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Cytochrome c oxidase

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Cytochrome c oxidase
The crystal structure of bovine cytochromecoxidase in a phospholipid bilayer. The intermembrane space lies to top of the image. Adapted fromPDB:1OCC​ (It is a homodimer in this structure)
Identifiers
EC no.1.9.3.1
CAS no.9001-16-5
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Cytochrome c oxidase
Subunit I and II of Complex IV excluding all other subunits,PDB:2EIK​
Identifiers
SymbolCytochrome c oxidase
OPM superfamily4
OPM protein2dyr
Membranome257

Theenzymecytochrome c oxidaseorComplex IV(wasEC1.9.3.1,now reclassified as a translocaseEC 7.1.1.9) is a largetransmembrane proteincomplex found inbacteria,archaea,and themitochondriaofeukaryotes.[1]

It is the last enzyme in therespiratoryelectron transport chainofcellslocated in themembrane.It receives an electron from each of fourcytochrome cmolecules and transfers them to oneoxygenmolecule and fourprotons,producing two molecules of water. In addition to binding the four protons from the inner aqueous phase, it transports another four protons across the membrane, increasing the transmembrane difference of protonelectrochemical potential,which theATP synthasethen uses to synthesizeATP.

Structure

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The complex

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The complex is a largeintegral membrane proteincomposed of severalmetal prosthetic sitesand 14[2]protein subunits in mammals. In mammals, eleven subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains twohemes,acytochrome aandcytochrome a3,and two copper centers, the CuAand CuBcenters.[3]In fact, the cytochrome a3and CuBform a binuclear center that is the site of oxygen reduction.Cytochrome c,which is reduced by the preceding component of the respiratory chain (cytochrome bc1 complex, Complex III), docks near the CuAbinuclear center and passes an electron to it, being oxidized back to cytochrome c containing Fe3+.The reduced CuAbinuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a3>-CuBbinuclear center. The two metal ions in this binuclear center are 4.5 Å apart and coordinate ahydroxide ionin the fully oxidized state.

Crystallographic studiesof cytochrome c oxidase show an unusual post-translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). It plays a vital role in enabling the cytochrome a3- CuBbinuclear center to accept four electrons in reducing molecular oxygen and four protons to water. The mechanism of reduction was formerly thought to involve aperoxideintermediate, which was believed to lead tosuperoxideproduction. However, the currently accepted mechanism involves a rapid four-electron reduction involving immediate oxygen–oxygen bond cleavage, avoiding any intermediate likely to form superoxide.[4]: 865–866 

