Folate Biosynthesis

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting direcdy with nitrites, and consequently may potentially reduce cancer risk. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

En2ymatic reduction of folic acid leads to the 7,8-dihydrofolic acid (H2 folate) (2), a key substance in biosynthesis. Further reduction, cataly2ed by the en2yme dihydrofohc acid reductase, provides (65)-5,6,7,8-tetrahydrofohc acid (H folate) (3). The folate (3) is the key biological intermediate for the formation of other folates (4—8) (Table 2). 

Methyltetrahydrofohc acid folate) (4) is involved in methionine biosynthesis. Condensation of formaldehyde with folate (3),... 

Methylenetetrahydrofohc acid (5,10-CH2-H4 folate) (5) is a coen2yme in thymidylate biosynthesis the natural (6R)-stereoisomer is prepared by en2ymatic reduction of H2 folate (2), foUowed by condensation with formaldehyde (54). 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

Several reactions of IMP biosynthesis require folate derivatives and glutamine. Consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. 

Goyer, A. et al.. Folate biosynthesis in higher plants. cDNA cloning heterologous expression and characterization of dihydroneopterin aldolases, Plant. Physiol, 135, 103, 2004. 

Rebeille, F. et al.. Folates in plants biosynthesis, distribution and enhancement, Physiol. Plant, 126, 330, 2006. 

Biotin metabolism Folate biosynthesis One carbon pool by folate Retinol metabolism Porphyrin and chlorophyll metabolism Terpenoid biosynthesis Xenobiotics metabolism Ubiquinone biosynthesis Flavonoids, stilbene, and lignin biosynthesis... 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Genes encoding phosphotransferases confer resistance to streptomycin Genes encoding a drug-resistant dihydropteroate synthase enzyme required for folate biosynthesis confer resistance to sulfonamide Tetracycline... 

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. 

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. 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

Folate play an important role in the biosynthesis of DNA bases and in amino acid metabolism. An adeguate intake of folate reduces the risk of abnormalities in early embryonic brain development, specifically the risk of malformations of the embryonic brain/spinal cord. Therefore a proper intake is strictly recommended for pregnant women. Megaloblastic anemia is the ultimate consequence of an inadequate folate intake. No adverse effects have been associated with the consumption of excess folate from foods [417]. 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

Glycinamide ribonucleotide transformylase (GAR Tfase) is a folate-dependent enzyme essential to the de novo purine biosynthetic pathway. It utilizes the cofactor 10-formyl tetrahydrofohc acid (10-formyl-THF) to transfer a formyl group to the primary amine of its substrate a-glycinamide ribonucleotide. Potent, and potentially selective, inhibitors of GARTfase and de novo purine biosynthesis have been shown to be promising as antitumor drugs. 

Mechanism of Action A folate antagonist that blocks bacterial biosynthesis of nucleic acids and proteins by interfering with the metabolism of folinic acid. Therapeutic Effect Bacteriostatic. 

Folate biosynthesis has also been studied in plants and the dihydroneopterin aldolase from Arabidopsis thaliana has been crystallized and its structure determined the construction of the active site has similarities with those of other... 

The mode of action of sulfanilamides became known around 1947, when the structure and biosynthesis of folic acid were elucidated. This compound is built by bacteria from the heterocyclic pteroyl moiety, p-aminobenzoate, and glutamate. p-Aminobenzene-sulfonamide (9.89, sulfanilamide) is a competitive inhibitor of the synthase enzyme, acting as an antimetabolite of p-aminobenzoate. Occasionally, the sulfanilamide can even be incorporated into the modified folate, resulting in an inactive compound and thus an inactive enzyme. This theory, proposed by Woods and Fildes in 1940, became the first molecular explanation of drug action. 

Like folate and vitamin C, vitamin B6 (pyroxidine) is water soluble and like folate has several vitamers. Vitamin B6 may be involved in more bodily functions than any other nutrient (Tambasco-Studart et al., 2005), is a cofactor for many enzymes, especially those involved in protein metabolism, and is also a cofactor for folate metabolism. Vitamin B6 has anticancer activity (Theodoratou et al., 2008), is a strong antioxidant (Denslow et al., 2005), is involved in hemoglobin biosynthesis, lipid and glucose metabolism and immune and nervous system function. Possible consequences of deficiency include anemia, impaired immune function, depression, confusion, and dermatitis (Spinneker et al., 2007). Vitamin B6 deficiency is generally not a problem in the developed world, but there could be as yet poorly defined consequences of suboptimal intake particularly for the elderly. 

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. 

A5-Methyltetrahydrofolate is the methyl-group donor substrate for methionine synthase, which catalyzes the transfer of the five-methyl group to the sulfhydryl group of homocysteine. This and selected reactions of the other folate derivatives are outlined in figure 10.15, which emphasizes the important role tetrahydrofolate plays in nucleic acid biosynthesis by serving as the immediate source of one-carbon units in purine and pyrimidine biosynthesis. 

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