MTHFR methylenetetrahydrofolate

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

MTHFR methylenetetrahydrofolate reductase MW molecular weight Mylar PET (Dupont)... 

Figure 21-2. Metabolism of homocysteine. BHMT, betaineihomocysteine methyl-transferase CBS, cystathionine P-synthase Cob, cobalamin CTH, cystathionine y-lyase DHF, dihydrofolate DMG, dimethylglycine FAD, flavin adenine dinucleotide MAT, methionine adenosyltransferase 5-MTHF, 5-methyltetrahydrofolate 5,10-MTHF, 5,10-methylenetetrahydrofolate MTHFR, methylenetetrahydrofolate reductase MS, methionine synthase MTRR, methionine synthase reductase MTs, methyl transferases PLE pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase SAM, 5-adenosylmethionine SHMT, serine hydroxymethyltransferase THF, tetrahydrofolate Zn, zinc.

Fig. 6 Methyl trap hypothesis 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetiahy-drofolate in an irreversible reaction. When vitamin Bn is deficient, methyl groups are trapped as 5-methyltetrahydrofolate, resulting in decreased substrates for DNA synthesis and neural lipid methylation. MTHFR, methylenetetrahydrofolate reductase DHFR, dihydrofolate reductase MS, Methionine synthase TS, thymidylate synthase SAM, S-adenosyl-methionine dUMP, deoxyuridine 5 -monophosphate dTTP, deoxythymidine 5 -monophosphate...

Figure 8 Extended folate metabolism, including compartmentation. MTHFR, methylenetetrahydrofolate reductase SHMT, serine hydroxymethyltransferase BHMT, betaine homocysteine methyltransferase, MAT, methionine adenosyltransferase SAH-hydrolase, S-adenosylhomocysteine hydrolase MT, methyltransferase CBS, cystathionine /i-synthase SAM, S-adenosylmethionine SAH, S-aden-osylhomocysteine THF, tetrahydrofolate and 5-MeTHF, 5-methyltetrahydrofolate. (Reproduced from Van der Put etal. (2001) Folate, homocysteine and neural tube defects An overview. Experimental Biology and Medicine 226 243-270.)...

MTHFR Methylenetetrahydrofolate rsl801133 (C677T) reductase Cocaine Disulfiram... 

MTHFR Methylenetetrahydrofolate reductase MS Methionine synthase THF Tetrahydrofoiate A an enzyme... 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

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. 

Methylentetrahydrofolate reductase (MTHFR) is another key enzyme of 5-FU metabolism, alternating 5-FU sensitivity indirectly by folate pool variations. MTHFR plays an important role in the action of 5-FU, an inhibitor of TS, by converting 5,10-methylenetetrahydrofolate, a substrate of TS, to 5-methyltetrahydrofolate (19). 

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). 

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... 

MSCB (master seed cell bank) 746 MTHFR, see methylenetetrahydrofolate reductase MTT (3,4,5-dmethylthiazol-2yl-2,5-diphenyl tetrazolium bromide) 640 Mucolytic enzymes 1376 Mucopolysaccharidosis 24, 862 Multiangle light scattering (MALS) 162 Multilamellae vesicles 1370 Multifunctional-type nanodevice (MEND) 1522... 

---