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3.D.4 The Proton-translocating Cytochrome Oxidase (COX) Superfamily

Multi-subunit enzyme complexes of the COX superfamily are found in bacteria, archaea and eukarya. These enzyme complexes reduce O2 to water and concomitantly pump four protons across the membrane. Specific proposals, based on the three-dimensional structure of the enzyme complex, have been put forth to explain proton pumping (Branden et al., 2006; Brzezinski, 2004; Namslauer et al., 2007). They possess a unique bimetallic active site consisting of a heme and a closely associated copper atom where O2 is reduced. The COX superfamily is therefore also called the heme-copper superfamily. Mitochondrial COX is also referred to as Mitochondrial Respiratory Complex IV. There are two main enzyme types in the COX superfamily which have distinct substrate specificities: cytochrome c oxidases and quinol oxidases. The reduced substrates of the latter enzymes are ubiquinol or menaquinol rather than reduced cytochrome c. Both types of oxidases pump protons. COX pumps one H+ per electron transferred to O2 (Brzezinski and Johansson, 2010). X-ray structures of catalytic intermediates of cytochrome c oxidase have provided insight into its O2-activation and unidirectional proton-pump mechanisms (Shimada et al. 2020). Allosteric cooperativity stabilizes the favorable conformational state for conversion of redox energy into a transmembrane pmf (Capitanio et al. 2020). Letts et al. have presented structures of a supercomplex, which suggest how the interaction choreography may control overall functionality (Letts and Sazanov 2017; Letts et al. 2019). A mechanism for proton pumping, involving a specific role for the active site tyrosine, conserved in all CcOs, has been suggested (Blomberg 2020). The structure of cytochrome c oxidase Subunit 1 from Aedes aegypti has been proposed (Josyula and Mutheneni 2022). Relatively weak protein-protein and protein-lipid interactions exert effects on the enzymatic activities of transmembrane electron carriers  such as CcO (Kato et al. 2022).

Eukaryotic COX complexes contain 3 mitochondrially encoded subunits (I, II and III) and up to ten nuclearly-encoded subunits. All prokaryotic members of the COX superfamily contain homologues of subunit I and most also contain homologues of subunits II and III. The nuclearly-encoded subunits of the eukaryotic complexes are not found in bacteria. The cytochrome oxidases of Paracoccus denitrificans and Rhodobacter sphaeroides contain only 3 subunits, but they function as efficiently as the 13-subunit bovine enzyme complex. Some evidence suggests that the monomeric complex of the Rhodobacter enzyme is fully functional for electron flow and proton pumping in artificial membrane (Cvetkov and Prochaska, 2007). For Rhodobacter sphaeroides CytcO (cytochrome aa3), the E286 side chain of subunit I appears to be a branching point from which protons are shuttled either to the catalytic site for O2 reduction or to the acceptor site for pumped protons (Busenlehner et al., 2008). The 3-dimensional structures of the bovine and Paracoccus enzymes have been elucidated by x-ray crystallography. Liu et al. (2011) published crystallographic and online spectral evidence for the roles of conformational changes and conserved water in the Rhodobacter spheroides cytochrome oxidase proton pump.

The E. coli homologue, a ubiquinol oxidase, cytochrome bo, has homologues of subunits I, II and III. Subunits I of various COXs have at least twelve (but not more than 20) transmembrane spanners. Subunits I bind crucial prosthetic groups and probably provide the proton channel. The probable pathways of H+ translocation and the mechanism involved has been reviewed by Schultz and Chan (2001). Most phylogenetic analyses have been conducted with the sequences of subunits I and II. The cytochrome bd complex includes one of two homologous small subunit, either AppX or CydX.  Members of the CydX/AppX family of small proteins (30 - 50 aas with 1 TMS) interact with and activate the Cytochrome bd oxidase complex (TC# 3.D.4.3.2) (VanOrsdel et al. 2013).

In the chemolithotrophic, thermophilic, acidophilic crenarchaeota, Acidianus ambivalens, the essential residues comprising the H+ channel of the quinol oxidase (TC #3.D.4.9.1) are lacking, and the enzyme is believed to pump protons purely by chemical charge separation. In this six subunit enzyme complex, only the heme-bearing subunit I (DoxB) is demonstrably homologous to subunits in other quinol oxidases.

The bacterial respiratory nitric oxide reductase (NOR (3.D.4.10.1 and 2)) is a member of the super-family of O2-reducing, proton-pumping, heme-copper oxidases. Even though NO reduction is a highly exergonic reaction, NOR is not a proton pump and rather than taking up protons from the cytoplasmic (membrane potential negative) side of the membrane, like the heme-copper oxidases, NOR derives its substrate protons from the periplasmic (membrane potential positive) side of the membrane. In these complexes, Glu-122 in NorB contributes to defining the aperture of a non-electrogenic 'E-pathway' that serves to deliver protons from the periplasm to the buried active site in NOR (Flock et al., 2007).

