Folic acid coenzymes derived from

Many, although not all, coenzymes are derived from vitamins—substances that an organism requires for growth but is unable to synthesize and must receive in its diet. Coenzyme A from pantothenate (vitamin B3), NAD" from niacin, FAD from riboflavin (vitamin B2), tetrahydrofolate from folic acid, pyridoxal phosphate from pyridoxine (vitamin Be), and thiamin diphosphate from thiamin (vitamin Bi) are examples (Table 19.3). We ll discuss the chemistry and mechanisms of coenzyme reactions at appropriate points later in the text. 

Folic acid (Fig. 6) is the precursor of a number of coenzymes vital for the synthesis of many important molecules. These derivatives of folic acid, referred to collectively as active formate and active formaldehyde , are responsible for the donation of one carbon fragments in the enzymatic synthesis of a number of essential molecules. In the formation of methionine from homocysteine, the folic acid coenzyme donates the S-methyl group, and in the conversion of glycine to serine it is necessary for the formation of the hydroxymethyl group. Folic add is converted into its active coenzyme forms by an initial two step reduction to tetra-hydrofolic add (Fig. 6) by means of two enzymes, folic reductase and dihydrofolic reductase. Conversion of tetrahydrofolic acid (THF) to an active coenzyme folinic acid subsequently occurs by ad tion of an Ns formyl group (Fig. 6). The formation of similar compounds such as an Nio formyl derivative, or the bridged Ns,Nio-methylenetetrahydrofolic acid, also leads to active coenzymes. 

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. 

Tetrahydrofolate (THF, 6) is a coenzyme that can transfer Cj residues in different oxidation states. THF arises from the vitamin folic acid (see p. 366) by double hydrogenation of the heterocyclic pterin ring. The Ci units being transferred are bound to N-5, N-10, or both nitrogen atoms. The most important derivatives are ... 

Several coenzymes comprising a pyrimidine ring motif are derived from GTP (22) (Fig. 3). Specifically, this group comprises two members of the B vitamin group, riboflavin (vitamin B2) (24) and folic acid/tetrahydrofolate (33). Two other members of the group, tetrahydrobiopterin (31) and molybdopterin (8), are biosynthesized de novo in animals and do not have vitamin status (20, 21). 

Folic acid is itself inactive it is converted into the biologically active coenzyme, tetrahydrofolic acid, which is important in the biosynthesis of amino acids and DNA and therefore in cell division. The formyl derivative of tetrahydrofolic acid is folinic acid and this is used to bypass the block when the body fails to effect the conversion of folic acid (see Folic acid antagonists, p. 606). Ascorbic acid protects the active tetrahydrofolic acid from oxidation the anaemia of scurvy, although usually normoblastic, may be megaloblastic due to deficiency of tetrahydrofolic acid. 

Vitamin M Vitamin M is also called pteroylglutaminic add or folic acid. It was isolated from yeast extract by Wills in 1930. Its structure was described by Anger in 1946. Folic add is made up of pteridine + p-aminobenzoic add + glutamic add. There are several known derivatives, called folates, which are capable of mutual restructuring. The coenzyme tetrahydrofolic acid, which plays a role in many biochemical reactions, is formed with the help of Bi2. Around 50% of total body folate are stored in the liver. A folate-binding protein (FBP) is available for transport. Folate undergoes enterohepatic circulation. The release of folate from the liver cells is stimulated by alcohol, which increases urine excretion. Folate deficiency (e.g. in the case of alcohol abuse) is accompanied by the development of macrocytosis. 

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-... 

Tyrosine is not an essential amino acid in animals because it is synthesized from phenylalanine in a hydroxylation reaction. The enzyme involved, phenylala-nine-4-monoxygenase, requires the coenzyme tetrahydrobiopterin (Section 14.3), a folic acid-like molecule derived from GTP. Because this reaction also is a first step in phenylalanine catabolism, it is discussed further in Chapter 15. 

Pyrazino[2,3-d/]pyrimidines are known as pteridines , because the first examples of the ring system, as natural products, were found in pigments, like xanthopterin (yellow), in the wings of bntterflies (Lepidoptera). The pteridine ring system has subsequently been found in coenzymes that use tetrahydrofolic acid (derived from the vitamin folic acid), and in the cofactor of the oxomolybdoenzymes and comparable tungsten enzymes. 

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). 

The conversion of serine to glycine involves the transfer of a one-carbon unit from serine to an acceptor. This reaction is catalyzed by senne hydroxymethylase, with pyridoxal phosphate as a coenzyme. The acceptor in this reaction is tetra-hydrofolate, a derivative of folic acid and a frequently encountered carrier of one-carbon units in metabolic pathways. Its structure has three parts a substituted pteridine ring, /(-aminobenzoic acid, and glutamic acid (Figure 23.11). Folic acid is a vitamin that has been identified as essential in preventing birth defects consequently, it is now a recommended supplement for all women of... 

Differences between bacteria and Man in the absorption and the biosynthesis of dihydrofolic acid 2.14) and its derivatives are so great that the whole system of sulfonamide chemotherapy rests on it (Section 9.3.1). In brief, pathogenic bacteria can synthesize their requirements of folic acid, but cannot absorb preformed folic acid in their nutriment. Man, on the other hand, cannot synthesize this coenzyme, but has no difficulty in absorbing it from food. 

As indicated above, derivatives of folic acid play a key role in the biosynthesis of purines and pyrimidines. These pteridines are the coenzymes responsible for inserting the carbon atoms into both positions 2 and 8 of purines, and they also insert the methyl-group into thymine (4.7 ). When bacteria are treated with low concentrations of sulfonamides, 4-aminoimidazole-5-carboxamide ribotide 9.22) accumulates in the culture media. This substance is an intermediate in the biosynthesis of inosinic acid 9.23) from which all purines are derived. 

It is of interest that many of the reduced folic derivatives prepared as a result of chemical studies of growth factors have subsequently been foimd to serve directly as coenzymes in the transfer of single carbon units. Reversible enzymatic transfer of the single carbon unit from anhydrofolinic acid to glycineamide ribotide, from Ai -formyltetrahydrofolic acid to 5-amino-4-imidazolecarboxamide ribotide, and from folinic acid to glutamic acid have been observed to be specific for these respective formyl donors -. ... 

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