How do metal ions modulate the rate‐determining electron transfer step in Cytochrome P450 reactions?

Cytochrome P450 (CYP450) enzymes have important
functions related to human health and their reaction rate is dependent
on the first electron transfer from the reduction partner. Interestingly,
experimental work showed that this step is highly affected by the
addition of metal ions. To understand the effect of external
perturbations on the CYP450 first reduction step, we performed a
computational study with model complexes in the presence of metal
and organic ions, solvent molecules and an electric field effect. The
work shows that these medium-range interactions affect the driving
force as well as electron transfer rates dramatically. Based on the
location, distance and direction of the ions/electric field the reaction
rate values are improved or impaired for catalysis. Calculations on a
large crystal structure with alkali metal ions bound implicated inhibition
patterns of the ions; therefore, we predict that active forms of the
natural CYP450 isozymes will not have more than one alkali metal
ions bound in the second-coordination sphere. As such the work
gives insight into the activity of CYP450 enzymes and the effect of
ions and electric field perturbations on its activity.