5-Formyl-tetrahydrofolic acid derivatives

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. 

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. 

Because methionine synthase is the only mammalian enzyme known to act on 5-methyltetrahydrofolate, the decreased intracellular activity of this enzyme causes 5-methyltetrahydrofolate to accumulate, at the expense of depleted pools of the other tetrahydrofolate coenzymes. Thus, even though total folate levels may seem ample, there is a functional folate deficiency, with insufficient levels of the formyl and methylene derivatives needed for synthesis of nucleic acid precursors. 

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... 

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. 

A reduced form of folic acid (tetrahydrofolic acid, FH4) is active in so-called one-carbon metabolism. A formyl group may be substituted on N(5) or N(io) and the N(5)-N(io) methenyl derivative (Figure 36) is also active. Reactions involving the introduction of one-carbon fragments include the conversion of glycine to serine (Section V.C.3), ethanolamine to choline (Section V.C.3) and the introduction of C(8) of the purine nucleus (Section V.D.3). 

Homocysteine is the amino acid that results after S-adenosyl methionine donates its methyl group, and then the product S-adenosyl homocysteine is hydrolyzed by a molecule of water. In mammals, homocysteine can be converted to cysteine so that the latter is not an essential amino acid, or it can be converted back to methionine by methylation with a compound which serves as a source of one carbon fragments (methyl, formyl, etc.) in biological systems tetrahydrofolic acid. In some bacteria, homocysteine can be converted back to methionine by methylation with methylcobalamin (the methyl derivative of vitamin B12), in the presence of other required compounds or cofactors. This latter methylation reaction is of interest because it can occur, at a reduced rate, in the absence of any enzymes, and a simpler model system has been developed to mimic this reaction (see details in Chapter 6). 

The formylation of GAR to produce FGAR is catalyzed by glycinamide ribonucleotide transformylase. The immediate formyl donors are derivatives of tetrahydrofolic acid (FIR) (96, 107, 108). With purified enzyme preparations, iV, Ar -anhydroformyltetrahydrofolic acid alone donates its formyl group to GAR (/09). Because of their rapid interconversion by the enzyme cyclohydrolase (110), both JV -formyltetrahydrofolic acid and W, Ar -arjhydroformyltetrahydrofolio acid were reactive in crude enzyme... 

In enzymic reactions, the active form of folic acid is generally considered to be a derivative of 5,6,7,8-tetrahydrofolic acid (FH ) which reversibly forms formyl or hydroxymethyl compounds for participation in singlecarbon transfer reactions (S, S). The formyl or hydroxymethyl group in the coenz3one is usually assumed to be attached to the nitrogen in position 10 from which point either group can reversibly form a bridge to position 5. 

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. 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

Tetrahydrofolate (THF) is the major source of 1-carbon units used in the biosynthesis of many important biological molecules. This cofactor is derived from the vitamin folic acid and is a carrier of activated 1-carbon units at various oxidation levels (methyl, methylene, formyl, formimino, and methenyl). These compounds can be interconverted as required by the cellular process. The major donor of the 1-carbon unit is serine in the foUowing reaction ... 

FIGURE 18 The functioning of tetrahydrofolates (THF) in oxidation and reduction of single-carbon fragments. A PLP-dependent enzyme cleaves serine (Fig. 14), releasing formaldehyde, which combines in the active center with THF. Formic acid can be converted to formyl-THF. The various THF derivatives supply singlecarbon fragments for many biosynthetic processes. 

---