Folic acid metabolism

B3a. Baker, H., Frank, O., Hutner, S. H., Aaronson, S, Ziffer, H., and Sobotka, H., Lesions in folic acid metabolism induced by Primidone. Experientia 18, 224-226... 

Cl. Carpenter, E. M., Anticonvulsant therapy and folic acid metabolism. D. M. Thesis, University of Oxford, 1972. 

Because both drugs may interfere with folic acid metabolism, their use during pregnancy is usually contraindicated by the potential for effects on the fetus, such as the development of neural tube defects associated with folate deficiency. The use of trimethoprim is contraindicated in patients with blood dyscrasias, hepatic damage, and renal impairment. 

Sulfonamides are used for controlling urinary tract infections, acute and chronic lung infections (norcadiosis), protozoan infections of the nervous system (i.e., toxoplasmosis), and a variety of infections in humans and livestock. Their mode of activity is by inhibiting the multiplication of bacteria by competitively inhibiting para-aminobenzioc acid (PABA) in the folic acid metabolism cycle (O Neil et al., 2001). More specifically, they block the synthesis of folic acid in bacteria as the drugs are structurally similar to PABA. Folic acid is essential to the synthesis of amino acids and nucleic acids. In bacteria, folic acid is synthesized from PABA... 

FIGURE 33-2 Folic acid metabolism in bacterial cells. Certain antibacterial drugs [e.g., sulfonamides and trimethoprim] inhibit the dihydrofolate synthetase and reductase enzymes, thus interfering with DNA biosynthesis. 

Several compounds that interfere with folic acid metabolism are used in clinical medicine as inhibitors of cancer cells or bacterial growth. 

Four of the amino acids, alanine, aspartate, glutamate, and serine, are formed by the transamination of their corresponding oxoacids. The other nonessential amino acids are then derived from these four amino acids. The syntheses of serine and tyrosine are described below because of either their importance in aspects of metabolism or their clinical significance the synthesis of serine is essential for folic acid metabolism, while deficiencies in the enzymes synthesizing tyrosine can lead to phenylketonuria. 

Though both bacteria and humans have this enzyme, the bacterial version is different enough for us to attack it with specific drugs. An example is trimethoprim—yet another heterocyclic compound with a pyrimidine core (black on diagram). These two types of drugs that attack the folic acid metabolism of bacteria are often used together. 

Antibacterial drugs that affect the folate (folic acid) metabolism of bacteria include sulfonamides, pyrimethamine, and trimethoprim. 

Pyrimethamine acts synergistically with suifadoxine (as Fansidar) to inhibit folic acid metabolism (see antifols, above) suifadoxine is excreted in the urine. The combination is chiefly used with quinine to treat acute attacks of malaria caused by susceptible strains of Plasmodium falciparum a single dose of pyrimethamine 75 mg plus suifadoxine 1.5 g (3 tablets) usually suffices. 

There is a fundamental relationship between folic acid metabolism and vitamin B12. The reduction of methylene-THFA to S-methyl-THFA is essentially irreversible hence, there is only one pathway for the regeneration of THFA from... 

Vitamin C is used to metabolize carbohydrates, for tissue repair and capillary endothelium, and for synthesis of protein, lipids, and collagen. Vitamin C is also needed for absorption of iron and folic acid metabolism. Vitamin C is found in citrus fruits, tomatoes, leafy green vegetables, and potatoes. Excess serum levels of vitamin C are excreted without any negative effects. Vitamin C is commercially available as Ascorbicap, Cecon, Cevalin, and SoluCap C. 

Antimetabolites compete with normal endogenous substrates and cause inhibition of the processes that require those substrates. Examples include purine and pyrimidine antagonists, which prevent nucleic acid replication and cellular division in cancer chemotherapy. Another example is methotrexate, which can inhibit folic acid metabolism. 

Mason JB. Intestinal transport of monoglutamyl folates in mamalian systems. In Picciano MF, Stokstad ELR. Gregory JF, eds. Folic acid metabolism in health and disease. New York Wdey-Liss, 1990 47-64. 

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... 

The common name folic acid is derived from hatinfolium, leaf, because this vitamin was originally isolated from dark green, leafy vegetables such as spinach. Folic acid metabolism was discussed in Chapter 27. 

Trimethoprim inhibits another enzyme, dihydrofolate reductase, in the same folic acid metabolic pathway. Folic acid is converted into folate, which then has to be converted into an activated form by dihydrofolate reductase. In this way, trimethoprim interferes with the conversion of folate into its activated form, which is a cofactor in the synthesis of bacterial DNA. Dihydrofolate reductase also occurs in host cells, but it is less sensitive to trimethoprim. Trimethoprim is used to treat urinary tract infections. It is also formulated in combination with a sulphonamide, when it is known as co-trimoxazole, to treat pneumonia in patients with HIV (see page 170). Due to the synergistic effect of the two drugs, this combination is more effective than either drug alone. 

These drugs inhibit the synthesis of nucleotides. Classic cellular mechanisms include the inhibition of folic acid metabolism and pyrimidine antagonism. 

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. 

Antimetabolite A drug that through chemical similarity is able to interfere with the role of an endogenous compound in cellular metabolism. The term includes antibacterial agents that inhibit bacterial folic acid metabolism... 

Since folic acid is critical to the formation of purines, antagonists of folic acid metabolism are used as chemotherapy drugs to inhibit nucleic acid synthesis and cell growth. Rapidly dividing cells, such as those found in cancer and tumors, are more susceptible to these antagonists. 

Ml. McLean, F. W., Heine, M. W., Held, B., and Streiff, R. R., Relationship between oral contraceptive and folic acid metabolism Serum folate concentrations. Amer. J. Obstet. Gynecol. 104, 745-747 (1969). 

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