Reviewed, UniProtKB/Swiss-Prot P42898 (MTHR_HUMAN)

Names and origin

Protein names

Recommended name:
    Methylenetetrahydrofolate reductase
    EC=1.5.1.20

Gene names

Name:

MTHFR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	656 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (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 structure	Homodimer.
Polymorphism	Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.
Involvement in 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. 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. 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.
Sequence similarities	Belongs to the methylenetetrahydrofolate reductase family.

Ontologies

Keywords
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	FAD Flavoprotein NADP
Molecular function	Oxidoreductase
Technical term	Allosteric enzyme
Gene Ontology (GO)
Biological process	blood circulation Ref.10 Traceable author statement. Source: ProtInc oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.8 Inferred from Experiment. Source: Reactome
Molecular function	methylenetetrahydrofolate reductase (NADPH) activity Ref.8 Ref.10 Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
LSM8	O95777	1	EBI-372435,EBI-347779

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 656	656	Methylenetetrahydrofolate reductase		PRO_0000190245
Natural variations
	Natural variant	51	1	R → P in MTHFRD.		VAR_009530
	Natural variant	52	1	R → Q in MTHFRD.		VAR_004319
	Natural variant	68	1	R → Q: dbSNP rs2066472.		VAR_014881
	Natural variant	157	1	R → Q in MTHFRD.		VAR_004320
	Natural variant	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.		VAR_009528
	Natural variant	227	1	T → M in MTHFRD.		VAR_004321
	Natural variant	251	1	P → L in MTHFRD.		VAR_004322
	Natural variant	323	1	L → P in MTHFRD.		VAR_009531
	Natural variant	324	1	N → S in MTHFRD.		VAR_009532
	Natural variant	325	1	R → C in MTHFRD.		VAR_004323
	Natural variant	335	1	R → C in MTHFRD.		VAR_004324
	Natural variant	339	1	W → G in MTHFRD.		VAR_009533
	Natural variant	357	1	R → C in MTHFRD.		VAR_004325
	Natural variant	377	1	R → C in MTHFRD.		VAR_009534
	Natural variant	387	1	G → D in MTHFRD.		VAR_009535
	Natural variant	422	1	G → R		VAR_018857
	Natural variant	428	1	E → A Common polymorphism; thermolabile; decreased activity.		VAR_009529
	Natural variant	429	1	E → A Common polymorphism; thermolabile; decreased activity; decreased risk for adult acute leukemia. dbSNP rs1801131.		VAR_014882
	Natural variant	519	1	R → C		VAR_018858
	Natural variant	572	1	P → L in MTHFRD.		VAR_009536
	Natural variant	586	1	E → K in MTHFRD.		VAR_009537
	Natural variant	594	1	R → Q: dbSNP rs2274976.		VAR_018859
	Natural variant	653	1	T → M: dbSNP rs35737219.		VAR_018860

Sequences

	Sequence		Length	Mass (Da)
	P42898-1 [UniParc]. Last modified December 7, 2004. Version 3. Checksum: F16E774833D054B8	FASTA	656	74,597
	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