The conserved subunits

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Table of conserved subunits of cytochrome c oxidase complex[5][6]
No. Subunit name Humanprotein Protein description fromUniProt Pfamfamily with Human protein
1 Cox1 COX1_HUMAN Cytochrome c oxidase subunit 1 PfamPF00115
2 Cox2 COX2_HUMAN Cytochrome c oxidase subunit 2 PfamPF02790,PfamPF00116
3 Cox3 COX3_HUMAN Cytochrome c oxidase subunit 3 PfamPF00510
4 Cox4i1 COX41_HUMAN Cytochrome c oxidase subunit 4 isoform 1, mitochondrial PfamPF02936
5 Cox4a2 COX42_HUMAN Cytochrome c oxidase subunit 4 isoform 2, mitochondrial PfamPF02936
6 Cox5a COX5A_HUMAN Cytochrome c oxidase subunit 5A, mitochondrial PfamPF02284
7 Cox5b COX5B_HUMAN Cytochrome c oxidase subunit 5B, mitochondrial PfamPF01215
8 Cox6a1 CX6A1_HUMAN Cytochrome c oxidase subunit 6A1, mitochondrial PfamPF02046
9 Cox6a2 CX6A2_HUMAN Cytochrome c oxidase subunit 6A2, mitochondrial PfamPF02046
10 Cox6b1 CX6B1_HUMAN Cytochrome c oxidase subunit 6B1 PfamPF02297
11 Cox6b2 CX6B2_HUMAN Cytochrome c oxidase subunit 6B2 PfamPF02297
12 Cox6c COX6C_HUMAN Cytochrome c oxidase subunit 6C PfamPF02937
13 Cox7a1 CX7A1_HUMAN Cytochrome c oxidase subunit 7A1, mitochondrial PfamPF02238
14 Cox7a2 CX7A2_HUMAN Cytochrome c oxidase subunit 7A2, mitochondrial PfamPF02238
15 Cox7a3 COX7S_HUMAN Putative cytochrome c oxidase subunit 7A3, mitochondrial PfamPF02238
16 Cox7b COX7B_HUMAN Cytochrome c oxidase subunit 7B, mitochondrial PfamPF05392
17 Cox7c COX7C_HUMAN Cytochrome c oxidase subunit 7C, mitochondrial PfamPF02935
18 Cox7r COX7R_HUMAN Cytochrome c oxidase subunit 7A-related protein, mitochondrial PfamPF02238
19 Cox8a COX8A_HUMAN Cytochrome c oxidase subunit 8A, mitochondrial P PfamPF02285
20 Cox8c COX8C_HUMAN Cytochrome c oxidase subunit 8C, mitochondrial PfamPF02285
Assembly subunits[7][8][9]
1 Coa1 COA1_HUMAN Cytochrome c oxidase assembly factor 1 homolog PfamPF08695
2 Coa3 COA3_HUMAN Cytochrome c oxidase assembly factor 3 homolog, mitochondrial PfamPF09813
3 Coa4 COA4_HUMAN Cytochrome c oxidase assembly factor 4 homolog, mitochondrial PfamPF06747
4 Coa5 COA5_HUMAN Cytochrome c oxidase assembly factor 5 PfamPF10203
5 Coa6 COA6_HUMAN Cytochrome c oxidase assembly factor 6 homolog PfamPF02297
6 Coa7 COA7_HUMAN Cytochrome c oxidase assembly factor 7, PfamPF08238
7 Cox11 COX11_HUMAN Cytochrome c oxidase assembly protein COX11 mitochondrial PfamPF04442
8 Cox14 COX14_HUMAN Cytochrome c oxidase assembly protein PfamPF14880
9 Cox15 COX15_HUMAN Cytochrome c oxidase assembly protein COX15 homolog PfamPF02628
10 Cox16 COX16_HUMAN Cytochrome c oxidase assembly protein COX16 homolog mitochondrial PfamPF14138
11 Cox17 COX17_HUMAN Cytochrome c oxidase copper chaperone PfamPF05051
12 Cox18[10] COX18_HUMAN Mitochondrial inner membrane protein (Cytochrome c oxidase assembly protein 18) PfamPF02096
13 Cox19 COX19_HUMAN Cytochrome c oxidase assembly protein PfamPF06747
14 Cox20 COX20_HUMAN Cytochrome c oxidase protein 20 homolog PfamPF12597

Assembly

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COX assembly inyeastare a complex process that is not entirely understood due to the rapid and irreversible aggregation of hydrophobic subunits that form the holoenzyme complex, as well as aggregation of mutant subunits with exposed hydrophobic patches.[11]COX subunits are encoded in both the nuclear and mitochondrial genomes. The three subunits that form the COX catalytic core are encoded in the mitochondrial genome. Over 30 different nuclear-encoded chaperone proteins are required for COX assembly.[12]

Cofactors, including hemes, are inserted into subunits I & II. The two heme molecules reside in subunit I, helping with transport to subunit II where two copper molecules aid with the continued transfer of electrons.[13]Subunits I and IV initiate assembly. Different subunits may associate to form sub-complex intermediates that later bind to other subunits to form the COX complex.[11]In post-assembly modifications, COX will form a homodimer. This is required for activity. Dimers are connected by acardiolipinmolecule,[11][14][15]which has been found to play a key role in stabilization of the holoenzyme complex. The dissociation of subunits VIIa and III in conjunction with the removal of cardiolipin results in total loss of enzyme activity.[15]Subunits encoded in the nuclear genome are known to play a role in enzyme dimerization and stability. Mutations to these subunits eliminate COX function.[11]

