Folic acid coenzyme function

Thymidylate synthetase is an important enzyme, which is responsible for the reductive methylation of deoxyuridylic acid (dUMP, 7) to deoxythymidylic acid (dTMP, 8). The methylation of the uracil moiety (present in RNA) to 5-methyl uracil (thymine, present in DNA) requires participation of a folic acid coenzyme, N, methylenetetrahydrofolate as a methyl donor. The functioning of thymidylate synthetase is coupled with the activity of DHF reductase. That is why this biochemical target is usually referred to as thymidylate synthetase/ DHF reductase. 

Fig. 9.3 Biosyntheses and functions of folic acid coenzymes. [DHFA and THFA = di-(and tetra-)hydrofolic acid, respectively.]...

In summary it can be seen that relatively little is yet known about the biosynthesis of pteroylglutamic acid although this is an active field of research. Enzyme studies with tissues from higher animals have established that PGA is reduced to FH4 and that this reduced form of folic acid plays a key role in accepting either —CHO or —CH OH by mechanisms cUscussed above and is thus equipped to carry out functions of single-carbon transfer. Table II and Figs. 5 and 6 summarize the enzymic reactions involving various folic acid coenzymes. 

NAD and NADP and FMN and FAD, respectively. Pantothenic acid is a component of the acyl group carrier coenzyme A. As its pyrophosphate, thiamin participates in decarboxylation of a-keto acids and folic acid and cobamide coenzymes function in one-carbon metabolism. 

Folic acid and its metabolites called folates are essential to the cell s functions. They act as coenzymes in many biochemical processes. Folate-dependent enzymes are vital to rapidly dividing cell populations, such as the neoplastic or normal-stem cells. Therefore, they are a target for anti-folates in anti-cancer treatment. 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

The coenzyme forms of folic acid are derivatives of tetrahydrofolic acid, FH4. See Fig. 7. Folic acid functions as a coenzyme in enzyme reactions which involve the transfer of one-carbon fragments at various levels of... 

In archaebacteria the folic acid pathway for C-l transformations is based upon methanopterin as an ancient precursor of these important cellular interconversions. Tetrahydromethanopterin (478) has been identified as the active coenzyme and carbon carrier (479-481) in methanogenesis <84JBC(259)9447> and functions et alia as formaldehyde activation factor <84PNA(8l)l976>. 

We have just seen that folic acid functions as a coenzyme in the synthesis of dXMP It also donates methyl groups in the synthesis of purine bases, so that it is actually quite impor-... 

The pterins include the redox cofactors biopterin and molybdopterin, as well as various insect pigments. Folic acid is a conjugated pterin, in which the pteridine ring is linked to p-aminobenzoyl-poly-y-glutamate it is this linkage that renders folate a dietary essential, because it is the ability to condense p-aminobenzoate to a pteridine, rather than to synthesize the pteridine nucleus itself, which has been lost by higher animals. Biopterin (Section 10.4) and molybdopterin (Section 10.5) are coenzymes in mixed-function oxidases they are not vitamins, but can be synthesized in the body. Rare genetic defects of biopterin synthesis render it a dietary essential for affected individuals. 

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. 

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. 

Folate and folic acid are generic terms for a family of compounds that function as coenzymes in the processing of one-carbon units and that are derived from pteroic acid (Pfe), to which one or more molecules of glutamic acid are attached. Pteroic acid is composed of a pteridine ring joined to a p-aminobenzoic acid residue (Figure 30-20). In basic solution, this substance has absorption maxima at 256, 282, and 365 nm and is fluorescent. When pteroic acid is conju-... 

Most vitamins function either as a hormone/ chemical messenger (cholecalciferol), structural component in some metabolic process (pantothenic acid), or a coenzyme (phytonadi-one, thiamine, riboflavin, niacin, pyridoxine, biotin, folic acid, cyanocobalamin). At least one vitamin has more than one biochemical role. Vitamin A as an aldehyde (retinal) is a structural component of the visual pigment rhodopsin and, in its acid form (retinoic acid), is a regulator of cell differentiation. The precise biochemical functions of ascorbic acid and a-tocopherol still are not well defined. 

In 1936, a growth-promoting factor termed vitamin B was isolated from bovine (cow) milk. There are now several different types of vitamin B known and chemically characterized, and they are collectively described as B complex vitamins because of relative similarities in their properties, physiological functions, and distribution in natural resources. Mostly recognized as coenzymes, the eight B complex vitamins currently include Bj (thiamine), B2 (riboflavin), niacin (nicotinamide), B (pyridoxine), pantothenic acid, biotin, B22 (cyanocobalamin), and folacin (folic acid). 

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. 

METABOLIC FUNCTIONS The active coenzymes methylcobalamin and 5-deoxyadeno-sylcobalamin are essential for cell growth and replication. Methylcobalamin is required for the conversion of homocysteine to methionine and its derivative, SAM. In addition, when concentrations of vitamin Bj are inadequate, folate becomes trapped as methyltetrahydrofolate, causing a functional deficiency of other required intracellular forms of folic acid (see Figures 53-6 and 53-7 and discussion above). The hematological abnormalities in vitamin Bj -deficient patients result from this process. 5-Deoxyadenosylcobalamin is required for the isomerization of L-methylmalonyl CoA to succinyl CoA (Figure 53-6). 

Jaenicke, L. Vitamin and coenzyme function Vitamin Bj2 and folic acid. Annu. Rev. Biochem. 33, 287-312 (1964)... 

After absorption into the cell, folic acid is converted into tetrahydrofolic acid, which functions as a coenzyme in the mobilisation and utilisation of single-carbon groups (e.g. formyl, methyl) that are added to, or removed from, such metabolites as histidine, serine, glycine, methionine and purines. It is involved in the synthesis of RNA, DNA and neurotransmitters. 

The finding in 1946 by T. Spies and colleagues that thymine can substitute the functions of folic acid and vitamin B12 led to the understanding that both folic acid and vitamin B12 are involved in methyl transfer reactions (Vilter et al. 1950). Donaldson and Keresztesy showed that folic acid can exist in various forms with one-carbon group attached. The coenzyme methylcobalamin was discovered in 1964 (Lindstrand 1964). 

Vitamins have diverse biochemical and physiological functions. Most vitamins e.g. the B complex vitamins) function as precursors for enzyme cofaetors, which help enzymes in their work as catalysts in the metabolism. In this role, vitamins may be tightly bound to enzymes as part of prosthetic groups. Vitamins may also be less tightly bound to enzyme catalysts as coenzymes i.e. detachable molecules that carry chemical groups or electrons between molecules) such as folic acid, which carries various forms of carbon groups—methyl, formyl and methylene— in the cell (Fenech 2001). 

Biotin and folic acid (FA) (Figure 23.1) are two members of the water-soluble B complex vitamins. Biotin plays an important role in gene expression, cell signalling and histone biotinylation, and functions as a coenzyme in the tricarboxylic acid (TCA) cycle. It also functions in the metabolism of fatty... 

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