Cytochrome c oxidase (EC 1.9.3.1) [1] is an oligomeric integral membrane protein complexes that catalyze the terminal step in the respiratory chain: they transfer electrons from cytochrome c or a quinol to oxygen. Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes). The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit 1 (CO I)) is found in all heme-copper respiratory oxidases. The presence of a bimetallic center, formed by a high-spin heme (heme a3) and copper B, as well as a low-spin heme (heme a), both ligated to six conserved histidine residues near the outer side of four transmembrane spans within CO I is common to all family members [2,3,4].

In contrary to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in heme and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according a variety of environmental growth conditions [1].

The crystal structure of the whole enzyme complexe have been solved [5]. Subunit I contains 12 transmembrane helical segments and binds heme a and heme a3-copper B binuclear centre where molecular oxygen is reduced to water. (see <PDB:1OCZ; A>).

Recently also a component of an anaerobic respiratory chain has been found to contain the copper B binding signature of this family: nitric oxide reductase (NOR) exists in denitrifying species of Archae and Eubacteria.

Enzymes that belong to this family are:

• Mitochondrial-type cytochrome c oxidase (EC 1.9.3.1) which uses cytochrome c as electron donor. The electrons are transferred via copper A (Cu(A)) and heme a to the bimetallic center of CO I that is formed by a penta- coordinated heme a and copper B (Cu(B)). Subunit 1 contains 12 transmembrane regions. Cu(B) is said to be ligated to three of the conserved histidine residues within the transmembrane segments 6 and 7.
• Quinol oxidase from prokaryotes that transfers electrons from a quinol to the binuclear center of polypeptide I. This category of enzymes includes Escherichia coli cytochrome O terminal oxidase complex which is a component of the aerobic respiratory chain that predominates when cells are grown at high aeration.
• FixN, the catalytic subunit of a cytochrome c oxidase expressed in nitrogen-fixing bacteroids living in root nodules. The high affinity for oxygen allows oxidative phosphorylation under low oxygen concentrations. A similar enzyme has been found in other purple bacteria.
• Nitric oxide reductase (EC 1.7.99.7) from Pseudomonas stutzeri. NOR reduces nitrate to dinitrogen. It is a heterodimer of norC and the catalytic subunit norB. The latter contains the 6 invariant histidine residues and 12 transmembrane segments [6].

As a signature pattern we used the copper-binding region. We also developed a profile that cover the whole subunit I.