Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS)

Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a key enzyme in folate metabolism, catalyzing essential reactions for the synthesis of DNA precursors, glycine, and purines. This bifunctional protein is especially notable in protozoa and some lower eukaryotes, where it exists as a single polypeptide with two distinct enzymatic domains: an N-terminal DHFR domain and a C-terminal TS domain, separated by a linker peptide. It is essential for de novo synthesis of thymidylate—a precursor needed exclusively for DNA replication—and thus critical for cell proliferation. DHFR inhibitors like methotrexate are widely used anticancer agents; however, bifunctional DHFR–TS enzymes found in protozoan pathogens often show resistance or reduced sensitivity to classical antifolates used against human targets. It has been validated genetically/chemically as an antiparasitic drug target.

DHFR inhibition, TS inhibition