10,11) One of the most common genetic defects of homocysteine metabolism is a mutation in the enzyme methylene tetrahydrofolate
Folic acid is reduced to tetrahydrofolate
(THF) and subsequently converted to 5-methyl THF.
The first step in this chain of events is the transfer of the one-carbon group to tetrahydrofolate
(THF), resulting in the formation of 5,10-MTHF.
This reaction involves the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing tetrahydrofolate
In the remethylation reaction, [Hcy] acquires a methyl group from the concentration of 5-methyl tetrahydrofolate
(5mTHF) and converted into methionine (Fig.
1,2) The major inherited thrombophilias include deficiencies of antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A gene polymorphism and hyperhomocystinaemia associated with methylene tetrahydrofolate
reductase (MTHFR) C 677 T mutation.
Inhibition of dihydrofolate reductase (DHFR) decreases tetrahydrofolate
(THF) levels, which results in attenuated DNA/protein/lipid methylation, inhibition of thymidylate synthase (TS) interference with DNA synthesis, and inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase blocks de novo purine synthesis.
19) A point mutation in the methylene tetrahydrofolate
reductase gene (C677T) has been associated with elevated levels of homocysteine in homozygotes.
Folate, in the form of methyl tetrahydrofolate
, donates a methyl group to homocysteine to form methionine.
Hyperhomocystinemia is an expression of a common inherited thrombophilia that results from a defect in either the methylene tetrahydrofolate
reductase gene or the cystathionine [beta]synthetase gene.
Abnormal FXIII cross-linking Factor VII Arg353Gln Low-normal FVII Factor VII H7H7 Low-normal FVII Factor VII G73A Low-normal FVII Factor XIII A subunit Va134Leu Increased activity Homocysteine Metabolism Cystathionine [beta]-synthase 833T Homocysteinemia [right arrow] C 5,10-methylene tetrahydrofolate
reductase Thermolabile enzyme, (MTHFR) 677C [right arrow] T mildly increased Hcy Platelet Surface Glycoproteins GP Illa Leu33Pro (P[L.
Patent 6,074,821 titled "cDNA for Human Methylenetetrahydrofolate Reductase" and in April 2001 issued US Patent 6,218,120 titled "Methods for detecting human methylene tetrahydrofolate
reductase allelic variants.