Folates metabolism

Inhibitors of Folate Metabolism Provide Cancer Chemotherapy Antibacterial Antimalarial Drugs... 

Ethambutol 5.1 Folate metabolism in microbial and mammalian cells... 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

Lambie, D. G., Johnson, R. H., Drugs and folate metabolism, Drugs 1985,... 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

Connections To folate metabolism and one-carbon metabolism in de novo synthesis. 

Folate inhibitors, bacterial resistance mechanisms, 3 32t Folate metabolism, 23 502 Folcysteine, 13 431, 52 Folded guide microwave applicator, 16 522 Folding-carton inks, 14 321 Folding carton packaging, converting, 25 21-22... 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Physiologically, distinction from folate deficiency is often clinically and haematologically difficult because vitamin B12, also known as cobalamin, functions as an essential cofactor for folate metabolism in the evenmal synthesis of deoxyribonucleic acid. 

Like folate and vitamin C, vitamin B6 (pyroxidine) is water soluble and like folate has several vitamers. Vitamin B6 may be involved in more bodily functions than any other nutrient (Tambasco-Studart et al., 2005), is a cofactor for many enzymes, especially those involved in protein metabolism, and is also a cofactor for folate metabolism. Vitamin B6 has anticancer activity (Theodoratou et al., 2008), is a strong antioxidant (Denslow et al., 2005), is involved in hemoglobin biosynthesis, lipid and glucose metabolism and immune and nervous system function. Possible consequences of deficiency include anemia, impaired immune function, depression, confusion, and dermatitis (Spinneker et al., 2007). Vitamin B6 deficiency is generally not a problem in the developed world, but there could be as yet poorly defined consequences of suboptimal intake particularly for the elderly. 

Methotrexate inhibits folate metabolism by preventing methylenetetrahydrofolate reductase from converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate thus inhibiting thymidylate synthase conversion of dUMP to dTMP. DNA replication is effectively decreased by the diminution of dTMP availability. As shown in Fig. 2, multiple enzymes mediate the folate cycle. Thus, genetic variation in these enzymes may... 

Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria. 

H FIGURE 22-49 Thymidylate synthesis and folate metabolism as targets of chemotherapy, (a) During thymidylate synthesis, /V5,N10-methylenetetrahydrofolate is converted to 7,8-dihydrofolate the N5,N10-methylenetetrahydrofolate is regenerated in two steps (see Fig. 22-44). This cycle is a major target of several chemotherapeutic agents, (b) Fluorouracil and methotrexate are important chemotherapeutic agents. In cells, fluorouracil is converted to FdUMP, which... 

Correct answer = A. Methotrexate interferes with folate metabolism by acting as a competitive inhibitor of the enzyme dihydrofolate reductase. This starves cells for tetrahydrofolate, and makes them unable to synthesize purines and dTMP This is especially toxic to rapidly-growing cancer cells. Overproduction of dihydrofolate reductase, usually caused by amplification of its gene, can overcome the inhibition of the enzyme at the methotrexate concentrations used for chemotherapy, and can result in resistance of the tumor to treatment by this drug. 

The evaluation of folic acid status must often also include evaluation of vilamin B1 because of its effect on folate metabolism. A vilamin Bu-dependenl reaction is necessary for an cit/vmc involved in the catabolism of branchcd-chain amino acids (mclhylmalonyl CoA to succinyl CoA). This reaction may provide the basis for a functional assessment method for vitamin Biz status. See also Hormones and Vitamin. 

Methylation of dUMP to give thymidylate is catalyzed by thymidylate synthase and utilizes 5,10-methylenetetra-hydrofolate as the source of the methyl group. This reaction is unique in the metabolism of folate derivatives because the folate derivative acts both as a donor of the one-carbon group and as its reductant, using the reduced pteridine ring as the source of reducing potential. Consequently, in this reaction, unlike any other in folate metabolism, dihydrofolate is a product (fig. 23.16). Since folate derivatives are present in cells at very low concentrations, continued syn-... 

Piper, J.R. et al. (1982) Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism, J. Med. Chem. 25, 182-187. Wright, J.E. et al. (1993) Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts, Biochem. Pharmacol. 46, 871-6. 

Methotrexate Antiproliferative inhibits folate metabolism, purine synthesis and cell proliferation Porcine coronary artery Local application by balloon catheter Did not prevent neointimal thickening (101)... 

Because vitamin B12 in the oxidized form inactivates methionine synthetase, it could be expected to interfere with folate metabolism because 5-methyltetrahydrofolate would be unable to donate its methyl group. This... 

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