DHFRs

Dihydrofolate reductase, often abbreviated as DHFR, is an essential enzyme found in nearly all organisms, from bacteria to humans. Its primary function is to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). This reaction is a critical step in the folate metabolic pathway, which is indispensable for the synthesis of purines, pyrimidines, and certain amino acids. These biomolecules are the building blocks of DNA, RNA, and proteins, making THF a vital cofactor for cell growth, division, and repair.

The importance of DHFR in cellular processes has made it a significant target for therapeutic intervention. In many bacteria, DHFR is essential for survival, and its inhibition can be lethal. This has led to the development of antibacterial drugs like trimethoprim, which selectively target bacterial DHFR over its human counterpart. Similarly, in mammals, DHFR is crucial for cell proliferation. Cancer cells, with their rapid division rates, are particularly dependent on folate metabolism. This vulnerability is exploited by anticancer drugs such as methotrexate, which inhibits human DHFR, thereby starving rapidly dividing cancer cells of the necessary nucleotides for DNA replication. Methotrexate is also used in the treatment of autoimmune diseases like rheumatoid arthritis due to its immunosuppressive effects, which stem from its inhibition of immune cell proliferation. The selective toxicity of these drugs highlights the therapeutic significance of targeting DHFR.