Assembly is known to occur in at least three distinct rate-determining steps. The products of these steps have been found, though specific subunit compositions have not been determined.[11]

Synthesis and assembly of COX subunits I, II, and III are facilitated by translational activators, which interact with the 5’ untranslated regions of mitochondrial mRNA transcripts. Translational activators are encoded in the nucleus. They can operate through either direct or indirect interaction with other components of translation machinery, but exact molecular mechanisms are unclear due to difficulties associated with synthesizing translation machinery in-vitro.[16][17]Though the interactions between subunits I, II, and III encoded within the mitochondrial genome make a lesser contribution to enzyme stability than interactions between bigenomic subunits, these subunits are more conserved, indicating potential unexplored roles for enzyme activity.[18]

Biochemistry

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The overall reaction is

4 Fe2+– cytochromec+ 4 H++ O2→ 4 Fe3+– cytochromec+ 2 H2O ΔGo' = - 218 kJ/mol,Eo' = +565 mV

Two electrons are passed from two cytochrome c's, through the CuAand cytochrome a sites to the cytochrome a3–CuBbinuclear center, reducing the metals to the Fe2+form and Cu+.The hydroxide ligand is protonated and lost as water, creating a void between the metals that is filled by O2.The oxygen is rapidly reduced, with two electrons coming from the Fe2+-cytochrome a3,which is converted to the ferryl oxo form (Fe4+=O). The oxygen atom close to CuBpicks up one electron from Cu+,and a second electron and a proton from thehydroxylof Tyr(244), which becomes a tyrosyl radical. The second oxygen is converted to a hydroxide ion by picking up two electrons and a proton. A third electron from another cytochrome c is passed through the first two electron carriers to the cytochrome a3–CuBbinuclear center, and this electron and two protons convert the tyrosyl radical back to Tyr, and the hydroxide bound to CuB2+to a water molecule. The fourth electron from another cytochrome c flows through CuAand cytochrome a to the cytochrome a3–CuBbinuclear center, reducing the Fe4+=O to Fe3+,with the oxygen atom picking up a proton simultaneously, regenerating this oxygen as a hydroxide ion coordinated in the middle of the cytochrome a3–CuBcenter as it was at the start of this cycle. Overall, four reduced cytochrome c's are oxidized while O2and four protons are reduced to two water molecules.[4]: 841–5 

Inhibition

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COX exists in three conformational states: fully oxidized (pulsed), partially reduced, and fully reduced. Each inhibitor has a high affinity to a different state. In the pulsed state, both the heme a3and the CuBnuclear centers are oxidized; this is the conformation of the enzyme that has the highest activity. A two-electron reduction initiates a conformational change that allows oxygen to bind at the active site to the partially-reduced enzyme. Four electrons bind to COX to fully reduce the enzyme. Its fully reduced state, which consists of a reduced Fe2+at the cytochrome a3heme group and a reduced CuB+binuclear center, is considered the inactive or resting state of the enzyme.[19]

Cyanide,azide,andcarbon monoxide[20]all bind to cytochrome c oxidase, inhibiting the protein from functioning and leading to the chemicalasphyxiationof cells. Higher concentrations of molecular oxygen are needed to compensate for increasing inhibitor concentrations, leading to an overall decrease in metabolic activity in the cell in the presence of an inhibitor. Other ligands, such as nitric oxide and hydrogen sulfide, can also inhibit COX by binding to regulatory sites on the enzyme, reducing the rate of cellular respiration.[21]

Cyanide is a non-competitive inhibitor for COX,[22][23]binding with high affinity to the partially-reduced state of the enzyme and hindering further reduction of the enzyme. In the pulsed state, cyanide binds slowly, but with high affinity. The ligand is posited to electrostatically stabilize both metals at once by positioning itself between them. A high nitric oxide concentration, such as one added exogenously to the enzyme, reverses cyanide inhibition of COX.[24]

