Disease relevance of MTHFR

• Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to alter risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications, and certain cancers [1].

High impact information on MTHFR

• Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine methylation to methionine [2].
• 3. Two mutations were identified in MTHFR-deficient patients: a missense mutation (Arg to Gln), in a residue conserved in bacterial enzymes, and a nonsense mutation (Arg to Ter) [2].
• This cDNA was used to isolate a human cDNA, the predicted amino acid sequence of which shows strong homology to porcine MTHFR and to bacterial metF genes [2].
• Folate-dependent 1-carbon transfer to biogenic amines mediated by methylenetetrahydrofolate reductase [3].
• In the absence of light, 8-N3AdoMet is itself an inhibitor of methylenetetrahydrofolate reductase activity, with a Ki value 4.8-fold higher than AdoMet, and like AdoMet it induces slow transitions between active and inactive forms [4].

Biological context of MTHFR

• MTHFR has several polyadenylation sites creating 3?UTR lengths of 0.2 kb-5.0 kb or 0.6 kb-4.0 kb in human and mouse, respectively [1].
• The 5? and 3? termini of the MTHFR cDNA were found to overlap with the 5? terminus of a chloride ion channel gene (CLCN-6) and the 3? terminus of an unidentified gene, respectively; this finding has resulted in finer mapping of MTHFR on Chromosome (Chr) 1p36 [1].
• Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms [1].
• Methylenetetrahydrofolate reductase can also suppor phenylalanine hydroxylation in vitro by regeneration of the tetrahydropterin cofactor [5].

Associations of MTHFR with chemical compounds

• Our studies demonstrate that CH3-H4PteGlu6, and suggest that incorporation of plasma CH3-H4PteGlu1 will only occur when methylenetetrahydrofolate reductase is inhibited by adenosylmethionine and cellular pools of CH3-H4PteGlu6 are at very low levels [6].
• Studies of four enzymes from pig liver, methylenetetrahydrofolate reductase, serine hydroxymethyltransferase, methylenetetrahydrofolate dehydrogenase and thymidylate synthase, have indicated that folylpolyglutamate inhibitors are bound 3-500 fold more tightly than the corresponding monoglutamates [6].
• Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine [1].
• Photoaffinity labeling of methylenetetrahydrofolate reductase with 8-azido-S-adenosylmethionine [4].
• Inhibition of pig liver methylenetetrahydrofolate reductase by dihydrofolate: some mechanistic and regulatory implications [7].

Other interactions of MTHFR

• Two enzymes, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase, show decreases in Km values for folylpolyglutamate substrates [6].
• In addition, the analytical procedure is very simple and economical; it may be a useful tool for studying methylenetetrahydrofolate reductase and methionine synthase activities [8].

Analytical, diagnostic and therapeutic context of MTHFR

• Scanning transmission electron microscopy of individual unfixed molecules of methylenetetrahydrofolate reductase has been used to determine the molecular mass distribution of the protein [9].
• Assays of methylenetetrahydrofolate reductase and methionine synthase activities by monitoring 5-methyltetrahydrofolate and tetrahydrofolate using high-performance liquid chromatography with fluorescence detection [8].

References