Tetrahydrofolic acid formylation

Folic acid 1941/1941 Liver Tetrahydrofolic acid Formyl group transfer... 

The chiralities at C-6 of natural 5,6,7,8-tetrahydrofolic acid and related folates, e.g. 5,10-methylene-, 5-methyl- and 5-formyl-5,6,7,8-tetrahydrofolic acid, from various biological systems are the same and possess the absolute configuration (S) at C-6 as deduced from an X-ray study of the ion (51) (79JA6114). 

Catalytic reduction of folic acid to 5,6,7,8-tetrahydrofolic acid (225) proceeds fast in trifluoroacetic acid (66HCA875), but a modified method using chemical reductants leads with sodium dithionite to 7,8-dihydrofolic acid (224). Further treatment with sodium borohydride gives (225) which has been converted into 5-formyl-(6i ,S)-5,6,7,8-tetrahydro-L-folic acid (leucovorin) (226) by reaction with methyl formate (equation 70) (80HCA2554). 

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

In living systems, folinic acid can be synthesized ultimately from folic acid by reduction to tetrahydrofolic acid followed by addition of a 1-carbon fragment to the molecule (N5.N1°-methylenetetrahydrofolate, V). After a 2-step oxidation, the formyl group resides either at the N5 or N10 position or as an equilibrium mixture. The essential reactions are summarized below 32... 

N5-Formyl tetrahydrofolic acid, 25 803 N10-Formyl tetrahydrofolic acid, 25 801 Fornacite, 6 4 7 It... 

Tetrahydrofolic acid then functions as a carrier of one-carbon groups for amino acid and nucleotide metabolism. The basic ring system is able to transfer methyl, methylene, methenyl, or formyl groups, and it utilizes slightly different reagents as appropriate. These are shown here for convenience, we have left out the benzoic acid-glutamic acid portion of the structure. These compounds are all interrelated, but we are not going to delve any deeper into the actual biochemical relationships. 

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. 

It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative of tetrahydrofolic acid and it acts as an antidote to folic acid antagonists like methotrexate or pyrimethamine which inhibit the enzyme dihydrofolate reductase. 

The atoms of a purine are contributed by amino acids (aspartic acid, glutamine, and glycine), CO2, and N10-formyl tetrahydrofolic acid. 

Tetrahydrofolic acid Folic acid (B9) Glutamate Methyl, formyl, residues methylene and formimino groups Bacteria, archaea and eukaryotes... 

Fig. 11.6. Interconversions of tetrahydrofolate derivatives. FH2 = dihydrofolic acid FH4 = tetrahydrofolic acid AICAR -= 5 aminoimidazole 4-carboxamide ribonucleotide FAICAR = formyl AICAR GAR = glycinamide ribonucleotide FGAR = formyl GAR Glu = glutamic acid FIGLU = formimino glutamic acid. (Modified from Mudd and Cantoni, 1964.)...

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. 

Folic acid or the folate coenzyme [6] is a nutritional factor both for the parasites and the hosts. It exists in two forms, viz. dihydro- and tetrahydrofolic acids [4,5] which act as cofactors involved in the transfer of one carbon units like methyl, hydroxymethyl and formyl. The transfer of a one carbon unit is associated with de novo synthesis of purines, pyrimidines and amino acids. Mammals can not synthesize folate and, therefore, depend on preformed dietary folates, which are converted into dihydrofolate by folate reductase. Contrary to this, a number of protozoal parasites like plasmodia, trypanosomes and leishmania can not utilize exogenous folate. Consequently, they carry out a de novo biosynthesis of their necessary folate coenzymes [12]. The synthesis of various folates follows a sequence of reactions starting from 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine (1), which is described in Chart 4 [13,14]. 

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N -formyl FH ), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven useful in treating other cancers. 

Several processes described above use one-carbon derivatives of tetrahydrofolic acid (Fig. 14-22). E.g., the synthesis of the purine ring (Eig. 14-18) requires N °-formyl tetrahydrofolate. Thymidylate synthetase, a key enzyme in pyrimidine synthesis, uses FP,N -methylene tetrahydrofolate both as a donor of a methyl group... 

Folic acid is part of the vitamin B complex, and its electrochemical and biological reduction schemes have been reported by Dryhurst. Its fully reduced form, tetrahydrofolic acid, is important because it acts as a carrier for a formate unit. Thus, formyl-N -tetrahydrofolic acid is involved in the biosynthesis of nucleic acid, primary constituents of living cells. Alternating current adsorptive stripping voltammetry has been applied to the determination of (I) in human seru. ... 

Tetrahydrofolic acid and conjugates IVansfer of formyl, hydroxymethyl and methyl groups Folic acid... 

Tetrahydrofolic acid, THF, folate-H coenzyme F 5,6,7,8-tetrahydropteroylglutamic acid, the coenzyme responsible for the binding, activation and transfer of all active one carbon units, with the exception of carbon dioxide (the F in coenzyme F stands for formylation). M, 445.4 (after chemical preparation involving acetic add, it retains two molecules CH3-COOH and has M, 565.4), 298 nm in 0.01 M... 

Tetrahydrofolic acid (THF) holds a central position in one-carbon metabolism. Formyl groups, hydroxymethyl, and methyl groups may be transferred via the THF derivatives given in Table 16. 

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. 

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