Substrate entasis and electronic coupling elements in electron transfer from Fe^II in a multicopper ferroxidase

Outersphere electron transfer in multicopper oxidases occurs at the type 1, blue Cu^II. One class of MCO proteins exhibits a specificity in this reaction towards Fe^II. In work carried out in collaboration with the Solomon lab over the past 7 years, we have delineated the structural motifs that support this ferroxidase specificity and have quantified the contributions that each makes to this outersphere electron transfer reaction from Fe^II to the type 1 Cu^II. Two features of this electron transfer catalysis stand out. First, the protein provides a binding site for Fe^II that actually favors Fe^III; this coordination sphere places the bound Fe^II in a state of "entasis" that can be relieved by loss of an electron. In short, the E^{{ring operator}} of the bound Fe^II is lowered relative to that of aqueous ferrous iron making electron transfer thermodynamically favorable. Second, carboxylates within this coordination sphere provide an electronic coupling pathway for the electron transfer via their H-bond network with type 1 Cu histidine ligands thus making electron transfer kinetically efficient. This brief report breaks down these contributions to ferroxidase specificity in terms of the semi-classical Marcus equation describing outersphere electron transfer.