7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (HPPK)

7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (HPPK) is an essential enzyme in the de novo folate biosynthesis pathway, found in bacteria, plants, and some protozoa (UniProt, 2023). It catalyzes the ATP-dependent pyrophosphorylation of 7,8-dihydro-6-hydroxymethylpterin to form 7,8-dihydro-6-hydroxymethylpterin pyrophosphate, a precursor for dihydropteroate (BRENDA, EC 2.7.6.3). Because humans lack this pathway and obtain folate through diet, HPPK is a highly selective target for novel antimicrobial agents (PubMed, PMID: 11513581). Inhibition of HPPK disrupts the synthesis of tetrahydrofolate, which is vital for nucleic acid and amino acid production, leading to the inhibition of microbial growth. While no HPPK-specific drugs are currently FDA-approved, experimental inhibitors such as pterin analogs and bisubstrate inhibitors are being developed to combat antibiotic resistance (PubMed, PMID: 22403114). These compounds aim to provide a new line of defense against pathogens that have evolved resistance to existing folate pathway inhibitors like sulfonamides. The enzyme's unique catalytic mechanism involving three magnesium ions and significant conformational changes makes it a complex but rewarding target for structure-based drug design.

Other names

6-hydroxymethyl-7,8-dihydropterin pyrophosphokinaseFolK7,8-dihydro-6-hydroxymethylpterin kinase2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine pyrophosphokinase

Inhibition of the de novo folate biosynthesis pathway by blocking the conversion of 7,8-dihydro-6-hydroxymethylpterin to its pyrophosphate form, thereby depleting the pool of tetrahydrofolate required for microbial DNA synthesis.