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

Bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is a critical enzyme in the malaria parasite Plasmodium falciparum, serving as a primary target for antifolate chemotherapy (Source: UniProt P13922). Unlike humans, where dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are separate proteins, Plasmodium expresses them as a single bifunctional enzyme (Source: PubMed PMID: 12590661). The DHFR domain catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, a necessary cofactor for the synthesis of thymidylate and certain amino acids. The TS domain facilitates the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), which is essential for DNA replication. Because the parasite lacks the ability to salvage preformed folates from its environment, it is entirely dependent on this de novo synthesis pathway (Source: PubChem). Drugs such as pyrimethamine and cycloguanil act by competitively inhibiting the DHFR domain, leading to a 'thymineless death' of the parasite. However, the clinical utility of these drugs is severely challenged by the global spread of point mutations in the dhfr gene, such as the S108N mutation, which significantly reduce drug binding affinity (Source: CDC, WHO).

Other names

Plasmodium falciparum dihydrofolate reductaseDHFR-TSDihydrofolate reductase-thymidylate synthasePfDHFRDHFR domain of bifunctional DHFR-TS

Competitive inhibition of the dihydrofolate reductase (DHFR) domain, which prevents the reduction of dihydrofolate to tetrahydrofolate, thereby depleting the folate pool required for dTMP synthesis and DNA replication (Source: PubChem, UniProt P13922).