The Biosynthesis of Folic Acid

The biological importance of p-aminobenzoic acid was recognized only in 1940 when Woods showed that the compound antagonized the bacteriostatic effects of sulfonamides (2). Later, p-aminobenzoic acid was found to be an essential part of the folic acid molecule (3, 4), and it now seems quite likely that the sole metabolic function of p-aminobenzoate is to serve as a precursor for the biosynthesis of folic acid compounds. Experiments with a variety of bacterial species have established that sulfonamides inhibit synthesis in vivo of compounds with folic acid activity and that p-aminobenzoate competitively reverses the inhibition (5-7). These results, along with other observations that folate-utilizing bacteria are not affected by sulfonamides (7-lo), have led to the conclusion that sulfonamides inhibit the growth of bacteria by competitively inhibiting the utilization of p-aminobenzoate for the biosynthesis of folic acid. Recent observations that bacterial cell-free extracts can form folate compounds from pteridine compounds, p-aminobenzoate, and glutamate (11-16) have provided the opportunity to study the effects of sulfonamides on the enzymatic synthesis of folate. It has already been reported in brief notes that sulfonamides are effective inhibitors of enzymatic synthesis of folic acid compounds (12-15). The results to be presented in the present paper show that various sulfonamides inhibit folate synthesis to varying degrees by specifically inhibiting the enzymatic step whereby p-aminobenzoate and 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine react to yield dihydropteroate. Also, evidence will be presented which indicates that pteridine compounds can react with sulfonamides in place of p-aminobenzoate to yield products thought to be sulfonamide analogues of dihydroand tetrahydropteroic acid.