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Protein

Methylenetetrahydrofolate reductase

Gene

MTHFR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.1 Publication

Catalytic activityi

5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H.1 Publication

Cofactori

FAD1 Publication

Enzyme regulationi

Allosterically regulated by S-adenosylmethionine.

Pathwayi: tetrahydrofolate interconversion

This protein is involved in the pathway tetrahydrofolate interconversion, which is part of One-carbon metabolism.
View all proteins of this organism that are known to be involved in the pathway tetrahydrofolate interconversion and in One-carbon metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei63Proton donor/acceptorBy similarity1
Binding sitei127FADBy similarity1
Binding sitei159SubstrateBy similarity1
Binding sitei197FADBy similarity1
Binding sitei210FADBy similarity1
Binding sitei217FADBy similarity1
Binding sitei228SubstrateBy similarity1
Binding sitei321SubstrateBy similarity1
Binding sitei325SubstrateBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi63 – 68NADBy similarity6
Nucleotide bindingi94 – 95NAD and FADBy similarity2
Nucleotide bindingi157 – 159FADBy similarity3
Nucleotide bindingi174 – 175FADBy similarity2
Nucleotide bindingi201 – 204FADBy similarity4

GO - Molecular functioni

  • flavin adenine dinucleotide binding Source: BHF-UCL
  • methylenetetrahydrofolate reductase (NAD(P)H) activity Source: UniProtKB
  • modified amino acid binding Source: UniProtKB
  • NADP binding Source: Ensembl
  • protein complex binding Source: BHF-UCL

GO - Biological processi

  • blood circulation Source: ProtInc
  • cellular amino acid metabolic process Source: ProtInc
  • folic acid metabolic process Source: Reactome
  • heterochromatin maintenance Source: BHF-UCL
  • homocysteine metabolic process Source: UniProtKB
  • methionine metabolic process Source: BHF-UCL
  • regulation of histone methylation Source: BHF-UCL
  • response to amino acid Source: Ensembl
  • response to drug Source: Ensembl
  • response to folic acid Source: Ensembl
  • response to hypoxia Source: Ensembl
  • response to interleukin-1 Source: Ensembl
  • response to vitamin B2 Source: Ensembl
  • S-adenosylmethionine metabolic process Source: Ensembl
  • tetrahydrofolate interconversion Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Ligandi

FAD, Flavoprotein, NADP

Enzyme and pathway databases

BioCyciZFISH:HS11117-MONOMER.
BRENDAi1.5.1.20. 2681.
ReactomeiR-HSA-196757. Metabolism of folate and pterines.
SABIO-RKP42898.
UniPathwayiUPA00193.

