Structure and Function of Bacterial Cytochrome c Oxidases

  • Joseph A. Lyons
  • Florian Hilbers
  • Martin CaffreyEmail author
Part of the Advances in Photosynthesis and Respiration book series (AIPH, volume 41)


Cytochrome c oxidase or complex IV is the terminal enzyme of the aerobic respiratory chain performing the essential process of reducing molecular oxygen to water. The energy resulting from this reaction is exploited to drive proton pumping across the membrane, which in turn contributes to the generation of a proton motive force and the downstream synthesis of ATP. This chapter highlights current progress in the field of bacterial cytochrome c oxidase research from the perspective of the structural and functional characterisation of this family of essential enzymes.


Spin Heme Bacterial Cytochrome Binuclear Centre Proton Pathway High Spin Heme 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Adenosine tri-phosphate


Cytochrome c oxidase


Electron paramagnetic resonance


Fourier transform infra-red spectroscopy


Heme copper oxidase


High potential iron-sulfur protein


Molecular dynamics


Nicotinamide adenine dinucleotide (oxidised form)


Nicotinamide adenine dinucleotide (reduced form)


Nuclear magnetic resonance


Electrochemically negative side of the membrane


Protein Data Bank


Electrochemically positive side of the membrane


Reactive oxygen species





J.A. Lyons is funded through an individual postdoctoral fellowship from the Danish Research Council for Natural Sciences. F. Hilbers is funded through the Danish Research Institute of Translational Neuroscience. M. Caffrey is supported through Science Foundation Ireland (12/IA/1255), COST Action CM1306 and the National Institutes of Health (P50GM073210, U54GM094599).


