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[Biochemistry](https://durgical.com/en/biochemistry/) · Enzyme

# Cytochrome c oxidase (complex IV)

Cytochrome c oxidase is the last complex of the chain: it hands the electrons to oxygen, makes water and pumps protons.

Updated 2026-11-01

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## Key facts

- 4 cytochrome c (Fe²⁺) + O₂ + 8 H⁺ (matrix) → 4 cytochrome c (Fe³⁺) + 2 H₂O + 4 H⁺ pumped.
- Metal centres in order: CuA → heme a → heme a₃–CuB, where O₂ binds and is reduced.
- It binds O₂ tightly and releases no toxic intermediates: that is why almost all the oxygen we breathe ends up as water.
- Cyanide, CO, azide and H₂S bind heme a₃ and block it.

**Also called**
Complex IV, Cytochrome aa₃

**EC number**
[7.1.1.9](https://www.enzyme-database.org/query.php?ec=7.1.1.9)

**Genes**
MT-CO1, MT-CO2, MT-CO3…; SURF1

**Structure (PDB)**
[3AG4](https://www.rcsb.org/structure/3AG4)

## Regulation

- Nitric oxide competes with O₂ and slows it physiologically.
- Subunit isoforms vary with tissue and oxygen level.

## Inhibitors and toxins

- Cyanide
- Carbon monoxide
- Azide
- Hydrogen sulfide (H₂S)

## Clinical notes

- Cyanide poisoning blocks it within minutes: severe lactic acidosis with highly oxygenated venous blood.
- CO, besides occupying hemoglobin, binds it and inhibits cellular respiration.
- Variants in SURF1 and other assembly genes cause complex IV deficiency with Leigh syndrome.
- In a muscle biopsy, fibres without cytochrome c oxidase activity (COX-negative) suggest mitochondrial disease.

## Pathways

- [Electron transport chain and oxidative phosphorylation](https://durgical.com/en/biochemistry/pathways/electron-transport-chain-and-oxidative-phosphorylation/)

## Related conditions

- [Cyanide poisoning](https://durgical.com/en/conditions/cyanide-poisoning/)
- [Carbon monoxide poisoning](https://durgical.com/en/conditions/carbon-monoxide-poisoning/)
- [Leigh syndrome](https://durgical.com/en/conditions/leigh-syndrome/)
- [Lactic acidosis](https://durgical.com/en/conditions/lactic-acidosis/)

## Related

- [Cytochrome c](https://durgical.com/en/biochemistry/enzymes/cytochrome-c/)
- [Complex III (cytochrome bc₁)](https://durgical.com/en/biochemistry/enzymes/complex-iii/)
- [ATP synthase (complex V)](https://durgical.com/en/biochemistry/enzymes/atp-synthase/)
- [Hemoglobin and 2,3-BPG](https://durgical.com/en/biochemistry/enzymes/hemoglobin-and-2-3-bpg/)
- [Chemiosmosis and the proton gradient](https://durgical.com/en/biochemistry/topics/chemiosmosis-and-the-proton-gradient/)

## Test yourself

Think of the answer, then tap the question to see it.

## Where does cyanide bind in the respiratory chain?

To the heme a₃ iron of cytochrome c oxidase (complex IV): the chain stops and O₂ is not used.

## Which metals does cytochrome c oxidase contain?

Copper (CuA and CuB) and iron in hemes a and a₃.

## How many electrons does complex IV need to reduce one O₂ molecule?

Four, received from four cytochrome c molecules; two water molecules are formed.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [MT-CO1: Cytochrome c oxidase subunit 1 (human)](https://www.uniprot.org/uniprotkb/P00395/entry) (UniProt, 2026); [3AG4: Bovine Heart Cytochrome c Oxidase in the Cyanide Ion-bound Fully Reduced State at 100 K](https://www.rcsb.org/structure/3AG4) (RCSB Protein Data Bank, 2026); [SURF1 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/surf1/) (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/biochemistry/enzymes/cytochrome-c-oxidase/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/cytochrome-c-oxidase/