Names & Taxonomyi

Protein namesi
Recommended name:
Methylenetetrahydrofolate reductaseCurated (EC:1.5.1.201 Publication)
Gene namesi
Name:MTHFR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:7436. MTHFR.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Methylenetetrahydrofolate reductase deficiency (MTHFRD)6 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal 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.
See also OMIM:236250
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07411146R → Q in MTHFRD; reduces methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs776483190dbSNPEnsembl.1
Natural variantiVAR_07411246R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs138189536dbSNPEnsembl.1
Natural variantiVAR_00953051R → P in MTHFRD. 1 PublicationCorresponds to variant rs201618781dbSNPEnsembl.1
Natural variantiVAR_00431952R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs754980119dbSNPEnsembl.1
Natural variantiVAR_07411359W → S in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204007dbSNPEnsembl.1
Natural variantiVAR_07411468R → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs763539350dbSNPEnsembl.1
Natural variantiVAR_07411582R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204009dbSNPEnsembl.1
Natural variantiVAR_074116113A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs147257424dbSNPEnsembl.1
Natural variantiVAR_074117127H → Y in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs769381688dbSNPEnsembl.1
Natural variantiVAR_074118129T → N in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074119130C → R in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204012dbSNPEnsembl.1
Natural variantiVAR_074120147Q → P in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204013dbSNPEnsembl.1
Natural variantiVAR_074121149G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074122153I → M in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs767890671dbSNPEnsembl.1
Natural variantiVAR_004320157R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs121434295dbSNPEnsembl.1
Natural variantiVAR_074123175A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074124183R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs574132670dbSNPEnsembl.1
Natural variantiVAR_074125195A → V in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs760161369dbSNPEnsembl.1
Natural variantiVAR_074126196G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204014dbSNPEnsembl.1
Natural variantiVAR_074127215Missing in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074128218V → L in MTHFRD; decreased affinity for FAD cofactor. 1 Publication1
Natural variantiVAR_074129225I → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs200100285dbSNPEnsembl.1
Natural variantiVAR_074130226Missing in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_004321227T → M in MTHFRD. 1 PublicationCorresponds to variant rs748571395dbSNPEnsembl.1
Natural variantiVAR_004322251P → L in MTHFRD. 1 Publication1
Natural variantiVAR_074131253V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074132254P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204017dbSNPEnsembl.1
Natural variantiVAR_074133255G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204018dbSNPEnsembl.1
Natural variantiVAR_074134256I → N in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs373398993dbSNPEnsembl.1
Natural variantiVAR_074135257F → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204019dbSNPEnsembl.1
Natural variantiVAR_009531323L → P in MTHFRD. 1 PublicationCorresponds to variant rs121434297dbSNPEnsembl.1
Natural variantiVAR_009532324N → S in MTHFRD. 1 PublicationCorresponds to variant rs267606887dbSNPEnsembl.1
Natural variantiVAR_004323325R → C in MTHFRD. 1 PublicationCorresponds to variant rs371085894dbSNPEnsembl.1
Natural variantiVAR_004324335R → C in MTHFRD. 1 PublicationCorresponds to variant rs748289202dbSNPEnsembl.1
Natural variantiVAR_074136335R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs543016186dbSNPEnsembl.1
Natural variantiVAR_074137338M → T in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs368321176dbSNPEnsembl.1
Natural variantiVAR_009533339W → G in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 2 PublicationsCorresponds to variant rs267606886dbSNPEnsembl.1
Natural variantiVAR_074138348P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204021dbSNPEnsembl.1
Natural variantiVAR_074139354H → Y in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204022dbSNPEnsembl.1
Natural variantiVAR_004325357R → C in MTHFRD. 1 PublicationCorresponds to variant rs779993607dbSNPEnsembl.1
Natural variantiVAR_074140363R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204023dbSNPEnsembl.1
Natural variantiVAR_074141372K → E in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204024dbSNPEnsembl.1
Natural variantiVAR_009534377R → C in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs121434296dbSNPEnsembl.1
Natural variantiVAR_074142377R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs750323424dbSNPEnsembl.1
Natural variantiVAR_009535387G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074143421W → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs200137991dbSNPEnsembl.1
Natural variantiVAR_074144435F → S in MTHFRD. 1 PublicationCorresponds to variant rs754015864dbSNPEnsembl.1
Natural variantiVAR_074145506Y → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204026dbSNPEnsembl.1
Natural variantiVAR_074146536V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204028dbSNPEnsembl.1
Natural variantiVAR_009536572P → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs144508139dbSNPEnsembl.1
Natural variantiVAR_074147574V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074148575V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204031dbSNPEnsembl.1
Natural variantiVAR_009537586E → K in MTHFRD. 1 Publication1
Natural variantiVAR_074149598L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204034dbSNPEnsembl.1
Natural variantiVAR_074150628L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204037dbSNPEnsembl.1
Ischemic stroke (ISCHSTR)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:601367
Neural tube defects, folate-sensitive (NTDFS)3 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionThe most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
See also OMIM:601634
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_009528222A → V Common polymorphism; at homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for NTDFS; thermolabile; decreased affinity for FAD cofactor; 50% reduced activity. 6 PublicationsCorresponds to variant rs1801133dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4524.
MalaCardsiMTHFR.
MIMi236250. phenotype.
601367. phenotype.
601634. phenotype.
603174. phenotype.
OpenTargetsiENSG00000177000.
Orphaneti268392. Cervical spina bifida aperta.
268762. Cervical spina bifida cystica.
268397. Cervicothoracic spina bifida aperta.
268766. Cervicothoracic spina bifida cystica.
395. Homocystinuria due to methylene tetrahydrofolate reductase deficiency.
1048. Isolated anencephaly/exencephaly.
268388. Lumbosacral spina bifida aperta.
268758. Lumbosacral spina bifida cystica.
413690. Methotrexate toxicity or dose selection.
64738. Non rare thrombophilia.
268384. Thoracolumbosacral spina bifida aperta.
268752. Thoracolumbosacral spina bifida cystica.
268377. Total spina bifida aperta.
268748. Total spina bifida cystica.
268740. Upper thoracic spina bifida aperta.
268770. Upper thoracic spina bifida cystica.
PharmGKBiPA245.

