page_title: Dihydrofolate reductase
section_title: Conformational changes of DHFR
hierarchical_section_title: Dihydrofolate reductase / Mechanism / Conformational changes of DHFR
caption_attribution_description: English: Structure difference of substrate binding in E. coli and R67 DHFR
context_page_description: Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene.
  It is found in the q11→q22 region of chromosome 5. Bacterial species possess distinct DHFR enzymes, but mammalian DHFRs are highly similar.
context_section_description: The catalytic cycle of the reaction catalyzed by DHFR incorporates five important intermediate: holoenzyme (E:NADPH), Michaelis complex (E:NADPH:DHF), ternary product complex (E:NADP⁺:THF), tetrahydrofolate binary complex (E:THF), and THF‚NADPH complex (E:NADPH:THF). The product (THF) dissociation step from E:NADPH:THF to E:NADPH is the rate determining step during steady-state turnover.
  Conformational changes are critical in DHFR's catalytic mechanism. The Met20 loop of DHFR is able to open, close or occlude the active site. Correspondingly, three different conformations classified as the opened, closed and occluded states are assigned to Met20. In addition, an extra distorted conformation of Met20 was defined due to its indistinct characterization results. The Met20 loop is observed in its occluded conformation in the three product ligating intermediates, where the nicotinamide ring is occluded from the active site. This conformational feature accounts for the fact that the substitution of NADP⁺ by NADPH is prior to product dissociation. Thus, the next round of reaction can occur upon the binding of substrate.
caption: Structure difference of substrate binding in E. coli and R67 DHFR
exif: {}