Hartmut Michel (2013) - Structure and Mechanism of Otto Warburg's Respiratory Enzyme, the Cytochrome c Oxidase

Hartmut Michel (2013)

Structure and Mechanism of Otto Warburg's Respiratory Enzyme, the Cytochrome c Oxidase

Hartmut Michel (2013)

Structure and Mechanism of Otto Warburg's Respiratory Enzyme, the Cytochrome c Oxidase

Abstract

The oxygen, you breathe in, is converted to water by cytochrome c oxidase, using electrons provided by cytochrome c and protons from the aqueous milieu of the body. This fundamental enzyme has been discovered already in 1886, and studied extensively by Otto Warburg, who worked in Berlin, Germany, and received the Nobel Prize “for his discovery of the nature and mode of action of the respiratory enzyme” in 1931, and by David Keilin in Cambridge, England. Nevertheless, hundreds of scientists still try to work out its function and mechanism of action.
Otto Warburg did not know: Cytochrome c oxidase is located in the inner membranes of mitochondria and of many prokaryotes. The electrons are provided from the outer side of the membrane, whereas the protons originate from the inner side. This separation of the charged substrates leads to the generation, upon water formation, of an electric voltage across the membranes. This electric voltage is enhanced by the additional “pumping” of protons across the mitochondrial or bacterial membranes. The electric voltage (“membrane potential”) and to a minor extent the transmembrane pH gradient drive protons back via the ATP-synthase leading to the synthesis of the universal biological energy carrier adenosine-5’-triphosphate (“ATP”) from adenosine-5’-diphosphate (“ADP”) and inorganic phosphate.
Despite the fact that we have published the first atomic structure of a cytochrome c oxidase already in 1995 the reaction catalysed by the cytochrome c oxidase is understood insufficiently and the subject of controversial discussions. There are proton transfer pathways in the enzyme which allow and control the access of protons, required for water formation, to the active site. One of these pathways is also used for protons to be pumped. More recently we have determined the structure of a cbb3 type cytochrome c oxidase. These enzymes are essential for biological nitrogen fixation, and for the pathogenicity of some bacteria like Helicobacter and Campylobacter. The cbb3 type cytochrome c oxidases show a very high affinity for oxygen and possess only one proton transfer pathway. Nevertheless they pump protons. For all cytochrome c oxidase it is unclear which chemical entity is bound to the active site when the enzyme is in its oxidized form. Evidence will be presented that the oxidized form contains a peroxide dianion, the classical reaction cycle of the enzyme may have to be revised completely.

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