Biosynthesis of Folic Acid

Sulfanilamide, whose structure is similar to the structure of p-aminobenzoic acid, competes with p-aminobenzoic acid for inclusion in the folic acid molecule. In short, by taking the place of p-aminobenzoic acid, it interferes with the biosynthesis of folic acid. As a result, the misled enzymes construct a false molecule of folic acid, which is not able to carry out the vital function of true folic acid. 

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. 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

Figure 25-19 The biosynthesis of folic acid and other pterins.

This substance inhibits the growth of bacteria by interfering with the synthesis of folic acid, 7, which is an essential substance for bacteria and animals alike. However, animals acquire folic acid from a normal diet, whereas bacteria have to synthesize it. Biosynthesis of folic acid is blocked by 4-aminobenzenesulfonamide, probably because of the structural similarity of the sulfonamide to 4-aminobenzoic acid, which is a normal ingredient in the biosynthesis of folic acid. The enzyme system involved apparently substitutes the sulfonamide for... 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

Trimethoprim (Proloprim, Trimpex) interferes with the bacterial folic acid pathway by inhibiting the dihydrofolate reductase enzyme in susceptible bacteria (see Fig. 33-2). This enzyme converts dihydrofolic acid to tetrahydrofolic acid during the biosynthesis of folic acid cofactors. By inhibiting this enzyme, trimethoprim directly interferes with the production of folic acid cofactors, and subsequent production of vital bacterial nucleic acids is impaired. 

However, because malonic acid has only one methylene group, it is obvious that no oxidation-reduction can take place. Only association of the enzyme and inhibitor, and dissociation of the I complex, can occur. Another classical example of a competitive inhibitor is the sulfa drug sulfanilamide, which interferes with the biosynthesis of folic acid from the precursor -aminobenzoic acid (PABA). 

Walter, R. D., and Konigk, E. (1974a). Biosynthesis of folic acid compounds in plasmodia. Purification and properties of the 7,8-dihydropteroate-synthesizing enzyme from Plasmodium chabaudi. Hoppe Seylers. Z. Physiol. Chem. 355,431-437. 

G. M. Brown J. M. Williamson, Biosynthesis of Folic Acid, Riboflavin, Thiamine, and Pantothenic Acid. In Escherichia coli and Salmonella typhimurium Cellular and Molecular Biology F. C. Neidhardt, J. L. Ingraham, K. B. Low, B. Magasanik,... 

The sulfonamides are bacteriostatic when administered to humans in achievable doses. They inhibit the enzyme dihydropteroate synthase, an important enzyme needed for the biosynthesis of folic acid derivatives and, ultimately, the thymidine required for DNA. They do this by competing at the active site with... 

Goswami, R. (2012) Biosynthesis of folic acid and biotin from probiotic strain L. helveticus MTCC 5463. M. Sc. thesis submitted to Dairy Microbiology Department, SMC College of Dairy Science, Anand Agricultural University, Anand, Gujarat, India. 

Biosynthesis of folic acid from guanosine monophosphate. 

Dihydroneopterin is a branch point in pteridine metabolism. In the formation of tetrahydrobiopterin, sepiapterin, and isosepiapterin its three-carbon side chain is retained. In the biosynthesis of folic acid derivatives two carbon atoms are eliminated, whereas in the formation of xanthopterin and leucopterin the side chain is lost completely. 

This compound does not contain a glutamic acid group and it is active in promoting the growth of S. faecalis R. This may indicate that glutamic acid is added as a later step in the formation of folic acid and hence that PABG is not necessarily an intermediate in the biosynthesis of folic acid. This conclusion also follows from Brown s report (lib). 

It may thus be concluded that in the biosynthesis of folic acid by microorganisms the aromatic ring of the p-aminobenzoic acid group is formed from carbohydrate via shikimic acid. Glutamic acid is possibly added after p-aminobenzoic acid has combined with the pteridine group of the molecule. 

Sulfanilamide and other sulfa drugs owe their antibacterial properties to then-ability to mimic / -aminobenzoic acid (PABA) which is an essential metabolite for many baeteria (Chapter 6, ref. 33) since it is an intermediate in the biosynthesis of folic acid. Many strains of bacteria have now become resistant to the antibacterial action of sulfonamides and consequently their use has declined and they have been often superseded by antibioties in the treatment of many infectious diseases. However, sulfonamides are still important antimicrobial agents some of the most useful chemicals contain a heterocyclic nucleus, for instance sulfadiazine 5, sulfamethoxazole 6 and sulfaisoxazole 7. ... 

Antagonists for Herbicides Inhibiting the Biosynthesis of Folic Acid... 

The reversal of the inhibitory action of asulam on wheat, wild oats, and carrots by exogenous applications of folic acid and p-aminobenzoic acid has been demonstrated by a number of investigators. The antagonism of asulam by 2.4-D on bracken fern [Pteridium aquilinum (L.) Kuhn] appeared to be linked to an interaction of the two herbicides on protein synthesis rather than the biosynthesis of folic acid. ... 

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