6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) (HPPK)

6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the de novo folate biosynthesis pathway of bacteria, fungi, and protozoa [1]. It catalyzes the transfer of a pyrophosphate group from ATP to 6-hydroxymethyl-7,8-dihydropterin (HMDP), producing 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (HMDPP) [2]. This reaction is the second step in the folate pathway, occurring upstream of the dihydropteroate synthase (DHPS) step targeted by sulfonamides [3]. Because humans lack the de novo folate synthesis pathway and instead rely on dietary folate uptake, HPPK represents a highly selective target for the development of novel antimicrobial agents with minimal host toxicity [1,4]. Inhibition of HPPK leads to the depletion of essential folate cofactors required for DNA synthesis and amino acid metabolism, ultimately resulting in bacterial cell death [2]. Current drug discovery efforts focus on bisubstrate inhibitors that mimic both the pterin and nucleotide substrates to achieve high affinity and specificity [5].

Other names

7,8-dihydro-6-hydroxymethylpterin pyrophosphokinaseFolK6-hydroxymethyl-7,8-dihydropterin kinaseHPPK

Inhibition of the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin, thereby blocking the production of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate, a precursor for folate synthesis [1,2].