Coupled motions direct electrons along human microsomal P450 Chains.

Abstract

Author SummaryEnzymes are proteins that catalyze a large array of chemical reactions, often in partnership with other enzymes. We understand in detail the chemical mechanisms of many of these reactions; however, the importance of the physical movements of enzymes during catalysis (or protein dynamics) is, increasingly, becoming apparent. In this study, we have placed fluorescent markers on an enzyme called cytochrome P450 reductase (CPR) to probe the dynamic changes in the physical conformation of the protein as the reaction chemistry proceeds. CPR catalyses the transfer of electrons from a small molecule donor (called NADPH), ultimately passing them to their partner enzymes called CYPs. We were able to correlate specific conformational changes with distinct chemical steps in CPR. We found that the chemical transformation itself induces the enzyme to adopt conformations that are required for its efficient interaction with CYPs. These findings have allowed us to develop a model of CPR activity in which electron transfer along the pathway from NADPH through CPR to CYP is tightly integrated with physical conformational control of the enzyme.