Dihydrofolate reductase (DHFR) (DHFR)

Dihydrofolate reductase (DHFR) is an essential enzyme that catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate (Source: UniProt P00375). This reaction is a critical step in the folate cycle, providing the necessary tetrahydrofolate derivatives for the de novo synthesis of purines and thymidylate, which are required for DNA replication and repair (Source: NCBI Gene ID: 1719). Due to its vital role in cell division, DHFR is a major target for antifolate drugs, most notably methotrexate, which is used in the treatment of various malignancies and inflammatory diseases like rheumatoid arthritis (Source: StatPearls, Methotrexate). Rat liver DHFR has historically served as a model system for biochemical studies and drug screening due to its high homology with the human enzyme (Source: PMID: 6101413). Inhibition of this target leads to a thymineless death in rapidly dividing cells, making it effective against cancer but also leading to side effects in healthy tissues with high turnover rates (Source: PubMed, PMC3107505). Therapeutic use of DHFR inhibitors requires careful monitoring due to potential toxicities in rapidly dividing healthy tissues, such as the bone marrow and gastrointestinal mucosa (Source: FDA Label for Methotrexate).

Other names

DHFRDihydrofolate reductase5,6,7,8-tetrahydrofolate:NADP+ oxidoreductaseRat liver dihydrofolate reductaseDHF reductase

Competitive inhibition of the enzyme dihydrofolate reductase, which prevents the reduction of dihydrofolate to tetrahydrofolate, thereby depleting the pool of one-carbon donors required for DNA synthesis (Source: PubChem; PMID: 6101413).