Methylenetetrahydrofolate reductase
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| 5,10-methylenetetrahydrofolate reductase (NADPH)
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| Image:MTHFR active site.jpg | |||||||||||
| Ribbon diagram of the active site of E. coli MTHFR. The flavin cofactor (top) is shown interacting with the bound substrate NADH. Image drawn from PDB 1ZPT | |||||||||||
| Identifiers | |||||||||||
| Symbol(s) | MTHFR; | ||||||||||
| External IDs | OMIM: 607093 MGI: 106639 Homologene: 4349 | ||||||||||
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| RNA expression pattern | |||||||||||
| Image:PBB GE MTHFR 206800 at tn.png Image:PBB GE MTHFR 217071 s at tn.png | |||||||||||
| Orthologs | |||||||||||
| Human | Mouse | ||||||||||
| Entrez | 4524 | 17769 | |||||||||
| Ensembl | ENSG00000177000 | ENSMUSG00000029009 | |||||||||
| Uniprot | P42898 | Q3V399 | |||||||||
| Refseq | NM_005957 (mRNA) NP_005948 (protein) | NM_010840 (mRNA) NP_034970 (protein) | |||||||||
| Location | Chr 1: 11.77 - 11.79 Mb | Chr 4: 146.88 - 146.9 Mb | |||||||||
| Pubmed search | [1] | [2] | |||||||||
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20) that exists in the cytoplasm of cells. MTHFR contains a bound flavin cofactor and uses NAD(P)H as the reducing agent.
MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate (substrate) to 5-methyltetrahydrofolate. 5-Methyltetrahydrofolate is used to convert homocysteine (a potentially-toxic amino acid) to methionine by the enzyme methionine synthase.
Polymorphism and role in disease
There is a common DNA sequence variant (polymorphism) in MTHFR at basepair 677 (a change from a C to a T) that results in a thermolabile enzyme with decreased enzymatic activity. Ten percent of the North American population are homozygous for this polymorphism (the incidence is higher in Mediterranean countries and lower in African-Americans). Individuals of 677TT are predisposed to mild hyperhomocysteinemia (high blood homocysteine levels), because they have less MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). Low dietary intake of the vitamin folic acid can also cause mild hyperhomocysteinemia. This polymorphism and mild hyperhomocysteinemia are associated with neural tube defects in offspring, arterial and venous thrombosis, and cardiovascular disease. It is interesting to note that 677TT individuals are at a decreased risk for certain leukemias and colon cancer, but only when their dietary intake of folate is high. The MTHFR gene could be one of the factors of overall schizophrenia risk.[1] Schizophrenic patients having the risk allele (T\T) show more deficiencies in executive function tasks.[2]
Formula of action
MTHFR = methylenetetrahydrofolate reductase
5,10-CH2-FH4 = 5,10-methylene tetrahydrofolate
5-CH3-FH4 = 5-methyl tetrahydrofolate
NADPH = reduced form of Nicotinamide adenine dinucleotide phosphate
NADP+ = oxidized form of Nicotinamide adenine dinucleotide phosphate
References
- ↑ Meta-Analysis of All Published Schizophrenia-Association Studies (Case-Control Only) for rs1801133 (C677T) polymorphism, MTHFR gene - Schizophrenia Research Forum, retrieved 11 March 2007
- ↑ Roffman JL, Weiss AP, Deckersbach T, Freudenreich O, Henderson DC, Purcell S, Wong DH, Halsted CH, Goff DC. (2007) Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia. Schizophr Res. 2007 Mar 5; PMID 17344026
- MTHFR and homocysteine, Dr. Stephan Moll, retrieved 28 December 2004.
Further reading
- Matthews RG (2003). "Methylenetetrahydrofolate reductase: a common human polymorphism and its biochemical implications.". Chemical record (New York, N.Y.) 2 (1): 4-12. PMID 11933257.
- Schwahn B, Rozen R (2002). "Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.". American journal of pharmacogenomics : genomics-related research in drug development and clinical practice 1 (3): 189-201. PMID 12083967.
- Iqbal MP, Frossard PM (2003). "Methylene tetrahydrofolate reductase gene and coronary artery disease.". JPMA. The Journal of the Pakistan Medical Association 53 (1): 33-6. PMID 12666851.
- Bailey LB (2003). "Folate, methyl-related nutrients, alcohol, and the MTHFR 677C-->T polymorphism affect cancer risk: intake recommendations.". J. Nutr. 133 (11 Suppl 1): 3748S-3753S. PMID 14608109.
- Wiwanitkit V (2005). "Roles of methylenetetrahydrofolate reductase C677T polymorphism in repeated pregnancy loss.". Clin. Appl. Thromb. Hemost. 11 (3): 343-5. PMID 16015422.
- Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M (2006). "Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis.". Mol. Psychiatry 11 (2): 143-9. doi:10.1038/sj.mp.4001746. PMID 16172608.
- Lewis SJ, Lawlor DA, Davey Smith G, et al. (2006). "The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis.". Mol. Psychiatry 11 (4): 352-60. doi:10.1038/sj.mp.4001790. PMID 16402130.
- Pereira TV, Rudnicki M, Pereira AC, et al. (2007). "5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis.". Cancer Epidemiol. Biomarkers Prev. 15 (10): 1956-63. doi:10.1158/1055-9965.EPI-06-0334. PMID 17035405.
- Leclerc D, Rozen R (2007). "[Molecular genetics of MTHFR: polymorphisms are not all benign]". Med Sci (Paris) 23 (3): 297-302. PMID 17349292.
Protein: flavoproteins |
|---|
| Acetolactate synthase - Acyl CoA dehydrogenase - Apoptosis-inducing factor - Butyryl CoA dehydrogenase - Cryptochrome - Cytochrome b5 reductase - Dihydrolipoamide dehydrogenase - Flavodoxin - Methemoglobin reductase - Methylenetetrahydrofolate reductase - NADH dehydrogenase - NADPH oxidase - Nitrate reductase - Sarcosine oxidase - Thioredoxin reductase |
CH-NH oxidoreductases (EC 1.5) | |
|---|---|
| 1.5.1 - NAD or NADP acceptor | Dihydrofolate reductase - Saccharopine dehydrogenase - Methylenetetrahydrofolate reductase |
| 1.5.3 - oxygen acceptor | Dihydrobenzophenanthridine oxidase - Sarcosine oxidase |
| 1.5.5 - quinone acceptor | Electron-transferring-flavoprotein dehydrogenase |
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
