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TRANSULPHURATION PATHWAY

Vitamin B6 dependent

Fig. 3.3 Interrelationships between methionine and folate metabolic cycles.

Key:

  1. Methionine adenosyl transferase EC 2.5.1.6
  2. S-adenosylmethionine-dependent methyltransferase EC 2.1.1
  3. S-adenosylhomocysteine hydrolase EC 3.3.1.1
  4. Betaine:homocysteine methyltransferase EC 2.1.1.5
  5. 5-Methyltetrahydrofolate:homocysteine methyl transferase (vitamin B12 dependent) EC 2.1.1.13 7. 5,10-Methyltetrahydrofolate reductase (vitamin B2 dependent) EC 1.1.99.15
  6. Serine hydroxymethyl transferase (vitamin B6 dependent) EC 2.1.2.1.
  7. Tetrahydrofolate dehydrogenase 1.5.1.3.
  8. Thymidylate synthase EC 2.1.1.45

FOLATE

PROTEIN

adults (McNulty, 1997)! There are concerns about the bioavailability of dietary folate (Gregory, 1995). Food folates are present mainly as polyglutamate derivatives which have to be converted to a monoglutamyl form by folate conjugase to be absorbed by the jejunum. Changes in the pH of the lumen contents, or the presence of folate conjugase inhibitors, folate binders or other specific food components can all adversely affect the rate of hydrolysis and uptake of the vitamin (McNulty, 1997). These factors account for the wide range of folate bioavail-ability of the naturally occurring folate polyglutamates in all foods.

Stable isotope studies have found 50% relative bioavailability of polyglutamyl compared to monoglutamyl forms of folate (Gregory et al, 1991). Hence the relative bioavailability of folates from a mixed diet is difficult to predict and is considerably less than when the vitamin is eaten as a supplement or in a fortified food.

Folates are involved in a number of single carbon transfer reactions, especially in the synthesis of purines, pyrimidines, glycine and methionine. THF can have one-carbon units added, for example formyl, methyl or methylene and these are attached to either the N5 or N10 nitrogen or both (Scott, 2000). The principal source of the one-carbon units is serine. The one-carbon units are donated once to change uracil to a thymine-type base during the biosynthesis of pyrimidine, and twice during the biosynthesis of purines. Pyrimidine biosynthesis generates dihydrofolate from 5,10 THF, which is then reduced back to THF. In the two reactions of purine biosynthesis 5,10 formyl THF is the donor of carbon and THF is generated by both reactions. In all three reactions the cofactor THF is then available to attach another one-carbon unit and repeat the process. Only a small amount of the cofactor is required in cells because of the continuous regeneration back to the THF form. These cycles could be called the DNA and/or RNA biosynthetic cycles since they provide the de novo synthesis of the bases used to make these structures (Scott, 2000).

In addition to the role described above, folates also participate in the methy-lation cycle (Fig. 3.3). Enzymes called methyl transferases exist in all mammalian cells and transfer methyl groups to a wide range of acceptors. In all cases the source of the methyl groups is the methyl group of methionine, which is passed on after it has been activated with ATP to form S-adenosylmethionine (SAM). Donations of the methyl groups from SAM produce S-adenosylhomocysteine (SAH) which is rapidly hydrolysed to homocysteine. Homocysteine is remethy-lated either from choline or by the folate cofactor 5-methylTHF. The methylation cycle is essential in intermediary metabolism requiring a continuous supply of methyl groups and for which a major source is the folate cofactor.

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