Chemistry databases

DrugBankiDB00542. Benazepril.
DB00115. Cyanocobalamin.
DB00544. Fluorouracil.
DB00158. Folic Acid.
DB00134. L-Methionine.
DB00170. Menadione.
DB00563. Methotrexate.
DB00140. Riboflavin.
DB00116. Tetrahydrofolic acid.

Polymorphism and mutation databases

BioMutaiMTHFR.
DMDMi56405339.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001902451 – 656Methylenetetrahydrofolate reductaseAdd BLAST656

Proteomic databases

EPDiP42898.
MaxQBiP42898.
PaxDbiP42898.
PeptideAtlasiP42898.
PRIDEiP42898.

PTM databases

iPTMnetiP42898.
PhosphoSitePlusiP42898.

Expressioni

Gene expression databases

BgeeiENSG00000177000.
CleanExiHS_MTHFR.
ExpressionAtlasiP42898. baseline and differential.
GenevisibleiP42898. HS.

Organism-specific databases

HPAiHPA063389.

Interactioni

Subunit structurei

Homodimer.

GO - Molecular functioni

  • protein complex binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110624. 20 interactors.
IntActiP42898. 2 interactors.
STRINGi9606.ENSP00000365775.

Structurei

3D structure databases

ProteinModelPortaliP42898.
SMRiP42898.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0564. Eukaryota.
COG0685. LUCA.
GeneTreeiENSGT00390000012490.
HOGENOMiHOG000246234.
HOVERGENiHBG006414.
InParanoidiP42898.
KOiK00297.
OMAiVVGWGPS.
OrthoDBiEOG091G0YQK.
PhylomeDBiP42898.
TreeFamiTF105665.

Family and domain databases

CDDicd00537. MTHFR. 1 hit.
Gene3Di3.20.20.220. 1 hit.
InterProiIPR029041. FAD-linked_oxidoreductase-like.
IPR004621. Fadh2_euk.
IPR003171. Mehydrof_redctse.
[Graphical view]
PfamiPF02219. MTHFR. 1 hit.
[Graphical view]
SUPFAMiSSF51730. SSF51730. 1 hit.
TIGRFAMsiTIGR00677. fadh2_euk. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P42898-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MVNEARGNSS LNPCLEGSAS SGSESSKDSS RCSTPGLDPE RHERLREKMR
60 70 80 90 100
RRLESGDKWF SLEFFPPRTA EGAVNLISRF DRMAAGGPLY IDVTWHPAGD
110 120 130 140 150
PGSDKETSSM MIASTAVNYC GLETILHMTC CRQRLEEITG HLHKAKQLGL
160 170 180 190 200
KNIMALRGDP IGDQWEEEEG GFNYAVDLVK HIRSEFGDYF DICVAGYPKG
210 220 230 240 250
HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV KACTDMGITC
260 270 280 290 300
PIVPGIFPIQ GYHSLRQLVK LSKLEVPQEI KDVIEPIKDN DAAIRNYGIE
310 320 330 340 350
LAVSLCQELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA
360 370 380 390 400
LSAHPKRREE DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL
410 420 430 440 450
KDYYLFYLKS KSPKEELLKM WGEELTSEES VFEVFVLYLS GEPNRNGHKV
460 470 480 490 500
TCLPWNDEPL AAETSLLKEE LLRVNRQGIL TINSQPNING KPSSDPIVGW
510 520 530 540 550
GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL VNVKGENITN
560 570 580 590 600
APELQPNAVT WGIFPGREII QPTVVDPVSF MFWKDEAFAL WIERWGKLYE
610 620 630 640 650
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDTL ELLNRPTQNA

RETEAP
Length:656
Mass (Da):74,597
Last modified:December 7, 2004 - v3
Checksum:iF16E774833D054B8
GO
Isoform 2 (identifier: P42898-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MDHRKARVLPAGHYCPSLGIWASQVGSVRSSVPPSISRNPAM

