Cytochrome c oxidase

File:ETC.PNG

Electron transport chain. Complex IV is at the right.

The crystal structure of bovine cytochrome c oxidase in a phospholipid bilayer. The intermembrane space lies to top of the image. Adapted from PDB: 1OCC​ (It is a homo dimer in this structure)

The enzyme cytochrome c oxidase or Complex IV (PDB: 2OCC​, EC 1.9.3.1) is a large transmembrane protein complex found in bacteria and the mitochondrion.

Function

It is the last protein in the electron transport chain. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. In the process, it translocates four protons, helping to establish a chemiosmotic potential that the ATP synthase then uses to synthesize ATP.

Reaction

Summary reaction:

4 Fe²⁺-cytochrome c + 8 H⁺_in + O₂ → 4 Fe³⁺-cytochrome c + 2 H₂O + 4 H⁺_out

Structure

The complex is a large lipoprotein composed of several metal prosthetic sites and 13 protein subunits in mammals. In mammals, ten subunits are nuclear in origin and three are synthesized mitochondrially. The complex contains two hemes, the a and a₃ hemes, and two copper centers, the Cu_A and Cu_B centers. In fact, the heme a₃ and Cu_B are a binuclear center that is the site of oxygen reduction. The mechanism of action of this large complex is still an active research topic.

Crystallographic studies of cytochrome c oxidase show an unusual post translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). This cross-linked tyrosine has been proposed to serve as a hydrogen donor, providing a proton and an electron to cleave the dioxygen bond. Other redox reactive amino acids used for catalysis include glycine, cysteine, tyrosine, tryptophan and a similarly modified tyrosine (cross-linked to cysteine).

Inhibition

Cyanide, sulfide, azide and carbon monoxide all bind to Cytochrome c Oxidase, thus inhibiting the protein from functioning which results in chemical suffocation of cells.

Genetic Defects and Disorders

Defects involving genetic mutations altering cytochrome c oxidase (COX) functionality or structure can rsult in severe, often fatal metabolic disorders. Such disorders usually manifest in early childhood and predominantly affect tissues with high energetic demands (brain, heart, muscle). Among the many classified mitochondrial diseases, those involving dysfunctional COX assembly are thought to be the most severe

The vast majority of COX disorders are linked to mutations in nuclearly encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality and are involved in sevral essential processess including transcription and translation of mitochondrial encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.

Currently, mutations have been identified in six COX assembly factors: SURF1, SCO1, SCO2, COX10, COX15, and LRPPRC. Mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. Each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. Disorders involving dysfunctional COX assembly via gene mutations include Leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness.

Additional images

• ETC
  ETC
• 
  Complex IV

External links

• The Cytochrome Oxidase home page at Rice University
• Interactive Molecular model of cytochrome c oxidase (Requires MDL Chime)
• UMich Orientation of Proteins in Membranes families/superfamily-4
• Cytochrome-c+Oxidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)