Copper A of cytochrome c oxidase, a novel, long-embattled, biological electron-transfer site

This review traces the history of understanding of the Cu-A site in cytochrome c oxidase (COX) from the beginnings, when few believed that there was any significant Cu in COX, to the verification of three atoms Cu/monomer and to the final identification of the site as a dinuclear, Cys-bridged average valence Cu1.5+...Cu1.5+ structure through spectroscopy, recombinant DNA techniques, and crystallography. The critical steps forward in understanding the nature of the Cu-A site are recounted and the present state (as of the end of 1996) of our knowledge of the molecular and electronic structure is discussed in some detail. The contributions made through the years by the development of methodology and concepts for solving the enigma of Cu-A are emphasized and impediments, often rooted in contemporary preconceptions and attitudes rather than solid data, are mentioned, which discouraged the exploitation of early valuable clues. Finally, analogies in construction principles of polynuclear Cu-S and Fe-S proteins are pointed out.