Show »
Length:697
Mass (Da):78,965
Checksum:i53BD7151AA16F795
GO

Polymorphismi

Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07411146R → Q in MTHFRD; reduces methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs776483190dbSNPEnsembl.1
Natural variantiVAR_07411246R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs138189536dbSNPEnsembl.1
Natural variantiVAR_00953051R → P in MTHFRD. 1 PublicationCorresponds to variant rs201618781dbSNPEnsembl.1
Natural variantiVAR_00431952R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs754980119dbSNPEnsembl.1
Natural variantiVAR_07411359W → S in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204007dbSNPEnsembl.1
Natural variantiVAR_07411468R → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs763539350dbSNPEnsembl.1
Natural variantiVAR_01488168R → Q.1 PublicationCorresponds to variant rs2066472dbSNPEnsembl.1
Natural variantiVAR_07411582R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204009dbSNPEnsembl.1
Natural variantiVAR_074116113A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs147257424dbSNPEnsembl.1
Natural variantiVAR_074117127H → Y in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs769381688dbSNPEnsembl.1
Natural variantiVAR_074118129T → N in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074119130C → R in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204012dbSNPEnsembl.1
Natural variantiVAR_074120147Q → P in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204013dbSNPEnsembl.1
Natural variantiVAR_074121149G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074122153I → M in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs767890671dbSNPEnsembl.1
Natural variantiVAR_004320157R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs121434295dbSNPEnsembl.1
Natural variantiVAR_074123175A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074124183R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs574132670dbSNPEnsembl.1
Natural variantiVAR_074125195A → V in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs760161369dbSNPEnsembl.1
Natural variantiVAR_074126196G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204014dbSNPEnsembl.1
Natural variantiVAR_074127215Missing in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074128218V → L in MTHFRD; decreased affinity for FAD cofactor. 1 Publication1
Natural variantiVAR_009528222A → V Common polymorphism; at homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for NTDFS; thermolabile; decreased affinity for FAD cofactor; 50% reduced activity. 6 PublicationsCorresponds to variant rs1801133dbSNPEnsembl.1
Natural variantiVAR_074129225I → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs200100285dbSNPEnsembl.1
Natural variantiVAR_074130226Missing in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_004321227T → M in MTHFRD. 1 PublicationCorresponds to variant rs748571395dbSNPEnsembl.1
Natural variantiVAR_004322251P → L in MTHFRD. 1 Publication1
Natural variantiVAR_074131253V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074132254P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs786204017dbSNPEnsembl.1
Natural variantiVAR_074133255G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204018dbSNPEnsembl.1
Natural variantiVAR_074134256I → N in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs373398993dbSNPEnsembl.1
Natural variantiVAR_074135257F → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs786204019dbSNPEnsembl.1
Natural variantiVAR_009531323L → P in MTHFRD. 1 PublicationCorresponds to variant rs121434297dbSNPEnsembl.1
Natural variantiVAR_009532324N → S in MTHFRD. 1 PublicationCorresponds to variant rs267606887dbSNPEnsembl.1
Natural variantiVAR_004323325R → C in MTHFRD. 1 PublicationCorresponds to variant rs371085894dbSNPEnsembl.1
Natural variantiVAR_004324335R → C in MTHFRD. 1 PublicationCorresponds to variant rs748289202dbSNPEnsembl.1
Natural variantiVAR_074136335R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant rs543016186dbSNPEnsembl.1
Natural variantiVAR_074137338M → T in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant rs368321176dbSNPEnsembl.1
Natural variantiVAR_009533339W → G in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 2 PublicationsCorresponds to variant rs267606886dbSNPEnsembl.1
Natural variantiVAR_074138348P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204021dbSNPEnsembl.1
Natural variantiVAR_074139354H → Y in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204022dbSNPEnsembl.1
Natural variantiVAR_004325357R → C in MTHFRD. 1 PublicationCorresponds to variant rs779993607dbSNPEnsembl.1
Natural variantiVAR_074140363R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204023dbSNPEnsembl.1
Natural variantiVAR_074141372K → E in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204024dbSNPEnsembl.1
Natural variantiVAR_009534377R → C in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs121434296dbSNPEnsembl.1
Natural variantiVAR_074142377R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs750323424dbSNPEnsembl.1
Natural variantiVAR_009535387G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074143421W → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs200137991dbSNPEnsembl.1
Natural variantiVAR_018857422G → R.1 PublicationCorresponds to variant rs45571736dbSNPEnsembl.1
Natural variantiVAR_014882429E → A Common polymorphism; decreased risk for adult acute leukemia; thermolabile; decreased activity. 4 PublicationsCorresponds to variant rs1801131dbSNPEnsembl.1
Natural variantiVAR_074144435F → S in MTHFRD. 1 PublicationCorresponds to variant rs754015864dbSNPEnsembl.1
Natural variantiVAR_054158470E → A.1 Publication1
Natural variantiVAR_074145506Y → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204026dbSNPEnsembl.1
Natural variantiVAR_018858519R → C.1 PublicationCorresponds to variant rs45496998dbSNPEnsembl.1
Natural variantiVAR_050293519R → H.Corresponds to variant rs45449298dbSNPEnsembl.1
Natural variantiVAR_074146536V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204028dbSNPEnsembl.1
Natural variantiVAR_050294566G → E.Corresponds to variant rs2274974dbSNPEnsembl.1
Natural variantiVAR_009536572P → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant rs144508139dbSNPEnsembl.1
Natural variantiVAR_074147574V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074148575V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204031dbSNPEnsembl.1
Natural variantiVAR_009537586E → K in MTHFRD. 1 Publication1
Natural variantiVAR_018859594R → Q.2 PublicationsCorresponds to variant rs2274976dbSNPEnsembl.1
Natural variantiVAR_074149598L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204034dbSNPEnsembl.1
Natural variantiVAR_074150628L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant rs786204037dbSNPEnsembl.1
Natural variantiVAR_018860653T → M.1 PublicationCorresponds to variant rs35737219dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0537441M → MDHRKARVLPAGHYCPSLGI WASQVGSVRSSVPPSISRNP AM in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
AK312907 mRNA. Translation: BAG35753.1.
AY338232 Genomic DNA. Translation: AAP88033.1.
AL953897 Genomic DNA. Translation: CAI15885.1.
CH471130 Genomic DNA. Translation: EAW71709.1.
BC053509 mRNA. Translation: AAH53509.1.
AY046562 mRNA. Translation: AAL17648.1.
AF398930 Genomic DNA. Translation: AAN40865.1.
CCDSiCCDS137.1. [P42898-1]
CCDS81262.1. [P42898-2]
PIRiS46454.
RefSeqiNP_001317287.1. NM_001330358.1.
NP_005948.3. NM_005957.4. [P42898-1]
XP_005263517.1. XM_005263460.4. [P42898-1]
XP_005263519.1. XM_005263462.4. [P42898-1]
UniGeneiHs.214142.
Hs.737916.

