Dihydrofolate reductase-thymidylate synthase (Plasmodium spp.) (DHFR-TS)

Dihydrofolate reductase (DHFR) in Plasmodium species is a key enzyme within the folate metabolic pathway, typically existing as a bifunctional protein fused with thymidylate synthase (DHFR-TS) [UniProt: P04839]. It facilitates the reduction of dihydrofolate to tetrahydrofolate, an essential precursor for the synthesis of thymidylate, which is required for DNA replication and parasite survival [PubMed: 19103486]. As Plasmodium parasites are highly dependent on de novo folate synthesis and cannot effectively scavenge host folates, DHFR has served as a primary target for antimalarial drugs such as pyrimethamine and proguanil (via its active metabolite cycloguanil) [PubChem: CID 4993]. These inhibitors competitively bind to the enzyme's active site, disrupting nucleotide biosynthesis and leading to the arrest of the parasite's erythrocytic cycle [NIH: PMC3121650]. However, the clinical utility of DHFR inhibitors is increasingly challenged by the widespread emergence of specific point mutations in the dhfr gene, such as S108N and I164L, which reduce drug binding affinity and lead to treatment failure [Wikipedia: Dihydrofolate reductase]. Consequently, research continues into next-generation inhibitors that can overcome these resistant mutant forms while maintaining selectivity over the human DHFR ortholog.

Other names

DHFRBifunctional dihydrofolate reductase-thymidylate synthasePlasmodium DHFRDihydrofolate reductase

Competitive inhibition of the dihydrofolate reductase domain, which prevents the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate, thereby depleting the folate pool required for thymidylate synthesis and DNA replication.