Methylenetetrahydrofolate reductase

MA J, STAMPFER M J, GIOVANNUCCI E, ARTIGAS C, HUNTER D J, FUCHS C, WILLETT W C, SELHUB J, HENNEKENS c H and ROZEN R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer . Cancer Res, 57, 1098-102. 

Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA 1998 95 13217-13220. 

Brattstrom L, Zhang Y, Hurtig M et al. A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis 1998 141 315-319. 

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH2-THF) to 5-methyltetrahydrofolate (CH3-THF). CH3-THF then serves as a methyl donor for the synthesis of methionine. The MTHFR proteins and genes from mammalian liver and E. coli have been characterized,12"15 and MTHFR genes have been identified in S. cerevisiae16 and other organisms. The MTHFR of E. coli (MetF) is a homotetramer of 33-kDa subunits that prefers NADH as reductant,12 whereas mammalian MTHFRs are homodimers of 77-kDa subunits that prefer NADPH and are allosterically inhibited by AdoMet.13,14 Mammalian MTHFRs have a two-domain structure the amino-terminal domain shows 30% sequence identity to E. coli MetF, and is catalytic the carboxyterminal domain has been implicated in AdoMet-mediated inhibition of enzyme activity.13,14... 

SHEPPARD, C., TRIMMER, E., MATTHEWS, R.G., Purification and properties of NADH-dependent 5, 10-methylenetetrahydrofolate reductase (MetF) from Escherichia coli,J. Bacteriol., 1999,181, 718-725. 

MATTHEWS, R.G., SHEPPARD, C GOULDING, C., Methylenetetrahydrofolate reductase and methionine synthase biochemistry and molecular biology, Eur. J. Pediatr., 1998,157, S54-S59. 

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, 1998,9,652-656. 

RAYMOND, R.K., KASTANOS, E.K., APPLING, D.R., Saccharomyces cerevisiae expresses two genes encoding isozymes of methylenetetrahydrofolate reductase, Arch. Biochem. Biophys., 1999,372, 300-308. 

VANONI, M.A., MATTHEWS, R.G., Kinetic isotope effects on the oxidation of reduced nicotinamide adenine dinucleotide phosphate by the flavoprotein methylenetetrahydrofolate reductase, Biochemistry, 1984, 23, 5272-5279. 

Ulrich, C.M., et al., "Pharmacogenetics of Methotrexate Toxicity Among Marrow Transplantation Patients Varies with the Methylenetetrahydrofolate Reductase C677T Polymorphism," Blood, 98, 231-234 (2001). 

Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996 93 79. 

Tysoe, C., Galinsky, D., Robinson, D., et al. (1997) Analysis of alpha-1 antichymotrypsin, presenilin-1, angiotensin-converting enzyme, and methylenetetrahydrofolate reductase loci as candidates for dementia. Am. J. Med. Genet., 74, 207-212. 

Rozen, R. (1996) Molecular genetics of methylenetetrahydrofolate reductase deficiency. Journal of Inherited Metabolic Disease. 19, 589-594. 

Frosst, P., Blom, H.J., Milos, R., et al. (1995) A candidate genetic risk factor for vascular disease a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 10,111-113. 

Kang, S. S.,Zhou, J., Wong, P.W., Kowalisyn, J., and Strokosch, G. (1988)Intermediate homo-cysteinemia a thermolabile variant of methylenetetrahydrofolate reductase. American Journal of Human Genetics. 43, 414-421. 

Urano, W., Taniguchi, A., Yamanaka, H., et al. (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 12, 183-190. 

Kumagai, K., Hiyama, K., Oyama, T., Maeda, H., and Kohno, N. (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. International Journal of Molecular Medicine. 11, 593-600. 

Methylenetetrahydrofolate reductase (NADPH) [EC 1.5.1.20] is an FAD-dependent enzyme that catalyzes the reaction of 5-methyltetrahydrofolate with NADP to produce 5,10-methylenetetrahydrofolate and NADPH. 5,10-Methylenetetrahydrofolate reductase (FADH2) [EC 1.7.99.5] is an FAD-dependent enzyme that catalyzes the reaction of 5-methyltetrahydrofolate with an acceptor to produce 5,10-methylenetetrahydrofolate and the reduced acceptor. 

Cohen V, Panet-Raymond V, SabbaghianN et al. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003 9 1611-1615. 

Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001 98 231-234. 

Sohn KJ, Croxford R, Yates Z et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J... 

Methotrexate inhibits folate metabolism by preventing methylenetetrahydrofolate reductase from converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate thus inhibiting thymidylate synthase conversion of dUMP to dTMP. DNA replication is effectively decreased by the diminution of dTMP availability. As shown in Fig. 2, multiple enzymes mediate the folate cycle. Thus, genetic variation in these enzymes may... 

Methylenetetrahydrofolate reductase is an approximately 19,301 base pair gene with 11 exons and located on chromosome lp36.3 (2). Multiple polymorphic sites have been described, with the C677T and A1298G most often studied. As expected, allele frequency data varies by ethnicity The MTHFR C677T variant allele is present in 34% of Caucasians, 20% of Italians and Hispanics, 14% of African-Americans, and <1 % of Africans (3,4). The MTHFR A1298G allele is present in n%-36% of Western Europeans (4). 

Goyette P, Sumner JS, Milos R et al. Human methylenetetrahydrofolate reductase isolation of cDNA mapping and mutation identifieation. Nat Genet 1994 7 551. 

Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies a HuGE review. Am JEpidemiol 2000 151 862-877. 

Robien K, Ulrieh CM. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk a HuGE minireview. Am J Epidemiol 2003 157 571-582. 

Aplenc R, Thompson J, Han P et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005 65 2482-2487. 

Chiusolo P, Reddiconto G, Casorelli I et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002 13 1915-1918. 

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