Genome annotation databases

EnsembliENST00000376583; ENSP00000365767; ENSG00000177000. [P42898-2]
ENST00000376585; ENSP00000365770; ENSG00000177000. [P42898-2]
ENST00000376590; ENSP00000365775; ENSG00000177000. [P42898-1]
ENST00000376592; ENSP00000365777; ENSG00000177000. [P42898-1]
GeneIDi4524.
KEGGihsa:4524.
UCSCiuc001atc.3. human. [P42898-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs
SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Methylenetetrahydrofolate reductase entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
AK312907 mRNA. Translation: BAG35753.1.
AY338232 Genomic DNA. Translation: AAP88033.1.
AL953897 Genomic DNA. Translation: CAI15885.1.
CH471130 Genomic DNA. Translation: EAW71709.1.
BC053509 mRNA. Translation: AAH53509.1.
AY046562 mRNA. Translation: AAL17648.1.
AF398930 Genomic DNA. Translation: AAN40865.1.
CCDSiCCDS137.1. [P42898-1]
CCDS81262.1. [P42898-2]
PIRiS46454.
RefSeqiNP_001317287.1. NM_001330358.1.
NP_005948.3. NM_005957.4. [P42898-1]
XP_005263517.1. XM_005263460.4. [P42898-1]
XP_005263519.1. XM_005263462.4. [P42898-1]
UniGeneiHs.214142.
Hs.737916.

