Cytochrome c oxidase [E.C. 1.9.3.1], the terminal oxidase of the human respiratory chain, catalyses the four electron reduction of dioxygen to water with the concomitant pumping of four protons across the inner mitochondrial membrane. Heme a, found at the heme a - CuB enzyme active site, is unique to terminal oxidases. Using a maquette scaffold we are testing the chemical and biophysical consequences of substitution of the more widely utilized heme b by analogues of heme a. One functional consequence of the use of heme a is in elevating the midpoint reduction potential of the iron. Heme a and heme a3 have two of the highest Fe(III)/Fe(II) midpoint potentials of any heme proteins, Em values of +230 and +275 mV vs. SHE.