Oxidative Phosphorylation and Electron Transport Chain

Oxidative Phosphorylation

• Oxidative phosphorylation (OXPHOS) is a metabolic pathway in mitochondria.
• It uses energy released from nutrient oxidation to create ATP.
• All aerobic organisms use this pathway.
• In 1906, Arthur Harden's work showed phosphate's role in cellular fermentation.
• Later, it was established that ATP is crucial in energy transfer, as proposed by Fritz Albert Lipmann in 1941.
• Morris Friedkin and Albert L. Lehninger, in 1949, linked the citric acid cycle to ATP synthesis via NADH.
• This pathway is highly efficient, compared to alternative processes like anaerobic glycolysis.

Electron Transport Chain (ETC)

• The ETC uses NADH and FADH₂ produced in glycolysis, beta-oxidation and other catabolic processes.
• These processes are oxidized, releasing energy stored as ATP.
• Chemiosmotic phosphorylation is the mechanism by which ATP is formed via the ETC.
• The ETC is located in the inner mitochondrial membrane of eukaryotes and the plasma membrane of prokaryotes.
• Several protein complexes of electron carriers are involved, acting like a proton pump.
• The pumping of protons (H+) creates a proton gradient across the membrane.

NADH-coenzyme ubiquinone oxidoreductase (Complex I)

• An integral protein that transfers hydride ions from NADH to ubiquinone(Q10).
• The reaction involves NADH oxidation and ubiquinone reduction.
• Electrons enter complex I via FMN and then pass through iron-sulfur clusters.
• Four protons are pumped from the matrix to the intermembrane space during electron transfer.

Succinate-Q oxidoreductase (Complex II)

• A peripheral protein receiving electrons from succinate (TCA cycle intermediate).
• It oxidizes succinate to fumarate, forming FADH₂ in the process.
• Electrons are then transferred to ubiquinone.
• Unlike complex I, it does not transport protons across the membrane.

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-Q oxidoreductase)

• Another entry point for the electron transport chain.
• It accepts electrons from electron-transferring flavoprotein, then transfers them to ubiquinone.
• This enzyme has a flavin and a [4Fe-4S] cluster.
• It is associated with the membrane surface, and doesn't cross the bilayer.

Q-cytochrome c oxidoreductase (Complex III)

• Receives electrons from ubiquinol.
• Oxidizes ubiquinol and reduces cytochrome c.
• Cytochrome c usually carries only one electron, unlike ubiquinone.
• Protons are pumped during this process.

Cytochrome c oxidase (Complex IV)

• Receives electrons from cytochrome c and transfers them to oxygen.
• Oxygen is reduced to water.
• Protons are also pumped during this step, contributing to the proton gradient.

ATP synthase (Complex V)

• Uses the proton gradient (chemiosmotic phosphorylation) for ATP synthesis from ADP and inorganic phosphate.
• The enzyme consists of F0 and F1 subunits.
• F0 forms a proton channel through the membrane.
• F1 is the catalytic portion where ATP is generated.

Coupled Reactions

• Exergonic reactions can drive endergonic (requires energy) ones.
• The hydrolysis of ATP to ADP and Pi is an exergonic process, which can be coupled with other reactions.
• The binding-change mechanism in ATP synthase involves a conformational change cycle.
• Group transfer reactions are very common in living cells, involve acyl, glycosyl, and phosphoryl groups, and facilitate conversions involving nucleophiles.

Inhibitors

• Various compounds inhibit oxidative phosphorylation at different stages.
• Cyanide and carbon monoxide bind tightly to complex IV, inhibiting oxygen reduction.
• Oligomycin blocks proton flow through ATP synthase.
• Dinitrophenol (DNP) uncouples the proton gradient from ATP synthesis.

Other Topics

• Alternative oxidases and reductases exist in different organisms, varying from mammals.
• Prokaryotes use different electron donors/acceptors and have various electron chain pathways.
• The midpoint potential of a chemical reflects its energy release during oxidation or reduction.
• Various enzymes play various roles and their roles and function in metabolism.