Tetrahydrofolate homocysteine metabolism

Methylation of homocysteine by 5-methyltetrahydrofolate-homocysteine methyl reductase depends on an adequate supply of 5-methyltetrahydrofoIate. The unmethylated folate is recycled in a cobalamin-dependent pathway, by remethylation to 5,10-methylene-tetrahydrofolate, and subsequent reduction to 5-methyltetrahydrofolate. The transferase enzyme, also named 5,10-methyltretrahydrofolate reductase catalyzes the whole cycle [3,91]. S-adenosylmethionine and 5-methyltetrahydrofolate are the most important methyl unit donors in biological system. S-adenosylmethionine is reported to regulate methylation and transsulfuration pathways in the homocysteine metabolism [3,91]. 

Cyanocobalamin A cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine, and metabolize l-methylmalonyl-CoA Adequate supplies are required for amino acid and fatty acid metabolism, and DNA synthesis Treatment of vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes Toxicity No toxicity associated with excess vitamin B12... 

Tetrahydrofolate functions as a carrier of one-carbon units. There are numerous metabolic reactions that require either the addition or removal of a one-carbon unit of some specific oxidation state. THF binds one-carbon units of three oxidation levels the methanol, formaldehyde, and formate states. These are shown in Table 6.4 along with their origins and uses. The various one-carbon units are interconvertible, as shown in Figure 6.5. Nicotinamide coenzymes are involved. In addition, the one-carbon unit may be released as C02. The methanol-level THF-bound one-carbon unit 5-methyl-THF is the storage and transport form. Once formed, its main pathway of metabolism is to form methionine from homocysteine, a reaction that requires vitamin B12 in the form of methylcobalamin (see Figure 6.2 and Chapter 20) ... 

Figure 21-1. Structural and metabolic relationships between methionine, homocysteine, and cysteine. CBS, cystathionine b-synthase CTH, cystathionine y-lyase MAT, methionine adenosyltransferase MS, methionine synthase 5-MTHF, 5-methyltetrahydrofoIate MTs, methyl transferases PLR pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase THF, tetrahydrofolate.

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

The Methyl Folate Trap Hypothesis The reduction of meth-ylene-tetrahydrofolate to methyl-tetrahydrofolate is irreversible (Section 10.3.2.1), and the major source of folate for tissues is methyl-tetrahydrofolate. The only metabolic role of methyl-tetrahydrofolate is the methylation of homocysteine to methionine, and this is the only way in which methyl-tetrahydrofolate can be demethylated to yield free tetrahydrofolate in tissues. Methionine synthetase thus provides the link between the physiological functions of folate and vitamin B12. 

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

In vitamin Bj2 deficiency, methyltetrahydrofolate cannot donate its methyl group to homocysteine to regenerate methionine. Because the synthesis of methyltetrahydrofolate is irreversible, the cell s tetrahydrofolate will ultimately be converted into this form. No formyl or methylene tetrahydrofolate will be left for nucleotide synthesis. Pernicious anemia illustrates the intimate connection between amino acid and nucleotide metabolism. 

Vitamin B12 deficiency results in impairment in the activities of the B -requiring enzymes. This impairment prevents synthesis of the enzyme s products and forces the accumulation of reactants in the cell. Inhibition of methionine synthase prevents the synthesis of methionine and the regeneration of tetrahydrofolate. This inhibition results in interruption of the methylation cycle, which involves S-ade-nosylmethionine. The inhibition also results in an impairment of folate-mediated metabolism, because of the failure to regenerate H4folate from 5-methyl-H4folate. The major effect of 6 2 deficiency is an impairment of growth, particularly of rapidly growing cells such as immature red blood cells. B12 deficiency also results in the buildup of homocysteine in the cell and bloodstream. 

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.)...

C. Pharmacodynamics Vitamin B is essential in two reactions conversion of methyl-malonyl-CoA to succinyl-CoA and conversion of homocysteine to methionine. The second reaction is linked to folic acid metabolism and synthesis of deoxythymidylate (dTMP Figure 33-2, reaction 2), a precursor required for DNA synthesis. In vitamin B,2 deficiency, folates accumulate as AP-methyltetrahydrofolate the supply of tetrahydrofolate is depleted and the production of red blood cells slows. Administration of folic acid to patients with vitamin Bj deficiency helps refill the tetrahydrofolate pool (Figure 33-2, reaction 3) and partially or fully corrects the anemia. However, the exogenous folic acid does not correct the neurologic defects of vitamin Bj2 deficiency. 

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