Reviewed,
UniProtKB/Swiss-Prot P42898 (MTHR_HUMAN)
Last modified
November 25, 2008.
Version 83.
History...
Clusters with 100%,
90%,
50% identity |
Documents (7) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Methylenetetrahydrofolate reductase EC=1.5.1.20 | ||
| Gene names |
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| 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 | |
| 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 reductionInferred 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 bindingInferred from physical interaction. Source: IntAct |
| Complete GO annotation... | |
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
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References
| « Hide '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 | |
|---|---|
| U09806 mRNA. Translation: AAA74440.2. AF105987 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 |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
Relevant documents
| Human chromosome 1 Human chromosome 1: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PATHWAY comments Index of metabolic and biosynthesis pathways |
| UniProtKB secondary accession numbers Index of UniProtKB secondary accession numbers |
| SIMILARITY comments Index of protein domains and families |

Clusters with


