InterPro: IPR017925 Dihydrofolate reductase conserved site

Dihydrofolate reductase (DHFR) (EC:1.5.1.3) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in de novo synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [1], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [2].

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar [3]. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown [4] to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [5].

This entry covers the region in the N-terminal part of the DHFR domain, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme [6].