Hartmut Michel

Proton Pumping by Cytochrome c oxidases


Abstract

In biology, membranes are barriers for the transport of ions and polar substances. They are even electric insulators. These properties are exploited by the living cells for signal propagation in neurons and for energy transduction. For energy transduction nature uses mitochondrial and bacterial membranes by building up electric voltages (potentials) and ion gradients. Most of the energy used by the human body is made available by the respiratory chain in mitochondria in the form of the universal biological energy carrier adenosine-5’-triphosphate (“ATP”). The mitochondrial respiratory chain contains four electron transferring complexes, the last one in the chain being cytochrome c oxidase. This enzyme transfers electrons from cytochrome c onto oxygen and consumes protons to form water as a product. This reaction creates an electric voltage and a pH difference across the membrane, because cytochrome c delivers its electrons from the outer surface of the membrane whereas the protons originate form the inner surface of the mitochondria or bacteria. In addition, the enzyme translocates (“pumps”) four protons from the inner to the outer surface per reaction cycle enhancing the both electric voltage and pH difference. This so-called “electrochemical proton gradient” drives protons back via the ATP-synthase leading to the synthesis of the ATP from adenosine-5’-diphosphate (“ADP”) and inorganic phosphate. The reaction catalysed by the cytochrome c oxidase is understood insufficiently and the subject of controversial discussions. The active site of the enzyme, where oxygen is reduced and water is formed, consists of a heme-iron and a copper atom. It is located in the centre of the membrane. 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. However, it is e.g. unclear which chemical entity is bound in the active site when the enzyme is in its oxidized form. Evidence will be presented that the oxidized for is a peroxide dianion, the classical cycle may have to be revised completely.


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