Fast Motions in 5 Alpha Reductase and Its Impact on Enzyme Kinetics

The study examines the impact of the L224P mutation on the enzyme 5 alpha-reductase (SRD5A2) and its catalytic efficiency. The mutation disrupts the enzyme's ability to dynamically modulate its electric field, leading to increased activation barriers for hydride and proton transfer steps, and a significant reduction in catalytic efficiency. In the wild-type enzyme, specific residues form a tightly coupled network crucial for transition-state stabilization, which is disrupted by the mutation. This results in structural changes and a poorly defined transition-state ensemble. The research highlights the importance of dynamic electrostatic and mechanical coupling in enzyme function and provides insights into the molecular mechanisms underlying 5α-reductase deficiency, relevant for conditions like androgenetic alopecia.