Folic acid biosynthesis

Bacteria require p-aminobenzoic acid to biosyn thesize folic acid a growth factor Structurally sul fanilamide resembles p-aminobenzoic acid and is mistaken for it by the bacteria Folic acid biosynthesis IS inhibited and bacterial growth is slowed suffi ciently to allow the body s natural defenses to effect a cure Because animals do not biosynthesize folic acid but obtain it in their food sulfanilamide halts the growth of bacteria without harm to the host... 

Given this structural similarity, it should not be surprising to learn that sulfanilamide competes with p-aminobenzoic acid for a binding site on the surface of dihydropteroate synthetase. Put another way, sulfanilamide binds to the enzyme where p-aminobenzoic acid should bind but no reaction occurs. The consequence is that a step in folic acid biosynthesis is disrupted and the bacterial cell is deprived of adequate folic acid. Nucleic acid synthesis, among other things, is disrupted, leading to a cessation of cell growth and division. The human immune system can mop up what remains. No similar consequences befall the human host since it cannot make folic acid in the first place and must get an adequate supply of this vitamin in the diet. 

Folic acid is vital for both humans and bacteria. Bacteria synthesize this compound, but humans are unable to synthesize it and, consequently, obtain the necessary amounts from the diet, principally from green vegetables and yeast. This allows selectivity of action. Therefore, sulfa drugs are toxic to bacteria because folic acid biosynthesis is inhibited, whereas they produce little or no ill effects in humans. The structural relationships between carboxylic acids and sulfonic acids that we have observed in rationalizing chemical reactivity are now seen to extend to some biological properties. 

Competitive inhibitors bind to specific groups in the enzyme active site to form an enzyme-inhibitor complex. The inhibitor and substrate compete for the same site, so that the substrate is prevented from binding. This is usually because the substrate and inhibitor share considerable stmctural similarity. Catalysis is diminished because a lower proportion of molecules have a bound substrate. Inhibition can be relieved by increasing the concentration of substrate. Some simple examples are shown below. Thus, sulfanilamide is an inhibitor of the enzyme that incorporates j9-aminobenzoic acid into folic acid, and has antibacterial properties by restricting folic acid biosynthesis in the bacterium (see Box 11.13). Some phenylethylamine derivatives, e.g. phenelzine, provide useful antidepressant drags by inhibiting the enzyme monoamine oxidase. The cA-isomer maleic acid is a powerful inhibitor of the enzyme that utilizes the trans-isomer fumaric acid in the Krebs cycle. 

The rapid technological progress in X-ray crystallography has enabled the structural analysis of numerous enzymes involved in coenzyme biosynthesis. Complete sets of structures that cover all enzymes of a given pathway are available in certain cases such as riboflavin, tetrahydrobiopterin, and folic acid biosynthesis. Stmctures of orthologs from different taxonomic groups have been reported in certain cases. X-ray structures of enzymes in complex with substrates, products, and analogs of substrates, products, or intermediates have been essential for the elucidation of the reaction mechanisms. Structures of some coenzyme biosynthesis enzymes have been obtained by NMR-structure analysis. 

The folic acid biosynthesis has been extensively explored to design effective antimalarials. A number of classes of compounds have been developed, which interfere with different steps of the folate synthesis in plasmodia [14]. These antimalarials, which are collectively known as antifolates, may be broadly divided in three groups. 

Another class of drugs that has proven clinically valuable against malaria are the antifolates. Sulfonamides such as pyridoxine and sulfones like dapsone inhibit the plasmodial enzyme dihydropteroate synthetase on the pathway of folic acid biosynthesis (48). The 2,4-... 

Bermingham, A. and Derrick, J. P. (2002) The folic acid biosynthesis pathway in bacteria evaluation of potential for antibacterial drug discovery. Bioessays 24, 637-648. 

These target sites will include respiration, chlorophyll biosynthesis, isoprenoid biosynthesis, microtubule biosynthesis and function, cellulose biosynthesis, protein and nucleic acid biosynthesis, folic acid biosynthesis, and hormone biosynthesis and function. Only herbicides with proven direct activity on these target sites will be reviewed in this chapter. 

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