Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PfDHFR-TS)

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is a bifunctional enzyme that is essential for the survival and replication of the malaria parasite (UniProt P04839) [1]. Unlike humans, who have separate enzymes for these functions, P. falciparum expresses them as a single polypeptide chain that forms a homodimer (PubMed: 12411954) [2]. The DHFR domain catalyzes the reduction of dihydrofolate to tetrahydrofolate, while the TS domain catalyzes the conversion of dUMP to dTMP, both of which are vital for DNA synthesis (PubMed: 16330667) [3]. This enzyme is the primary target for several clinically important antimalarial drugs, most notably pyrimethamine and cycloguanil (PubChem CID 4993) [4]. These drugs act as competitive inhibitors of the DHFR domain, effectively starving the parasite of the folate precursors needed for nucleotide production. However, the widespread emergence of point mutations in the dhfr gene, such as S108N, N51I, and C59R, has led to significant drug resistance in many parts of the world (PubMed: 22106334) [5]. Consequently, PfDHFR-TS remains a focus of intense research for the development of next-generation antifolates that can bypass these resistance mechanisms.

Other names

Bifunctional dihydrofolate reductase-thymidylate synthasePfDHFRDHFR-TSDihydrofolate reductase-thymidylate synthase

Competitive inhibition of the dihydrofolate reductase domain, which prevents the reduction of dihydrofolate to tetrahydrofolate, leading to the depletion of folate pools required for DNA synthesis (PubMed: 12411954) [2].