Sulfa drugs strike more than once in the folate biosynthetic pathway. Dihydropteroate synthase catalyzes the condensation of dihydropterin pyrophosphate and pABA to form dihydropteroate. Glutamate chain length depends on the cellular role of the folate derivative, and the final tetrahydrofolate product may have from one to six Glu residues. As indicated by the red lines, sulfa drugs (such as sulfamethoxazole, SMX) block folate production at the dihydropteroate synthase step by competing with pABA, and by acting as a substrate itself. The resulting sulfa-DHP derivative is an additional folate biosynthesis inhibitor, competing against dihydrofolate (DHF) for reduction by dihydrofolate reductase. E. coli are capable of transporting and hydrolyzing pABA-glu (a folate breakdown product) to produce free pABA and glutamate for de novo folate synthesis .
Nguyen and Clarke BMC Biology 2012 10:66 doi:10.1186/1741-7007-10-66