Dihydropteroate diphosphate

In a few strains of bacteria, however, the picture is somewhat more complex. Here, sulfonamides are attached to the dihydropteroate diphosphate in the place of the normal PABA. The resulting unnatural product, however, is not capable of undergoing the next necessary reaction (condensation with glutamic acid). This false metabolite... 

This enzyme [EC 2.5.1.15], also known as dihydro-pteroate pyrophosphorylase, catalyzes the reaction of 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteri-dine diphosphate with 4-ammobenzoate to produce pyrophosphate and dihydropteroate. 

Intracellular protozoa of the phylum Apicomplexa such as plasmodium, toxoplasma, and eimeria have long been known to respond to sulfonamides and sulfones. This has led to the assumption that Apicomplexa must synthesize their own folate in order to survive. The reaction of 2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine diphosphate with />aminobenzoate to form 7,8-dihydropteroate has been demonstrated in cell-free extracts of the human malaria parasite Plasmodium falciparum. 2-Amino-4-hydroxy-6-hydroxymethyl-dihydropteridine pyrophosphokinase and 7,8-dihydropteroate synthase have also been identified. Sulfathiazole, sulfaguanidine, and sulfanilamide act as competitive inhibitors of p-aminobenzoate. It has not been possible to demonstrate dihydrofolate synthase activity in the parasites, which raises the possibility that 7,8-dihydropteroate may have substituted for dihydrofolate in malaria parasites. Similar lack of recognition of folate as substrate was also observed in the dihydrofolate reductase of Eimeria tenella, a parasite of chickens. 

Animals are unable to synthesize folic acid (6.62) and must consume adequate quantities in their diets. Plants and bacteria, however, are able to make folic acid. The first step of this synthesis is catalyzed by dihydropteroate synthetase and reacts dihydroptero-ate diphosphate (6.69) and para-aminobenzoic acid (PABA, 6.70) (Figure 6.25). Because this pathway is not found in humans, inhibition of the reaction is a method to ultimately stop TMP synthesis in an invading bacterium while not impacting the infected host. The sulfonamides, often called sulfa drugs, are a class of antibiotic that exploits the folic acid pathway and inhibits dihydropteroate synthetase. Sulfa drugs bind in the same fashion as PABA and act as competitive inhibitors. The active form of the first sulfa drug is sulfanilamide (6.71). Sulfamethoxazole (6.72) is a sulfa drug that is widely prescribed today.26... 

Crystal structures have been reported for dihydropteroate synthases from several pathogenic organisms (S. pneumoniae, S. aureus, M. tuberculosis. Bacillus anthracis) The structure represents an eight-stranded a/3-barrel. The substrate, 6-hydroxymethyl dihydropterin 6-diphosphate, binds in a deep cleft the second substrate, 4-aminobenzoate, binds closer to the protein surface. ... 

The combination of 6-hydroxymethyl-7,8-dihydropterin diphosphate with 4-aminobenzoate in a simple displacement reaction (dihydropteroate synthase, EC 2.5.1.15) produces 7,8-dihydropteroate (Equation 12.22). 

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