Cytochrome c oxidase catalyses the one-electron oxidation of four molecules of cytochrome c and the four-electron reduction of O2 to water. Electron transfer through the enzyme is coupled to proton pumping across the membrane. Protons that are pumped as well as those that are used for O2 reduction are transferred though a specific intraprotein (D) pathway. Replacement of residue Asn139 by an Asp, at the beginning of the D pathway, results in blocking proton pumping without slowing uptake of substrate protons used for O2 reduction. Introduction of the acidic residue results in an increase of the apparent pK(a) of E286, an internal proton donor to the catalytic site, from 9.4 to ~11. Lepp et al (2008) investigated intramolecular electron and proton transfer in a mutant cytochrome c oxidase in which a neutral residue, Thr, was introduced at the 139 site. The mutation resulted in uncoupling of proton pumping from O2 reduction with a decrease in the apparent pK(a) of E286 from 9.4 to 7.6.

Human diseases associated with COX deficiency including encephalomyopathies, Leigh syndrome, hypertrophic cardiomyopathies, and fatal lactic acidosis are caused by mutations in COX subunits or assembly factors (Diaz, 2010).  A mutation in COA3 causes a phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature (Ostergaard et al. 2015). Structures of respiratory supercomplex I+III2 revealed functional and conformational crosstalk (Letts et al. 2019). ATP interactions with Cox13 in S. cerevisiae (CoxVIa in mammals) is inhibitory of catalytic activity (Zhou et al. 2021).


Heme-copper oxidases (HCuOs) terminate the respiratory chain in mitochondria and most bacteria. They are transmembrane proteins that catalyse the reduction of oxygen and use the liberated free energy to maintain a proton-motive force across the membrane. The HCuO superfamily has been divided into the oxygen-reducing A-, B- and C-type oxidases as well as the bacterial NO reductases (NOR), catalysing the reduction of NO in the denitrification process. Proton transfer to the catalytic site in the mitochondrial-like A family occurs through two well-defined pathways termed the D- and K-pathways. The B, C, and NOR families differ in the pathways as well as the mechanisms for proton transfer to the active site and across the membrane. Structural and functional investigations, focussing on proton transfer in the B, C and NOR families are discussed by Lee et al. (2012).

Most proton-pumping terminal respiratory oxygen reductases are members of the heme-copper oxidoreductase superfamily. Most of these enzymes use reduced cytochrome c as a source of electrons, but a group of these enzymes have evolved to directly oxidize membrane-bound quinols, usually menaquinol or ubiquinol. All of the quinol oxidases have an additional transmembrane helix (TM0) in subunit I that is not present in the related cytochrome c oxidases. Xu et al. 2020 reported the 3.6-Å-resolution X-ray structure of the cytochrome aa 3-600 menaquinol oxidase from Bacillus subtilis containing 1 equivalent of menaquinone. The structure shows that TM0 forms part of a cleft to accommodate the menaquinol-7 substrate. Crystals which had been soaked with the quinol-analog inhibitor HQNO (N-oxo-2-heptyl-4-hydroxyquinoline) or 3-iodo-HQNO reveal a single binding site where the inhibitor forms hydrogen bonds to aas shown previously by spectroscopic methods to interact with the semiquinone state of menaquinone, a catalytic intermediate.

The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea3(2+) and CuB(1+), suggesting that a peroxide-bound state (Fea33+-O--O--CuB2+) rather than an O2-bound state (Fea32+-O2) is the initial catalytic intermediate. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism was proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces (Shimada et al., 2020; 33516318). An essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe-O distance of the ferryl center could best be described as Fea34+-O2-, not as Fea34+-OH-. Shimada et al, 2020 found an interstitial water molecule that could trigger rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+-O--O--CuB2+ state, preventing its detection. The H-pathway structures of both intermediates indicate that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

Respiratory electron transport complexes are organized as individual entities or combined as large supercomplexes (SC). Gram-negative bacteria deploy a mitochondrial-like cytochrome (cyt) bc1 (Complex III, CIII2), and may have specific cbb3-type cyt c oxidases (Complex IV, CIV) instead of the canonical aa3-type CIV. Electron transfer between these complexes is mediated by soluble (c2) and membrane-anchored (cy) cyts. Steimle et al. 2021 reported the structure of an engineered bc1-cbb3 type SC (CIII2CIV, 5.2 Å resolution) and three conformers of native CIII2 (3.3 Å resolution). The SC is active in vivo and in vitro, contains all catalytic subunits and cofactors, and two extra TMSs attributed to cyt cy and the assembly factor CcoH. The cyt cy is integral to SC, its cyt domain is mobile and it conveys electrons to CIV differently than cyt c2. The successful production of a native-like functional SC and determination of its structure illustrate the characteristics of membrane-confined and membrane-external respiratory electron transport pathways in Gram-negative bacteria (Steimle et al. 2021).

The generalized transport reaction catalyzed by cytochrome c (Cyt c) oxidases is:

2Cyt c (red) + 1/2 O2 + 6H+ (in) → 2Cyt c (ox) + H2O + 4H+ (out).

The generalized transport reaction catalyzed by quinol oxidases is:

quinol + 1/2 O2 + 4H+ (in) → quinone + H2O + 4H+ (out)

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