Tetrahydrofolic acid

Fig. 1. The choline and methionine cycles showing the origin and disposition of labile methyl groups. FAH = tetrahydrofolic acid CH3BJ2 = methylated...

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). 

Tetrahydrofolic acid (H PteGlu) accqrts and transfers activated one-carbon units in the form of 5-methyl-,... 

Figure 45-15. Tetrahydrofolic acid and the one-carbon substituted folates.

The use of chiral amide ligands has been restricted to rhodium, where the catalyst precursor is [Rh(BH4)(amide)py2Cl2]. The work has been reviewed (10, 35) cinnamate derivatives were reduced to up to 57% ee, and hydrogenation of a carbon- nitrogen double bond in folic acid leads to tetrahydrofolic acid with high biological activity (308). 

The answer is c. (Hardman, pp 1058-1059. Katzung, pp 793-795.) Trimethoprim inhibits dihydro folic acid reductase. Sulfamethoxazole inhibits p-aminobenzoic acid (PABA) from being incorporated into folic acid by competitive inhibition of dihydropteroate synthase. Either action inhibits the synthesis of tetrahydrofolic acid. 

FIGURE 40-3 Glycine cleavage system and some related reactions. Glycine and serine are readily interchangeable. Enzymes (1) Glycine cleavage system (2) and (4) Serine hydroxymethyltransferase (3) N5 10-methylenetetrahydrolate reductase. N5 I0-CH2-FH4, N5>10-methylenetetrahydrolate FH4, tetrahydrofolic acid. 

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... 

Methyl tert-butylhydroquinone, 20 105 Methyl-tertiary-butyl ether. See Methyl-tert-butyl ether (MTBE) Methyltestosterone, registered for use in aquaculture in Australia, 3 222t Nb-Methyl tetrahydrofolic acid, 25 802 2-Methyltetrahydrofuran (METHF),... 

Kwon, Nathan and Stuehr37 found tetrahydrofolic acid (BH4) to serve as a cofactor for the production of NO from mouse macrophages. This compound had been established... 

Folic acid becomes sequentially reduced in the body by the enzyme dihydrofolate reductase to give dihydrofolic acid (FH2) and then tetrahydrofolic acid (FFi4). Reduction occurs in the pyrazine ring portion. 

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. 

Tetrahydrofolic acid (THF) is a co-en-zyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and repUcation. Lack of THF leads to inhibition of cell proUferation. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

Trimethoprim acts in the body by interfering with the action of hydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This process is necessary for purine biosynthesis of live organisms and DNA, respectively. Reducing the dihydrofolic acid to tetrahydrofolic acid is also catalyzed in humans by dihydrofolate reductase. However, trimethoprim has thousands of more inhibitory effects with respect to bacterial enzymes than with respect of analogons enzymes of mammals, which is the main benefit of trimethoprim. 

Pharmacology SMZ inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. TMP blocks the production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. 

Tetrahydrofolic acid (THF) Loose Folic acid Methyl group donor in one-carbon transfer reactions critical in biosynthesis of purines and pyrimidines... 

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