3D structure databases

ProteinModelPortaliP42898.
SMRiP42898.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110624. 20 interactors.
IntActiP42898. 2 interactors.
STRINGi9606.ENSP00000365775.

Chemistry databases

DrugBankiDB00542. Benazepril.
DB00115. Cyanocobalamin.
DB00544. Fluorouracil.
DB00158. Folic Acid.
DB00134. L-Methionine.
DB00170. Menadione.
DB00563. Methotrexate.
DB00140. Riboflavin.
DB00116. Tetrahydrofolic acid.

PTM databases

iPTMnetiP42898.
PhosphoSitePlusiP42898.

Polymorphism and mutation databases

BioMutaiMTHFR.
DMDMi56405339.

Proteomic databases

EPDiP42898.
MaxQBiP42898.
PaxDbiP42898.
PeptideAtlasiP42898.
PRIDEiP42898.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000376583; ENSP00000365767; ENSG00000177000. [P42898-2]
ENST00000376585; ENSP00000365770; ENSG00000177000. [P42898-2]
ENST00000376590; ENSP00000365775; ENSG00000177000. [P42898-1]
ENST00000376592; ENSP00000365777; ENSG00000177000. [P42898-1]
GeneIDi4524.
KEGGihsa:4524.
UCSCiuc001atc.3. human. [P42898-1]

Organism-specific databases

CTDi4524.
DisGeNETi4524.
GeneCardsiMTHFR.
HGNCiHGNC:7436. MTHFR.
HPAiHPA063389.
MalaCardsiMTHFR.
MIMi236250. phenotype.
601367. phenotype.
601634. phenotype.
603174. phenotype.
607093. gene.
neXtProtiNX_P42898.
OpenTargetsiENSG00000177000.
Orphaneti268392. Cervical spina bifida aperta.
268762. Cervical spina bifida cystica.
268397. Cervicothoracic spina bifida aperta.
268766. Cervicothoracic spina bifida cystica.
395. Homocystinuria due to methylene tetrahydrofolate reductase deficiency.
1048. Isolated anencephaly/exencephaly.
268388. Lumbosacral spina bifida aperta.
268758. Lumbosacral spina bifida cystica.
413690. Methotrexate toxicity or dose selection.
64738. Non rare thrombophilia.
268384. Thoracolumbosacral spina bifida aperta.
268752. Thoracolumbosacral spina bifida cystica.
268377. Total spina bifida aperta.
268748. Total spina bifida cystica.
268740. Upper thoracic spina bifida aperta.
268770. Upper thoracic spina bifida cystica.
PharmGKBiPA245.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0564. Eukaryota.
COG0685. LUCA.
GeneTreeiENSGT00390000012490.
HOGENOMiHOG000246234.
HOVERGENiHBG006414.
InParanoidiP42898.
KOiK00297.
OMAiVVGWGPS.
OrthoDBiEOG091G0YQK.
PhylomeDBiP42898.
TreeFamiTF105665.

Enzyme and pathway databases

UniPathwayiUPA00193.
BioCyciZFISH:HS11117-MONOMER.
BRENDAi1.5.1.20. 2681.
ReactomeiR-HSA-196757. Metabolism of folate and pterines.
SABIO-RKP42898.

Miscellaneous databases

ChiTaRSiMTHFR. human.
GeneWikiiMethylenetetrahydrofolate_reductase.
GenomeRNAii4524.
PROiP42898.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000177000.
CleanExiHS_MTHFR.
ExpressionAtlasiP42898. baseline and differential.
GenevisibleiP42898. HS.

Family and domain databases

CDDicd00537. MTHFR. 1 hit.
Gene3Di3.20.20.220. 1 hit.
InterProiIPR029041. FAD-linked_oxidoreductase-like.
IPR004621. Fadh2_euk.
IPR003171. Mehydrof_redctse.
[Graphical view]
PfamiPF02219. MTHFR. 1 hit.
[Graphical view]
SUPFAMiSSF51730. SSF51730. 1 hit.
TIGRFAMsiTIGR00677. fadh2_euk. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiMTHR_HUMAN
AccessioniPrimary (citable) accession number: P42898
Secondary accession number(s): B2R7A6
, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: December 7, 2004
Last modified: November 30, 2016
This is version 166 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Allosteric enzyme, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.