Nitric oxidecan reversibly[25]bind to either metal ion in the binuclear center to be oxidized to nitrite. NO and CN−will compete with oxygen to bind at the site, reducing the rate of cellular respiration. Endogenous NO, however, which is produced at lower levels, augments CN−inhibition. Higher levels of NO, which correlate with the existence of more enzyme in the reduced state, lead to a greater inhibition of cyanide.[19]At these basal concentrations, NO inhibition of Complex IV is known to have beneficial effects, such as increasing oxygen levels in blood vessel tissues. The inability of the enzyme to reduce oxygen to water results in a buildup of oxygen, which can diffuse deeper into surrounding tissues.[25]NO inhibition of Complex IV has a larger effect at lower oxygen concentrations, increasing its utility as a vasodilator in tissues of need.[25]

Hydrogen sulfidewill bind COX in a noncompetitive fashion at a regulatory site on the enzyme, similar to carbon monoxide. Sulfide has the highest affinity to either the pulsed or partially reduced states of the enzyme, and is capable of partially reducing the enzyme at the heme a3center. It is unclear whether endogenous H2S levels are sufficient to inhibit the enzyme. There is no interaction between hydrogen sulfide and the fully reduced conformation of COX.[21]

Methanolinmethylated spiritsis converted intoformic acid,which also inhibits the same oxidase system. High levels of ATP canallostericallyinhibit cytochrome c oxidase, binding from within the mitochondrial matrix.[26]

Extramitochondrial and subcellular localizations

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Location of the 3 cytochrome c oxidase subunit genes in the human mitochondrial genome:COXI,COXII,andCOXIII(orange boxes).

Cytochrome c oxidase has 3 subunits which are encoded bymitochondrial DNA(cytochrome c oxidasesubunit I,subunit II,andsubunit III). Of these 3 subunits encoded by mitochondrial DNA, two have been identified in extramitochondrial locations. Inpancreaticacinar tissue, these subunits were found inzymogengranules. Additionally, in theanterior pituitary,relatively high amounts of these subunits were found ingrowth hormonesecretory granules.[27]The extramitochondrial function of these cytochrome c oxidase subunits has not yet been characterized. Besides cytochrome c oxidase subunits, extramitochondrial localization has also been observed for large numbers of other mitochondrial proteins.[28][29]This raises the possibility about existence of yet unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[27][29][30]

Genetic defects and disorders

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Defects involving genetic mutations altering cytochromecoxidase (COX) functionality or structure can result in severe, often fatalmetabolic disorders.Such disorders usually manifest in early childhood and affect predominantly tissues with high energy demands (brain, heart, muscle). Among the many classifiedmitochondrial diseases,those involving dysfunctional COX assembly are thought to be the most severe.[31]

The vast majority of COX disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.[32]

Currently, mutations have been identified in seven COX assembly factors:SURF1,SCO1,SCO2,COX10,COX15,COX20,COA5andLRPPRC.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 includeLeigh syndrome,cardiomyopathy,leukodystrophy,anemia,andsensorineural deafness.

Histochemistry

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The increased reliance of neurons on oxidative phosphorylation for energy[33]facilitates the use of COX histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity.[34]This can be seen in the correlation between COX enzyme amount and activity, which indicates the regulation of COX at the level of gene expression. COX distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. This pattern has been observed in the monkey, mouse, and calf brain. One isozyme of COX has been consistently detected in histochemical analysis of the brain.[35]Such brain mapping has been accomplished in spontaneous mutant mice with cerebellar disease such asreeler[36]and a transgenic model ofAlzheimer's disease.[37]This technique has also been used to map learning activity in the animal brain.[38]

Additional images

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  • ETC
    ETC
  • Complex IV
    Complex IV

See also

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References

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