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification." Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S., Matthews R.G., Rozen R. Nat. Genet. 7:195-200(1994) [PubMed: 7920641] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-415, VARIANT HOMOCYSTINURIA GLN-157. Tissue: Liver.
[2]	Erratum 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) [PubMed: 7951330] [Abstract]
[3]	"cDNA for human methylenetetrahydrofolate reductase." Rozen R., Goyette P. Patent number WO9533054, 07-DEC-1995 Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)." Goyette P., Pai A., Milos R., Frosst P., Tran P., Chen Z., Chan M., Rozen R. Mamm. Genome 9:652-656(1998) [PubMed: 9680386] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Revised translation initiation site of the human methylenetetrahydrofolate reductase (MTHFR)." Homberger A., Linnebank M., Winter C., Rapp B., Koch H.G. Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE.
[6]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." 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. Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-68; VAL-222; ARG-422; ALA-429; CYS-519; GLN-594 AND MET-653.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLN-594. Tissue: Lung.
[8]	"Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency." Goyette P., Frosst P., Rosenblatt D.S., Rozen R. Am. J. Hum. Genet. 56:1052-1059(1995) [PubMed: 7726158] [Abstract] Cited for: VARIANTS MTHFRD GLN-52; MET-227; LEU-251; CYS-325; CYS-335 AND CYS-357, SEQUENCE REVISION TO 177.
[9]	"Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida." 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. Lancet 346:1070-1071(1995) [PubMed: 7564788] [Abstract] Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD.
[10]	"A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase." 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. Nat. Genet. 10:111-113(1995) [PubMed: 7647779] [Abstract] Cited for: VARIANT VAL-222.
[11]	"5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects." 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. Am. J. Med. Genet. 63:610-614(1996) [PubMed: 8826441] [Abstract] Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD.
[12]	"Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR." Goyette P., Christensen B., Rosenblatt D.S., Rozen R. Am. J. Hum. Genet. 59:1268-1275(1996) [PubMed: 8940272] [Abstract] Cited for: VARIANTS MTHFRD PRO-51; PRO-323 AND CYS-377.
[13]	"A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer." Chen J., Giovannucci E., Kelsey K., Rimm E.B., Stampfer M.J., Colditz G.A., Spiegelman D., Willett W.C., Hunter D.J. Cancer Res. 56:4862-4864(1996) [PubMed: 8895734] [Abstract] Cited for: INVERSE ASSOCIATION OF VARIANT VAL-222 WITH COLORECTAL CANCER.
[14]	"Worldwide distribution of a common methylenetetrahydrofolate reductase mutation." Schneider J.A., Rees D.C., Liu Y.-T., Clegg J.B. Am. J. Hum. Genet. 62:1258-1260(1998) [PubMed: 9545406] [Abstract] Cited for: VARIANT VAL-222.
[15]	"A second mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?" 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. Am. J. Hum. Genet. 62:1044-1051(1998) [PubMed: 9545395] [Abstract] Cited for: VARIANT ALA-429.
[16]	"Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency." Kluijtmans L.A.J., Wendel U., Stevens E.M.B., van den Heuvel L.P.W.J., Trijbels F.J.M., Blom H.J. Eur. J. Hum. Genet. 6:257-265(1998) [PubMed: 9781030] [Abstract] Cited for: VARIANTS MTHFRD SER-324 AND GLY-339.
[17]	"A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity." Weisberg I., Tran P., Christiensen B., Sibani S., Rozen R. Mol. Genet. Metab. 64:169-172(1998) [PubMed: 9719624] [Abstract] Cited for: VARIANT ALA-429.
[18]	"Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects." 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. Am. J. Med. Genet. 84:151-157(1999) [PubMed: 10323741] [Abstract] Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD.
[19]	"Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults." Skibola C.F., Smith M.T., Kane E., Roman E., Rollinson S., Cartwright R.A., Morgan G. Proc. Natl. Acad. Sci. U.S.A. 96:12810-12815(1999) [PubMed: 10536004] [Abstract] Cited for: VARIANTS VAL-222 AND ALA-429, ASSOCIATION WITH SUSCEPTIBILITY TO ACUTE LEUKEMIA.
[20]	"Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria." Sibani S., Christensen B., O'Ferrall E., Saadi I., Hiou-Tim F., Rosenblatt D.S., Rozen R. Hum. Mutat. 15:280-287(2000) [PubMed: 10679944] [Abstract] Cited for: VARIANTS MTHFRD ASP-387; LEU-572 AND LYS-586.
[21]	"Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls." Casas J.P., Hingorani A.D., Bautista L.E., Sharma P. Arch. Neurol. 61:1652-1661(2004) [PubMed: 15534175] [Abstract] Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO ISCHEMIC STROKE.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Methylenetetrahydrofolate reductase entry

Cross-references

Sequence databases
EMBLGenBankDDBJ	U09806 mRNA. Translation: AAA74440.2. AF105987 , AF105977, AF105978, AF105979, AF105980, AF105981, AF105982, AF105983, AF105984, AF105985, AF105986 Genomic DNA. Translation: AAD17965.1. AJ237672 mRNA. Translation: CAB41971.1. AY338232 Genomic DNA. Translation: AAP88033.1. BC053509 mRNA. Translation: AAH53509.1.
PIR	S46454.
RefSeq	NP_005948.3.
UniGene	Hs.214142
3D structure databases
HSSP	HSSP built from PDB template 1B5T based on UniProtKB P00394.
ModBase	Search...
Protein-protein interaction databases
IntAct	P42898.
PTM databases
PhosphoSite	P42898.
Polymorphism databases
NIEHS-SNPs	Search...
Genome annotation databases
Ensembl	ENSG00000177000. Homo sapiens. [Contig view]
GeneID	4524.
KEGG	hsa:4524.
Organism-specific databases
HGNC	HGNC:7436. MTHFR.
MIM	236250. phenotype. 601367. phenotype. 601634. phenotype. 603174. phenotype. 607093. gene.
Orphanet	395. Homocystinuria due to methylenetetrahydrofolate reductase deficiency. 3388. Neural tube defects.
PharmGKB	PA245.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOVERGEN	P42898.
Enzyme and pathway databases
Reactome	REACT_11127. Metabolism of vitamins and cofactors.
Gene expression databases
ArrayExpress	P42898.
CleanEx	HS_MTHFR.
GermOnline	ENSG00000177000. Homo sapiens.
Family and domain databases
InterPro	IPR004621. Fadh2_euk. IPR003171. Mehydrof_redctse. [Graphical view]
Pfam	PF02219. MTHFR. 1 hit. [Graphical view]
TIGRFAMs	TIGR00677. fadh2_euk. 1 hit.
ProtoNet	Search...
Other Resources
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.
NextBio	17474.
SOURCE	Search...

Entry information

Entry name

MTHR_HUMAN

Accession

Primary (citable) accession number: P42898
Secondary accession number(s): Q7Z6M6, Q9UQR2

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	December 7, 2004
Last modified:	November 25, 2008
This is version 83 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)