Dihy dropteroic acid

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

Although folic acid is vital for human health, we don t have the enzymes to make it it s a vitamin, which means we must take it in our diet or we die. Bacteria, on the other hand, do make folic acid. This is very useful, because it means that if we inhibit the enzymes of folic acid synthesis we can kill bacteria but we cannot possibly harm ourselves as we don t have those enzymes. The sulfa drugs, such as sul-famethoxypyridazine or sulfamethoxazole, imitate p-aminobenzoic acid and inhibit the enzyme dihy-dropteroate synthase. Each has a new heterocyclic system added to the sulfonamide part of the drug. 

The key enzymes involved in the biosynthesis of DHFA and THFA are dihy-dropteroate synthetase, dihydrofolate synthetase and dihydrofolate reductase [1-3]. Drugs that block the synthesis of dihydropteroic acid are known as dihydropteroate synthetase inhibitors (PABA antagonists) and those which control the reduction of DHFA to THFA are called dihydrofolate reductase (DHFR) inhibitors. Collectively these drugs are known as antifolates. 

The two steps involved are the biosynthesis of dihydropteroic acid catalyzed by dihy-dropteroate synthetase and inhibited by sulfonamides and sulfones (Chapter 2), and the reduction of dihydrofolic acid by DHFR, which can be inhibited by MTX, PM, TM, and other DHFR inhibitors. Hitchings proposed such combinations, which ideally should pro-... 

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