  1. Adelroth P, Gennis RB, Brzezinski P (1998) Role of the pathway through K(I-362) in proton transfer in cytochrome c oxidase from R. sphaeroides. Biochemistry 37:2470–2476PubMedCrossRefGoogle Scholar
  2. Backgren C, Hummer G, Wikstrom M, Puustinen A (2000) Proton translocation by cytochrome c oxidase can take place without the conserved glutamic acid in subunit I. Biochemistry 39:7863–7867PubMedCrossRefGoogle Scholar
  3. Belevich I, Verkhovsky MI, Wikstrom M (2006) Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase. Nature 440:829–832PubMedCrossRefGoogle Scholar
  4. Bertini I, Cavallaro G, Rosato A (2005) A structural model for the adduct between cytochrome c and cytochrome c oxidase. J Biol Inorg Chem 10:613–624PubMedCrossRefGoogle Scholar
  5. Bolshakov IA, Vygodina TV, Gennis R, Karyakin AA, Konstantinov AA (2010) Catalase activity of cytochrome c oxidase assayed with hydrogen peroxide-sensitive electrode microsensor. Biochemistry (Moscow) 75:1352–1360CrossRefGoogle Scholar
  6. Brändén M, Sigurdson H, Namslauer A, Gennis RB, Ädelroth P, Brzezinski P (2001) On the role of the K-proton transfer pathway in cytochrome c oxidase. Proc Natl Acad Sci U S A 98:5013–5018PubMedPubMedCentralCrossRefGoogle Scholar
  7. Branden M, Tomson F, Gennis RB, Brzezinski P (2002) The entry point of the K-proton-transfer pathway in cytochrome c oxidase. Biochemistry 41:10794–10798PubMedCrossRefGoogle Scholar
  8. Brandt U (2006) Energy converting NADH:quinone oxidoreductase (complex I). Annu Rev Biochem 75:69–92PubMedCrossRefGoogle Scholar
  9. Brandt U (2011) A two-state stabilization-change mechanism for proton-pumping complex I. Biochim Biophys Acta 1807:1364–1369PubMedCrossRefGoogle Scholar
  10. Bratton MR, Pressler MA, Hosler JP (1999) Suicide inactivation of cytochrome c oxidase: catalytic turnover in the absence of subunit III alters the active site. Biochemistry 38:16236–16245PubMedCrossRefGoogle Scholar
  11. Buhrow L, Ferguson-Miller S, Kuhn LA (2012) From static structure to living protein: computational analysis of cytochrome c oxidase main-chain flexibility. Biophys J 102:2158–2166PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bundschuh FA, Hoffmeier K, Ludwig B (2008) Two variants of the assembly factor Surf1 target specific terminal oxidases in Paracoccus denitrificans. Biochim Biophys Acta 1777:1336–1343PubMedCrossRefGoogle Scholar
  13. Buschmann S, Warkentin E, Xie H, Langer JD, Ermler U, Michel H (2010) The structure of cbb 3 cytochrome oxidase provides insights into proton pumping. Science 329:327–330PubMedCrossRefGoogle Scholar
  14. Calhoun MW, Thomas JW, Gennis RB (1994) The cytochrome oxidase superfamily of redox-driven proton pumps. Trends Biochem Sci 19:325–330PubMedCrossRefGoogle Scholar
  15. Capitanio G, Martino PL, Capitanio N, De Nitto E, Papa S (2006) pH dependence of proton translocation in the oxidative and reductive phases of the catalytic cycle of cytochrome c oxidase. The role of H2O produced at the oxygen-reduction site. Biochemistry 45:1930–1937PubMedCrossRefGoogle Scholar
  16. Chang HY, Hemp J, Chen Y, Fee JA, Gennis RB (2009) The cytochrome ba 3 oxygen reductase from Thermus thermophilus uses a single input channel for proton delivery to the active site and for proton pumping. Proc Natl Acad Sci U S A 106:16169–16173PubMedPubMedCentralCrossRefGoogle Scholar
  17. Crofts AR (2004) The cytochrome bc 1 complex: function in the context of structure. Annu Rev Physiol 66:689–733PubMedCrossRefGoogle Scholar
  18. Dalziel K, O’Brien JR (1954) Spectrophotometric studies of the reaction of methaemoglobin with hydrogen peroxide. 1. The formation of methaemoglobin-hydrogen peroxide. Biochem J 56:648–659PubMedPubMedCentralCrossRefGoogle Scholar
  19. de Grotthuss CJT (1806) Sur la décomposition de l’eau et des corps qu’elle tient en dissolution à l’aide de l’électricité galvanique. Ann Chim (Paris) 58:54–73Google Scholar
  20. de Vries S (2008) The role of the conserved tryptophan272 of the Paracoccus denitrificans cytochrome c oxidase in proton pumping. Biochim Biophys Acta 1777:925–928PubMedCrossRefGoogle Scholar
  21. Drosou V, Malatesta F, Ludwig B (2002) Mutations in the docking site for cytochrome c on the Paracoccus heme aa 3 oxidase. Electron entry and kinetic phases of the reaction. Eur J Biochem 269:2980–2988PubMedCrossRefGoogle Scholar
  22. Farver O, Grell E, Ludwig B, Michel H, Pecht I (2006) Rates and equilibrium of CuA to heme a electron transfer in Paracoccus denitrificans cytochrome c oxidase. Biophys J 90:2131–2137PubMedCrossRefGoogle Scholar
