Mutational 'hot-spots' in mammalian, bacterial and protozoal dihydrofolate reductases associated with antifolate resistance: sequence and structural comparison.

摘要: Human dihydrofolate reductase (DHFR) is a primary target for antifolate drugs in cancer treatment, while DHFRs from Plasmodium falciparum, vivax and various bacterial species are targets the treatment of malaria infections. Mutations each these can result resistance towards clinically relevant antifolates. We review structural functional impact active-site mutations with respect to enzyme activity mammals, protozoa bacteria. The high homology between results number cross-species, ‘hot-spots’ broad-based resistance. In addition, we identify that confer species-specific resistance, or antifolate-specific This comparative binding diverse provides new insights into relationship design development mutational It also presents avenues designing antifolate-resistant mammalian as chemoprotective agents.