Folic acid vitamin biosynthesis

The number of vitamin B 12-dependent reactions is not large. Most of these involve rearrangements of the carbon skeletons of metabolites. Such reactions are important in linking some aspects of fatty acid metabolism to the citric acid cycle. In another form, a vitamin Bi2-derived coenzyme is involved, along with folic acid coenzymes, in the metabolism of one-carbon fragments, including the biosynthesis of methionine. 

Folic acid is a vitamin, as we developed in chapter 15. It is a complex molecule that serves as an essential precursor for coenzymes involved in the metabolism of one-carbon units. For example, folic acid-derived coenzymes are critically involved in the biosynthesis of thymidine for nucleic acid synthesis and methionine for protein biosynthesis. The synthesis of both demands donation of a methyl group and they come from folic acid-derived coenzymes. 

Given this structural similarity, it should not be surprising to learn that sulfanilamide competes with p-aminobenzoic acid for a binding site on the surface of dihydropteroate synthetase. Put another way, sulfanilamide binds to the enzyme where p-aminobenzoic acid should bind but no reaction occurs. The consequence is that a step in folic acid biosynthesis is disrupted and the bacterial cell is deprived of adequate folic acid. Nucleic acid synthesis, among other things, is disrupted, leading to a cessation of cell growth and division. The human immune system can mop up what remains. No similar consequences befall the human host since it cannot make folic acid in the first place and must get an adequate supply of this vitamin in the diet. 

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]. 

Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

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. 

Folic acid (or folate), which plays a key role in one-carbon metabolism, is essential for the biosynthesis of several compounds. Folic acid deficiency is probably the most common vitamin deficiency in the United States, particularly among pregnant women and alcoholics. 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

Folic acid - [FOOD TOXICANTS, NATURALLY OCCURRING] (Volll) - [FINECHEMICALS - PRODUCTION] (Vol 10) -m animal nutrition [VITAMINS - FOLIC ACID] (Vol 25) -biosynthesis [VITAMINS - FOLIC ACID] (Vol 25) -m dairy substitutes [DAIRY SUBSTITUTES] (Vol 7) -deficiency [VITAMINS - FOLIC ACID] (Vol 25) -metabolism of [VITAMINS - FOLIC ACID] (Vol 25) -metabolites [VITAMINS - FOLIC ACID] (Vol 25) -mmilk [MILKANDMILKPRODUCTS] (Vol 16) -one-pot synthesis [VITAMINS - FOLIC ACID] (Vol 25) -properties [VITAMINS - FOLIC ACID] (Vol 25) -role m veterinary medicine [VETERINARY DRUGS] (Vol 24)... 

Folacin (folic acid) is involved in metabolism and in the biosynthesis of purines and pyrimidines. It is a very stable vitamin but does not occur naturally in feedstuffs. Instead it occurs in reduced forms as polyglutamates, which are readily oxidized. These forms are converted to folic acid in the body. Diets commonly contain sufficient folacin but this is not assured. Folacin is therefore usually included in the vitamin supplement added to poultry diets to ensure adequacy. A deficiency in young chicks or poults results in retarded growth, poor feathering and perosis. Coloured plumage may lack normal pigmentation, and a characteristic anaemia is also present. Cervical paralysis is an additional symptom in deficient turkeys. 

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

Choiine. Choline is a component of many biomem-hranes and plasma phospholipids. Dietary sources include eggs. fish, liver, milk, and vegetables. These sources provide choline primarily as the phospholipid lecithin. Lecithin is hydrolyzed to glycerophosphorylcholinc by the intestinal mucosa before absorption. The liver liberates choline. Choline can be biosynthesized by humans con.sequcntly. it cannot be con.sidcred a (rue vitamin. Biosynthesis involves methylation of cthanolamine. The methyl groups arc provided by methionine or by a reaction involving vitamin B12 and folic acid. Therefore, deficiencies can occur only if all methyl donors are excluded from the diet. 

The sulfonamides act as competitive enzyme inhibitors and block the biosynthesis of the vitamin folic acid in bacterial cells (Fig. 10.14). They do this by inhibiting the... 

