## Complex IV and Cyanide Toxicity ### Mechanism of Cyanide Poisoning **Key Point:** Cyanide binds irreversibly to the ferric iron (Fe³⁺) in cytochrome a₃, the terminal electron acceptor of Complex IV (cytochrome c oxidase), preventing the transfer of electrons to oxygen. ### Why Complex IV? Complex IV catalyzes the final step of the electron transport chain: $$2 \text{Cytochrome } c^{2+} + \frac{1}{2}O_2 + 2H^+ \rightarrow 2 \text{Cytochrome } c^{3+} + H_2O$$ - **Cyanide binding site:** Cytochrome a₃ (heme a₃-Cu binuclear center) - **Result:** Electrons cannot be transferred to O₂, the ETC halts, and ATP synthesis ceases - **Cellular consequence:** Rapid aerobic respiration failure; tissues with high energy demand (brain, heart) are affected first ### Why Not Other Complexes? | Complex | Substrate | Cyanide Sensitivity | | --- | --- | --- | | Complex I | NADH | Not affected by cyanide | | Complex II | Succinate | Not affected by cyanide | | Complex III | Reduced ubiquinol | Not affected by cyanide | | Complex IV | Cytochrome c | **Highly sensitive** — terminal oxidase | **High-Yield:** Cyanide is a classic example of a non-competitive, irreversible inhibitor that specifically targets the final step of aerobic respiration. **Clinical Pearl:** Cyanide poisoning causes histotoxic hypoxia — tissues cannot use oxygen even though it is available in the blood.
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