6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase

Function

6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) or 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase is a prokaryotic enzyme which is part of the folate synthesis pathway. HPPK catalyzes the attachment of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin (HMDP) to form 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate. Mg+2 ion is important for binding ATP and HMDP.^[1]

The Plasmodium parasites encode a protein fused of HPPK and dihydroperoate synthase (HPPK-DHPS) which catalyse reaction in the folate biosynthesis pathway^[2].

The reaction catalyzed by HPPK involves the transfer of a pyrophosphate group from ATP to HMDP, leading to the formation of HMDPTP and ADP. This phosphorylation step is essential for subsequent reactions in the folate biosynthesis pathway, leading to the production of THF.

Relevance

HPPK is a potential target for antimicrobial drugs like trimethoprim and sulfonamides.

Deficiencies or dysregulation of HPPK can disrupt the folate biosynthesis pathway and lead to impaired cellular processes dependent on THF. Genetic mutations affecting HPPK function have been associated with rare metabolic disorders, such as dihydropteridine reductase deficiency, which is characterized by impaired production of THF and neurotransmitters.

Understanding the structure and function of HPPK has provided insights into the folate biosynthesis pathway and its role in cellular metabolism. Moreover, HPPK has been considered as a potential target for the development of antimicrobial agents, as the folate biosynthesis pathway is essential for the survival and proliferation of certain bacteria, making HPPK an attractive candidate for drug discovery.

In summary, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an enzyme involved in the biosynthesis of tetrahydrofolate (THF). It catalyzes the phosphorylation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (HMDP) to produce 6-hydroxymethyl-7,8-dihydropterin triphosphate (HMDPTP), an intermediate in the folate biosynthesis pathway. HPPK plays a critical role in regulating THF levels and is of biological and potential therapeutic importance.

Structural highlights

Three loop regions surround the HPPK active site. Upon binding of ATP, the region (purple) changes its conformation and enables the binding of HMDP. . Water molecules are shown as red spheres.

3D structures of HPPK

HPPK 3D structures