Formate 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. 

The pathway as presented in Table I shows that it is linear for the first 10 steps with no branch points before the pivotal IMP is formed. However, a branch point does exist for the synthesis of the pyrimidine moiety (Bi-pyrimidine) of thiamine. Convincing evidence has been obtained to indicate that AIR also serves as a precursor to Bi-pyrimi-dine [27]. This explains the concomitant growth requirement for thiamine for most of the mutants blocked in any one of the first five enzymes [27-29]. A complication in regulatory control is thus introduced in that any attempt to control purine biosynthesis at the first five steps would have dire consequences on the formation of thiamine. This has indeed been found in the often-reported cases where inhibition of growth by adenine and its derivatives can be reversed by thiamine or its pyrimidine moiety [29-31]. The situation is more complicated in a special class of adenine-sensitive mutants where the sensitivity appears to be related to disturbances in folic acid metabolism [32]. Mutations in the AICAR formyltransferase complex (steps 9 and 10) also create a pleiotropic thiamine requirement which is not due to a deficiency in the synthesis of thiamine but rather to an unexplained phenotypic... 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

The formation of sulfa drugs is another excimple of a multistep synthesis. The sulfa drugs cire bactericides, effective c ainst a wide variety of bacteria because they mimic p-aminobenzoic acid (Figure 13-48). Many bacteria require p-aminobenzoic acid, which they cire unable to synthesize, and need to synthesize folic acid. Many types of sulfa drugs exist, and most of them involve the substitution of one of the hydrogen atoms on the -SO2-NH2. Prontosil (Figure 13-49) was the first commercially available sulfa drug. The metabolism of prontosil produced sulfanilamide. 

Pharmacology Vitamin C, a water-soluble vitamin, is an essential vitamin in man however, its exact biological functions are not fully understood. It is essential for the formation and the maintenance of intercellular ground substance and collagen, for catecholamine biosynthesis, for synthesis of carnitine and steroids, for conversion of folic acid to folinic acid and for tyrosine metabolism. 

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... 

Administration of folinic acid (1 mg/ kg, IV) together with folic acid (1 mg/ kg IV) to accelerate the metabolic degradation of formate. 

Finally, sulfonamides can interfere with intermediary metabolism. Because of their structural similarity to para-aminobenzoic acid (PABA), they can function as competitive inhibitors for dihydropteroate synthase. The result is interruption of microbial synthesis of folic acid by blocking formation of the folic acid precursor dihydropteroic acid. Sensitive microorganisms are those that must synthesize their own folic acid. Conversely, resistant bacteria and normal mammalian cells are unaffected since they do not synthesize folic acid but use the preformed vitamin. 

BARBITURATES FOLIC ACID 1 levels of these antiepileptics Uncertain postulated that induction of CYP enzymes by these antiepileptics depletes folate reserves. Replacement of these reserves formation of CYP further, which metabolism of the antiepileptics Watch for poor response to these antiepileptics and doses as necessaiy... 

In the case of successful antimicrobial agents, altering metabolic processes unique to microorganisms, e.g. penicillin interferes with formation of the bacterial cell wall, or by showing enormous quantitative differences in affecting a process common to both humans and microbes, e.g. inhibition of folic acid s5mthesis by trimethoprim. 

The enzyme dihydrofolic acid (DHF) S5mthase (see below) converts p-aminobenzoic acid (PABA) to DHF which is subsequently converted to tetrahydric folic acid (THF), purines and DNA. The sulphonamides are structurally similar to PABA, successfully compete with it for DHF s)mthase and thus ultimately impair DNA formation. Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of sulphonamides. Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF. The drug is relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme. Both sulphonamides and trimethoprim are bacteriostatic. 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

It influences fat metabolism, decarboxylation and carbon dioxide fixation, and deamination of some amino acids. It is closely related metabolically to pantothenic acid and folic acid. A biotin deficiency may be induced by ingestion of avidin, a raw-egg protein, because of the formation of a nonabsorbable biotin-avidin complex. Biotin is synthesized in the intestinal tract of humans therefore, normally it is not essential in the diet. 

Folic acid Pteridine C metabolism, blood formation 20... 

Purine biosynthesis de novo was one of the hrst areas of metabolism in which a folic acid derivative was specifically identified as a cofactor in an enzymatic reaction. The ability of pigeon liver extracts to add formate to phosphoribosyl glycineamide was impaired by treatment with charcoal, but was restored by addition of H4-folate. Although the complicated interconversions of the Hrfolate coenzymes (see Chapter 5) caused confusion for some time, the specific one-carbon donor for this reaction was eventually identified as 5,10-methenyl H4-folate. The phosphoribosyl glycineamide formyltransferase reaction itself is irreversible. 

Dihydroneopterin is a branch point in pteridine metabolism. In the formation of tetrahydrobiopterin, sepiapterin, and isosepiapterin its three-carbon side chain is retained. In the biosynthesis of folic acid derivatives two carbon atoms are eliminated, whereas in the formation of xanthopterin and leucopterin the side chain is lost completely. 

A competitive inhibitor resembles the substrate in its chemical structure and is able to combine with the enzyme to form an enzyme-inhibitor complex. In so doing it competes with the substrate for the active sites of the enzyme, and formation of the enzyme-substrate complex is inhibited. This type of inhibition may be reversed by the addition of excess substrate, which displaces the inhibitor, forming normal enzyme-substrate complexes. One of the best-known examples is provided by the sulphonamide drugs. The synthesis of folic acid from p-aminobenzoic acid (PABA) is a vital metabolic process in the bacteria controlled by these drugs. The similarity between PABA and sulphanUamide, released by the sulphonamides, is obvious ... 

Water-Soluble Vitamins. Vitamin G (ascorbic acid) functions in the formation of collagen, wound healing, metabolic functions, and other roles. Foods high in vitamin G include citrus fruits, strawberries, cantaloupe, and cruciferous vegetables. B vitamins are important in energy metabolism. Thiamin (Bj) is called the antineuritic vitamin. Riboflavin (B ), rarely deficient in the diet, is found most abundantly in milk and dairy products. Niacin (Bj) is prevalent in meats, poultry, fish, peanut butter, and other foods. Other major B vitamins include folic acid (B ), B, and Bj2-... 

Some reactions of folic acid derivatives have been discussed as components of systems that synthesize and degrade purines. In the case of serine metabolism the function of folic acid is basically the same namely, transfer of a one-carbon moiety. Whereas the carbon of previously discussed one-carbon transfers has been at the oxidation level of formate, the 8-carbon of serine is at the oxidation level of formaldehyde. Reactions involving formaldehyde derivatives (hydroxymethyl compounds) of folic acid have recently been reported. 

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