New perspectives on proton pumping in cellular respiration

Complexes I, III (cytochrome bc₁), and IV (cytochrome c oxidase) of the respiratory chain employ fundamentally different mechanisms for redox-coupled proton pumping. In the Q-cycle of cytochrome bc₁, charge separation is the result of electron transfer through the membrane, whereas the protons are shuttled across the membrane by a neutral quinol carrier, QH². In this Q cycle, the mobile quinols get protonated on the N-side of the membrane and deprotonated on the P-side. Cytochrome bc₁ thus transduces chemical energy into an electrochemical gradient through a redox loop, but is not a true proton pump in the sense of moving protonic charge through the protein directly against a pmf. By contrast, cytochrome c oxidase, the terminal enzyme of the respiratory chain, operates as a true proton pump. In cytochrome c oxidase (CcO), the pathways of chemical electron and proton fluxes intersect in the binuclear center, and the pathway of pumped protons passes close to the BNC as well. This spatial proximity of proton and electron pathways establishes the tight electrostatic interactions one might expect for a redox-coupled proton pump.