Because all vitamins are essential, it is difficult to state that one vitamin is more important than another. Nevertheless, folic acid, with its coenzyme role in purine biosynthesis, can be considered crucial for some of the cells most fundamental biochemistry, cell division. This vitamin is intimately tied to vitamin (cobalamin), which has made estimating its DRIs difficult. Also, conditions that can cause a folic acid deficiency also can result in a vitamin Bi2 deficiency. 

Folic Acid Deficiency. It is obvious that folic acid is a very important vitamin for biosynthetic reactions, particularly those required for the biosynthesis of purines, methyl-... 

Tetrahydrofolate (THF) is the major source of 1-carbon units used in the biosynthesis of many important biological molecules. This cofactor is derived from the vitamin folic acid and is a carrier of activated 1-carbon units at various oxidation levels (methyl, methylene, formyl, formimino, and methenyl). These compounds can be interconverted as required by the cellular process. The major donor of the 1-carbon unit is serine in the foUowing reaction ... 

In summary, DNA synthesis requires synthesis of dTMP and the purines adenine and guanine. THF, derived from the vitamin folic acid, is required for the biosynthesis of these nucleotides. Treatment with methotrexate blocks the cell s ability to regenerate THF, leading to inhibition of these biosynthetic pathways. The lack of nucleotides prevents DNA synthesis, and these cancer cells cannot divide without DNA synthesis. Unfortunately, the effects of methotrexate are nonspecific and other rapidly dividing cells such as epithelial cells in the oral cavity, intestine, skin, and blood cells are also inhibited. This leads to the side effects associated with methotrexate (and other cancer chemotherapy drugs) such as mouth sores, low white blood cell counts, stomach upset, hair loss, skin rashes, and itching. 

DNA synthesis requires the formation of dTMP and the purines adenine and guanine. THF, derived from the vitamin folic acid, is required for the biosynthesis of these nucleotides. 

Vitamins are substances essential for a healthy life humans must ingest vitamins via their diet because there is no mechanism for their biosynthesis in the body. There are 14 vitamins - the name was coined when the first vitamin chemically identified (vitamin Bi in 1910) turned out to be an amine - a vital amine. A typical vitamin is folic acid, a complex molecule in which the functionally important unit is the bicyclic pyrazino[2,3- f pyrimidine (pteridine) ring system, and its arylaminomethyl substituent. Folic acid is converted in the body into tetrahydrofolic acid (FH4) which is crucial in carrying one-carbon units, at various oxidation levels, for example in the biosynthesis of purines, and is mandatory for healthy development of the foetus during pregnancy. Other essential co-factors that contain pteridine units must and can be biosynthesised in humans - without them we cannot survive - aud are incorporated into oxygen-transfer enzymes based on molybdenum, in which the metal is liganded by a complex ene-dithiolate. 

What are called antifolate drugs pertain in general to blocking the biosynthesis of purines and pyrimidines, the heterocyclic bases used in the further synthesis of DNA and RNA, where folic acid is required as a coenzyme (or vitamin) for the enzyme dihydrofolate reductase. The previously mentioned compound called methotrexate or amethopterin (4-amino-A °-methyl folic acid), being a structural analog of folate or folic acid, locks up the enzyme dihydrofolate reductase, which in turn blocks the synthesis of a thymidine nucleotide necessary for cell division. 

Folic acid is a vitamin required for the transfer of methyl groups in the biosynthesis of methionine and nitrogenous bases. Humans cannot synthesize folic acid and must obtain it from the diet. Bacteria, on the other hand, must make folic acid because they cannot take it in from the environment. 

Vitamin B12 is virtually nontoxic, even at high oral or injected doses excessive amounts are rapidly excreted. However, occasionally allergic responses to injected vitamin B12 occur (Fisher 1973), and adverse reactions to the combined administration of large injected doses of vitamin B12 and of oral vitamin C have been reported (Schrauzer 1979). Vitamin B12 is required for methionine biosynthesis and functions in conjunction with folic acid as the intermediate carrier of the methyl group. In its coenzyme form (5 -deoxyadenosylcobala-min), it is required for the conversion of methylmalonyl-CoA to succinyl-CoA. (Friedrich 1987). Bacteria utilize vitamin Bjj or its coenzyme in certain dehydrases, deaminases, and in methane biosynthesis. 

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