is autosomal recessive disorder with a wide range of features including homocysteinuria, homocysteinemia [MIM:603174], developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders.
DISEASE: Defects in MTHFR may be a cause of susceptibility to ischemic stroke [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.
DISEASE: Defects in MTHFR may be a cause of susceptibility to folate-sensitive neural tube defects (folate-sensitive NTD) [MIM:601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MTHFRID41448ch1p36.html";.
WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=MTHFR";.
WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=MTHFR";.
WEB RESOURCE: Name=Wikipedia; Note=Methylenetetrahydrofolate reductase entry; URL="http://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase";.

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

U09806; AAA74440.2; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105987; AAD17965.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105977; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105978; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105979; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105980; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105981; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105982; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105983; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105984; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105985; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF105986; AAD17965.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ237672; CAB41971.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AY338232; AAP88033.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC053509; AAH53509.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

S46454; S46454.

NP_005948.3; -.

3D structure databases

HSSP

P00394; 1B5T. [HSSP ENTRY / PDB]

ModBase

P42898.

Protein-protein interaction databases

IntAct

P42898; -.

PTM databases

PhosphoSite

P42898; -.

Enzyme and pathway databases

Reactome

REACT_11127; Metabolism of vitamins and cofactors.

Polymorphism databases

NIEHS-SNPs

MTHFR.

Organism-specific databases

HGNC:7436; MTHFR.

236250; phenotype. [NCBI / EBI]
601367; phenotype. [NCBI / EBI]
601634; phenotype. [NCBI / EBI]
603174; phenotype. [NCBI / EBI]
607093; gene. [NCBI / EBI]

Orphanet

395; Homocystinuria due to methylenetetrahydrofolate reductase deficiency.

PharmGKB

PA245; -.

GeneCards

P42898.

Gene expression databases

ArrayExpress

P42898; -.

CleanEx

HS_MTHFR; -.

GermOnline

ENSG00000177000; Homo sapiens.

Ontologies

GO:0005829;	Cellular component: cytosol (inferred from experiment from Reactome).
GO:0004489;	Molecular function: methylenetetrahydrofolate reductase (NADPH) activity (traceable author statement from ProtInc).
GO:0005515;	Molecular function: protein binding (inferred from physical interaction from IntAct).
GO:0006520;	Biological process: amino acid metabolic process (traceable author statement from ProtInc).
GO:0008015;	Biological process: blood circulation (traceable author statement from ProtInc).
QuickGo view.

Family and domain databases

InterPro

IPR004621; Fadh2_euk.
IPR003171; Mehydrof_redctse.
Graphical view of domain structure.

Pfam

PF02219; MTHFR; 1.
Pfam graphical view of domain structure.

TIGRFAMs

TIGR00677; fadh2_euk; 1.

BLOCKS

P42898.

Genome annotation databases

Ensembl

ENSG00000177000; Homo sapiens. [Contig view]

GeneID

4524; -.

KEGG

hsa:4524; -.

Phylogenomic databases

HOVERGEN

P42898; -.

Other

DrugBank

DB00542; Benazepril.
DB00115; Cyanocobalamin.
DB00158; Folic Acid.
DB00134; L-Methionine.
DB00170; Menadione.
DB00563; Methotrexate.
DB00114; Pyridoxal Phosphate.
DB00165; Pyridoxine.
DB00293; Raltitrexed.
DB00140; Riboflavin.
DB00118; S-Adenosylmethionine.
DB00116; Tetrahydrofolic acid.

MTHFR; Homo sapiens.

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

Allosteric enzyme; Disease mutation; FAD; Flavoprotein; NADP; Oxidoreductase; Polymorphism.

