Folic acid activity, biosynthetic

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 active form of folic acid, tetrahydrofolic acid (THF), is produced from folate by dihydrofolate reductase in a two-step reaction requiring two moles of NADPH. The carbon unit carried by THF is bound to nitrogen N5 or N10, or to both N5 and N10. THF allows one-carbon compounds to be recognized and manipulated by biosynthetic enzymes. Figure 20.11 shows the structures of the various members of the THF family, and indicates the sources of the one-carbon units and the synthetic reactions in which the specific members participate. 

Folic acid participates in the activation of single carbons and in the oxidation and reduction of single carbons. Folate-dependent single-carbon reactions are important in amino acid metabolism and in biosynthetic pathways leading to DNA, RNA, membrane lipids, and neurotransmitters. 

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. 

Tetrahydrofolate (THF) The active form of the vitamin folic acid. THF is one of the major carriers of one-carbon units at various oxidation states for biosynthetic reactions. It is required for the synthesis of the nucleotide thymidylate (dTMP). Although bacteria can synthesize folic acid, eukaryotes must obtain folate from the diet. Dietary sources of folate include leafy green vegetables (e.g., spinach and turnip greens), citrus fruits, and legumes. Many breakfast cereals, breads, and other grain products are fortified with folate. 

Arnstein (1067) has reviewed Cr reactions, and Greraiberg and Jaenicke (1957) the biosynthetic activities of folic acid. The stability of reduced pterins is discussed by filakley (1958). The defined folic enzymes are clas-... 

---