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From antibiotics to anticancer drugs: How did dihydrofolate reductase become a therapeutic breakthrough?
Dihydrofolate reductase (DHFR) is an enzyme that is essential to life. It not only plays a central role in nucleic acid synthesis in cells, but also becomes an important target in many therapeutic approaches. As scientists conduct in-depth research, the versatility of this enzyme is gradually being discovered, leading us to a new understanding of cancer and infectious diseases.
Dihydrofolate reductase catalyzes the conversion of dihydrofolate into tetrahydrofolate, a process that is essential for cell growth and reproduction.
Structure and function of DHFR
In humans, the DHFR gene is located in the q14.1 region of chromosome 5. The structure of this enzyme consists of eight β-sheets, which are linked together by four α-helices to form a complex active site. The main function of DHFR is to convert dihydrofolate into tetrahydrofolate, a compound that plays an important role in the synthesis of purine, thymic acid and certain amino acids. Having a properly functioning DHFR gene is essential for maintaining THF levels in the body.
Cells with mutant or missing DHFR require exogenous supplementation of glycine and other precursors for survival, highlighting its importance in cell growth.
Catalytic mechanism of DHFR
The catalytic process of DHFR involves the transfer of electrons, which requires NADPH as an electron donor. A series of reaction steps catalyzed by an enzyme results in the reduction of dihydrofolate to tetrahydrofolate. The study showed that the pH dependence of this process is crucial for efficient catalysis because changes in pH affect the electrical environment of the active sites.
Specific amino acid residues, especially Asp27, play an indispensable role in the catalytic process and are crucial for the protonation of the substrate and its stability.
Clinical significance and therapeutic application
Mutations in DHFR can cause dihydrofolate reductase deficiency, a rare autologous recessive genetic disease that can cause megaloblastic anemia and epilepsy, among other conditions. In this regard, supplementing with hydrogenated folic acid can effectively improve the patient's health status. In addition, DHFR is an important drug target and its inhibitors are widely used in the treatment of cancer and infection. For example, methotrexate, an anticancer drug, limits the proliferation of cancer cells by inhibiting DHFR.
Further research on DHFR may lead to the development of new strategies for treating cancer, particularly when targeting drug-resistance mutations.
Conclusion
As our understanding of DHFR's functions and its biomedical applications continues to deepen, we are witnessing a transformation in the therapeutic landscape for this enzyme. Future studies may reveal more about the potential applications of DHFR, changing our expectations about cancer and its treatment. In this context, can new therapeutic strategies effectively combat the challenges of cancer and other diseases?
