Methylenetetrahydrofolate reductase MTHFR

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... 

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. 

Methylenetetrahydrofolate is then reduced to CH3-THF by the vitamin B2 (riboflavin)-dependent enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), using NADPH as cosubstrate. MTHFR is the key enzyme for diverting 5,10-methylentetrahydrofolate to methylation of homocysteine or to DNA synthesis though the conversion of uracil to thymidine. 

Goyette R et al, 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 59(6) 1268-1275. 

Weisberg I, et al, A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998 64(3) 169-172. 

Methylenetetrahydrofolate reductase (MTHFR) is encoded by the MTHFR gene located on chromosome lp36.22. It is the rate-limiting enzyme in the folic acid metabolic cycle that is critical for the... 

Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36 539-545... 

Methylenetetrahydrofolate reductase (MTHFR) is part of the folate/ homocysteine metabolism (Figure 30.2). 

The deficiencies of cystathionine )5-synthase (CBS), sulfite oxidase, and methylenetetrahydrofolate reductase (MTHFR) may all result in central nervous system dysfunction, in particular mental retardation [1-3]. Defects of CBS and sulfite oxidase both cause dislocated lenses of the eyes, but the phenotypes are different otherwise. The manifestations of CBS deficiency, the most common of these disorders, and MTHFR deficiency range from severely affected to asymptomatic patients both may cause vascular occlusion. Deficiency of sulfite oxidase is clinically uniform, but genetically heterogeneous, and functional deficiency of the enzyme can result from several inherited defects of molybdenum cofactor biosynthesis [2, 4]. Hereditary folate malabsorption and defects of cobalamin transport (transcobala-min II deficiency) or cobalamin cofactor biosynthesis (cblC-G diseases) may cause megaloblastic anemia, in addition to CNS dysfunction [3, 5, 6]. 

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