Features

Feature table viewer

`Key`	`From To`	`Length`	`Description`	`FTId`
`CHAIN`	`1 656`	`656`	`Methylenetetrahydrofolate reductase.`	`PRO_0000190245`
`VARIANT`	`51 51`	`1`	`R -> P (in MTHFRD).`	`VAR_009530`
`VARIANT`	`52 52`	`1`	`R -> Q (in MTHFRD).`	`VAR_004319`
`VARIANT`	`68 68`	`1`	`R -> Q (in dbSNP:rs2066472 [NCBI]).`	`VAR_014881`
`VARIANT`	`157 157`	`1`	`R -> Q (in MTHFRD).`	`VAR_004320`
`VARIANT`	`222 222`	`1`	`A -> V (common polymorphism; thermolabile; 50% reduced activity; at homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for folate-sensitive NTD; dbSNP:rs1801133 [NCBI]).`	`VAR_009528`
`VARIANT`	`227 227`	`1`	`T -> M (in MTHFRD).`	`VAR_004321`
`VARIANT`	`251 251`	`1`	`P -> L (in MTHFRD).`	`VAR_004322`
`VARIANT`	`323 323`	`1`	`L -> P (in MTHFRD).`	`VAR_009531`
`VARIANT`	`324 324`	`1`	`N -> S (in MTHFRD).`	`VAR_009532`
`VARIANT`	`325 325`	`1`	`R -> C (in MTHFRD).`	`VAR_004323`
`VARIANT`	`335 335`	`1`	`R -> C (in MTHFRD).`	`VAR_004324`
`VARIANT`	`339 339`	`1`	`W -> G (in MTHFRD).`	`VAR_009533`
`VARIANT`	`357 357`	`1`	`R -> C (in MTHFRD).`	`VAR_004325`
`VARIANT`	`377 377`	`1`	`R -> C (in MTHFRD).`	`VAR_009534`
`VARIANT`	`387 387`	`1`	`G -> D (in MTHFRD).`	`VAR_009535`
`VARIANT`	`422 422`	`1`	`G -> R.`	`VAR_018857`
`VARIANT`	`428 428`	`1`	`E -> A (common polymorphism; thermolabile; decreased activity).`	`VAR_009529`
`VARIANT`	`429 429`	`1`	`E -> A (common polymorphism; thermolabile; decreased activity; decreased risk for adult acute leukemia; dbSNP:rs1801131 [NCBI]).`	`VAR_014882`
`VARIANT`	`519 519`	`1`	`R -> C.`	`VAR_018858`
`VARIANT`	`572 572`	`1`	`P -> L (in MTHFRD).`	`VAR_009536`
`VARIANT`	`586 586`	`1`	`E -> K (in MTHFRD).`	`VAR_009537`
`VARIANT`	`594 594`	`1`	`R -> Q (in dbSNP:rs2274976 [NCBI]).`	`VAR_018859`
`VARIANT`	`653 653`	`1`	`T -> M (in dbSNP:rs35737219 [NCBI]).`	`VAR_018860`

Sequence information

Length: 656 AA [This is the length of the unprocessed precursor]

Molecular weight: 74597 Da [This is the MW of the unprocessed precursor]

CRC64: F16E774833D054B8 [This is a checksum on the sequence]

        10         20         30         40         50         60 
MVNEARGNSS LNPCLEGSAS SGSESSKDSS RCSTPGLDPE RHERLREKMR RRLESGDKWF 

        70         80         90        100        110        120 
SLEFFPPRTA EGAVNLISRF DRMAAGGPLY IDVTWHPAGD PGSDKETSSM MIASTAVNYC 

       130        140        150        160        170        180 
GLETILHMTC CRQRLEEITG HLHKAKQLGL KNIMALRGDP IGDQWEEEEG GFNYAVDLVK 

       190        200        210        220        230        240 
HIRSEFGDYF DICVAGYPKG HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV 

       250        260        270        280        290        300 
KACTDMGITC PIVPGIFPIQ GYHSLRQLVK LSKLEVPQEI KDVIEPIKDN DAAIRNYGIE 

       310        320        330        340        350        360 
LAVSLCQELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA LSAHPKRREE 

       370        380        390        400        410        420 
DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL KDYYLFYLKS KSPKEELLKM 

       430        440        450        460        470        480 
WGEELTSEES VFEVFVLYLS GEPNRNGHKV TCLPWNDEPL AAETSLLKEE LLRVNRQGIL 

       490        500        510        520        530        540 
TINSQPNING KPSSDPIVGW GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL 

       550        560        570        580        590        600 
VNVKGENITN APELQPNAVT WGIFPGREII QPTVVDPVSF MFWKDEAFAL WIERWGKLYE 

       610        620        630        640        650 
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDTL ELLNRPTQNA RETEAP

P42898 in FASTA format

View entry in original UniProtKB/Swiss-Prot format
View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools