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Identification
HMDB Protein ID HMDBP00188
Secondary Accession Numbers
  • 5420
  • HMDBP04318
Name Methylenetetrahydrofolate reductase
Synonyms Not Available
Gene Name MTHFR
Protein Type Unknown
Biological Properties
General Function Involved in methylenetetrahydrofolate reductase (NADPH) activity
Specific Function Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
Pathways
  • Cystathionine Beta-Synthase Deficiency
  • Folate malabsorption, hereditary
  • Glycine N-methyltransferase Deficiency
  • Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type
  • Hypermethioninemia
  • Methionine Adenosyltransferase Deficiency
  • Methionine Metabolism
  • Methotrexate Action Pathway
  • Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)
  • Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)
  • One carbon pool by folate
  • One carbon pool by folate
  • S-Adenosylhomocysteine (SAH) Hydrolase Deficiency
  • tetrahydrofolate interconversion
Reactions
5-Methyltetrahydrofolic acid + NAD(P)(+) → 5,10-Methylene-THF + NAD(P)H details
5-Methyltetrahydrofolic acid + NADP → 5,10-Methylene-THF + NADPH + Hydrogen Ion details
5-Methyltetrahydrofolic acid + NAD → 5,10-Methylene-THF + NADH + Hydrogen Ion details
GO Classification
Biological Process
methionine biosynthetic process
blood circulation
folic acid metabolic process
tetrahydrofolate interconversion
homocysteine metabolic process
Cellular Component
cytosol
Function
catalytic activity
oxidoreductase activity, acting on the ch-nh group of donors
oxidoreductase activity, acting on the ch-nh group of donors, nad or nadp as acceptor
methylenetetrahydrofolate reductase (nadph) activity
oxidoreductase activity
Molecular Function
methylenetetrahydrofolate reductase (NADPH) activity
modified amino acid binding
Process
metabolic process
cellular metabolic process
sulfur amino acid metabolic process
methionine metabolic process
oxidation reduction
cellular amino acid and derivative metabolic process
cellular amino acid metabolic process
Cellular Location Not Available
Gene Properties
Chromosome Location 1
Locus 1p36.3
SNPs MTHFR
Gene Sequence
>1971 bp
ATGGTGAACGAAGCCAGAGGAAACAGCAGCCTCAACCCCTGCTTGGAGGGCAGTGCCAGC
AGTGGCAGTGAGAGCTCCAAAGATAGTTCGAGATGTTCCACCCCGGGCCTGGACCCTGAG
CGGCATGAGAGACTCCGGGAGAAGATGAGGCGGCGATTGGAATCTGGTGACAAGTGGTTC
TCCCTGGAATTCTTCCCTCCTCGAACTGCTGAGGGAGCTGTCAATCTCATCTCAAGGTTT
GACCGGATGGCAGCAGGTGGCCCCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGAC
CCTGGCTCAGACAAGGAGACCTCCTCCATGATGATCGCCAGCACCGCCGTGAACTACTGT
GGCCTGGAGACCATCCTGCACATGACCTGCTGCCGTCAGCGCCTGGAGGAGATCACGGGC
CATCTGCACAAAGCTAAGCAGCTGGGCCTGAAGAACATCATGGCGCTGCGGGGAGACCCA
ATAGGTGACCAGTGGGAAGAGGAGGAGGGAGGCTTCAACTACGCAGTGGACCTGGTGAAG
CACATCCGAAGTGAGTTTGGTGACTACTTTGACATCTGTGTGGCAGGTTACCCCAAAGGC
CACCCCGAAGCAGGGAGCTTTGAGGCTGACCTGAAGCACTTGAAGGAGAAGGTGTCTGCG
GGAGCCGATTTCATCATCACGCAGCTTTTCTTTGAGGCTGACACATTCTTCCGCTTTGTG
AAGGCATGCACCGACATGGGCATCACTTGCCCCATCGTCCCCGGGATCTTTCCCATCCAG
GGCTACCACTCCCTTCGGCAGCTTGTGAAGCTGTCCAAGCTGGAGGTGCCACAGGAGATC
AAGGACGTGATTGAGCCAATCAAAGACAACGATGCTGCCATCCGCAACTATGGCATCGAG
CTGGCCGTGAGCCTGTGCCAGGAGCTTCTGGCCAGTGGCTTGGTGCCAGGCCTCCACTTC
TACACCCTCAACCGCGAGATGGCTACCACAGAGGTGCTGAAGCGCCTGGGGATGTGGACT
GAGGACCCCAGGCGTCCCCTACCCTGGGCTCTCAGTGCCCACCCCAAGCGCCGAGAGGAA
GATGTACGTCCCATCTTCTGGGCCTCCAGACCAAAGAGTTACATCTACCGTACCCAGGAG
TGGGACGAGTTCCCTAACGGCCGCTGGGGCAATTCCTCTTCCCCTGCCTTTGGGGAGCTG
AAGGACTACTACCTCTTCTACCTGAAGAGCAAGTCCCCCAAGGAGGAGCTGCTGAAGATG
TGGGGGGAGGAGCTGACCAGTGAAGCAAGTGTCTTTGAAGTCTTTGTTCTTTACCTCTCG
GGAGAACCAAACCGGAATGGTCACAAAGTGACTTGCCTGCCCTGGAACGATGAGCCCCTG
GCGGCTGAGACCAGCCTGCTGAAGGAGGAGCTGCTGCGGGTGAACCGCCAGGGCATCCTC
ACCATCAACTCACAGCCCAACATCAACGGGAAGCCGTCCTCCGACCCCATCGTGGGCTGG
GGCCCCAGCGGGGGCTATGTCTTCCAGAAGGCCTACTTAGAGTTTTTCACTTCCCGCGAG
ACAGCGGAAGCACTTCTGCAAGTGCTGAAGAAGTACGAGCTCCGGGTTAATTACCACCTT
GTCAATGTGAAGGGTGAAAACATCACCAATGCCCCTGAACTGCAGCCGAATGCTGTCACT
TGGGGCATCTTCCCTGGGCGAGAGATCATCCAGCCCACCGTAGTGGATCCCGTCAGCTTC
ATGTTCTGGAAGGACGAGGCCTTTGCCCTGTGGATTGAGCGGTGGGGAAAGCTGTATGAG
GAGGAGTCCCCGTCCCGCACCATCATCCAGTACATCCACGACAACTACTTCCTGGTCAAC
CTGGTGGACAATGACTTCCCACTGGACAACTGCCTCTGGCAGGTGGTGGAAGACACATTG
GAGCTTCTCAACAGGCCCACCCAGAATGCGAGAGAAACGGAGGCTCCATGA
Protein Properties
Number of Residues 656
Molecular Weight 74595.895
Theoretical pI 5.334
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Methylenetetrahydrofolate reductase
MVNEARGNSSLNPCLEGSASSGSESSKDSSRCSTPGLDPERHERLREKMRRRLESGDKWF
SLEFFPPRTAEGAVNLISRFDRMAAGGPLYIDVTWHPAGDPGSDKETSSMMIASTAVNYC
GLETILHMTCCRQRLEEITGHLHKAKQLGLKNIMALRGDPIGDQWEEEEGGFNYAVDLVK
HIRSEFGDYFDICVAGYPKGHPEAGSFEADLKHLKEKVSAGADFIITQLFFEADTFFRFV
KACTDMGITCPIVPGIFPIQGYHSLRQLVKLSKLEVPQEIKDVIEPIKDNDAAIRNYGIE
LAVSLCQELLASGLVPGLHFYTLNREMATTEVLKRLGMWTEDPRRPLPWALSAHPKRREE
DVRPIFWASRPKSYIYRTQEWDEFPNGRWGNSSSPAFGELKDYYLFYLKSKSPKEELLKM
WGEELTSEESVFEVFVLYLSGEPNRNGHKVTCLPWNDEPLAAETSLLKEELLRVNRQGIL
TINSQPNINGKPSSDPIVGWGPSGGYVFQKAYLEFFTSRETAEALLQVLKKYELRVNYHL
VNVKGENITNAPELQPNAVTWGIFPGREIIQPTVVDPVSFMFWKDEAFALWIERWGKLYE
EESPSRTIIQYIHDNYFLVNLVDNDFPLDNCLWQVVEDTLELLNRPTQNARETEAP
GenBank ID Protein 6139053
UniProtKB/Swiss-Prot ID P42898
UniProtKB/Swiss-Prot Entry Name MTHR_HUMAN
PDB IDs Not Available
GenBank Gene ID U09806
GeneCard ID MTHFR
GenAtlas ID MTHFR
HGNC ID HGNC:7436
References
General References
  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039 ]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  3. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. [PubMed:16710414 ]
  4. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK: DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008 Nov 6;456(7218):66-72. doi: 10.1038/nature07485. [PubMed:18987736 ]
  5. 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. 1998 Aug;9(8):652-6. [PubMed:9680386 ]
  6. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R: Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994 Jun;7(2):195-200. [PubMed:7920641 ]
  7. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R: Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet. 1994 Aug;7(4):551. [PubMed:7951330 ]
  8. Goyette P, Frosst P, Rosenblatt DS, Rozen R: Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995 May;56(5):1052-9. [PubMed:7726158 ]
  9. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ: Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995 Oct 21;346(8982):1070-1. [PubMed:7564788 ]
  10. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al.: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. [PubMed:7647779 ]
  11. Ou CY, Stevenson RE, Brown VK, Schwartz CE, Allen WP, Khoury MJ, Rozen R, Oakley GP Jr, Adams MJ Jr: 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. Am J Med Genet. 1996 Jun 28;63(4):610-4. [PubMed:8826441 ]
  12. Goyette P, Christensen B, Rosenblatt DS, 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. 1996 Dec;59(6):1268-75. [PubMed:8940272 ]
  13. Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ: A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 1996 Nov 1;56(21):4862-4. [PubMed:8895734 ]
  14. Schneider JA, Rees DC, Liu YT, Clegg JB: Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998 May;62(5):1258-60. [PubMed:9545406 ]
  15. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ: A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 May;62(5):1044-51. [PubMed:9545395 ]
  16. Kluijtmans LA, Wendel U, Stevens EM, van den Heuvel LP, Trijbels FJ, Blom HJ: Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency. Eur J Hum Genet. 1998 May-Jun;6(3):257-65. [PubMed:9781030 ]
  17. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R: A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998 Jul;64(3):169-72. [PubMed:9719624 ]
  18. Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, Gilfix BM, Rosenblatt DS, Gravel RA, 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. 1999 May 21;84(2):151-7. [PubMed:10323741 ]
  19. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G: Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12810-5. [PubMed:10536004 ]
  20. Sibani S, Christensen B, O'Ferrall E, Saadi I, Hiou-Tim F, Rosenblatt DS, Rozen R: Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria. Hum Mutat. 2000;15(3):280-7. [PubMed:10679944 ]
  21. Casas JP, Hingorani AD, Bautista LE, Sharma P: Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. [PubMed:15534175 ]