  23. Ferguson-Miller S, Babcock GT (1996) Heme/copper terminal oxidases. Chem Rev 96:2889–2908PubMedCrossRefGoogle Scholar
  24. Fetter JR, Qian J, Shapleigh J, Thomas JW, Garcia-Horsman A, Schmidt E, Hosler J, …, Ferguson-Miller S (1995) Possible proton relay pathways in cytochrome c oxidase. Proc Natl Acad Sci U S A 92:1604–1608Google Scholar
  25. Flock D, Helms V (2002) Protein—protein docking of electron transfer complexes: cytochrome c oxidase and cytochrome c. Proteins 47:75–85PubMedCrossRefGoogle Scholar
  26. Florens L, Schmidt B, McCracken J, Ferguson-Miller S (2001) Fast deuterium access to the buried magnesium/manganese site in cytochrome c oxidase. Biochemistry 40:7491–7497PubMedCrossRefGoogle Scholar
  27. Forte E, Urbani A, Saraste M, Sarti P, Brunori M, Giuffre A (2001) The cytochrome cbb3 from Pseudomonas stutzeri displays nitric oxide reductase activity. Eur J Biochem 268:6486–6491PubMedCrossRefGoogle Scholar
  28. Garcia-Horsman JA, Puustinen A, Gennis RB, Wikstrom M (1995) Proton transfer in cytochrome bo 3 ubiquinol oxidase of Escherichia coli: second-site mutations in subunit I that restore proton pumping in the mutant Asp135 -> Asn. Biochemistry 34:4428–4433PubMedCrossRefGoogle Scholar
  29. Gilderson G, Salomonsson L, Aagaard A, Gray J, Brzezinski P, Hosler J (2003) Subunit III of cytochrome c oxidase of Rhodobacter sphaeroides is required to maintain rapid proton uptake through the D pathway at physiologic pH. Biochemistry 42:7400–7409PubMedCrossRefGoogle Scholar
  30. Giuffre A, Stubauer G, Sarti P, Brunori M, Zumft WG, Buse G, Soulimane T (1999) The heme-copper oxidases of Thermus thermophilus catalyze the reduction of nitric oxide: evolutionary implications. Proc Natl Acad Sci U S A 96:14718–14723PubMedPubMedCentralCrossRefGoogle Scholar
  31. Gray HB, Winkler JR (2010) Electron flow through metalloproteins. Biochim Biophys Acta 1797:1563–1572PubMedCrossRefGoogle Scholar
  32. Greiner P, Hannappel A, Werner C, Ludwig B (2008) Biogenesis of cytochrome c oxidase—in vitro approaches to study cofactor insertion into a bacterial subunit I. Biochim Biophys Acta 1777:904–911PubMedCrossRefGoogle Scholar
  33. Haltia T, Finel M, Harms N, Nakari T, Raitio M, Wikstrom M, Saraste M (1989) Deletion of the gene for subunit III leads to defective assembly of bacterial cytochrome oxidase. EMBO J 8:3571–3579PubMedPubMedCentralGoogle Scholar
  34. Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54:1015–1069PubMedCrossRefGoogle Scholar
  35. Hatefi Y, Haavik AG, Griffiths DE (1961) Reconstitution of the electron transport system. I. Preparation and properties of the interacting enzyme complexes. Biochem Biophys Res Commun 4:441–446PubMedCrossRefGoogle Scholar
  36. Hilbers F, von der Hocht I, Ludwig B, Michel H (2013) True wild type and recombinant wild type cytochrome c oxidase from Paracoccus denitrificans show a 20fold difference in their catalase activity. Biochim Biophys Acta 1827:319–327PubMedCrossRefGoogle Scholar
  37. Ho BK, Gruswitz F (2008) HOLLOW: generating accurate representations of channel and interior surfaces in molecular structures. BMC Struct Biol 8:49PubMedPubMedCentralCrossRefGoogle Scholar
  38. Hofacker I, Schulten K (1998) Oxygen and proton pathways in cytochrome c oxidase. Proteins 30:100–107PubMedCrossRefGoogle Scholar
  39. Honnami K, Oshima T (1984) Purification and characterization of cytochrome c oxidase from Thermus thermophilus HB8. Biochemistry 23:454–460CrossRefGoogle Scholar
  40. Hosler JP (2004) The influence of subunit III of cytochrome c oxidase on the D pathway, the proton exit pathway and mechanism-based inactivation in subunit I. Biochim Biophys Acta 1655:332–339PubMedCrossRefGoogle Scholar
  41. Hrabakova J, Ataka K, Heberle J, Hildebrandt P, Murgida DH (2006) Long distance electron transfer in cytochrome c oxidase immobilised on electrodes. A surface enhanced resonance Raman spectroscopic study. Phys Chem Chem Phys 8:759–766PubMedCrossRefGoogle Scholar
  42. Iwata S, Ostermeier C, Ludwig B, Michel H (1995) Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans. Nature 376:660–669PubMedCrossRefGoogle Scholar
  43. Junemann S, Meunier B, Gennis RB, Rich PR (1997) Effects of mutation of the conserved lysine-362 in cytochrome c oxidase from Rhodobacter sphaeroides. Biochemistry 36:14456–14464PubMedCrossRefGoogle Scholar
  44. Kaila VR, Verkhovsky MI, Hummer G, Wikstrom M (2008) Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase. Proc Natl Acad Sci U S A 105:6255–6259PubMedPubMedCentralCrossRefGoogle Scholar
  45. Kaila VR, Johansson MP, Sundholm D, Laakkonen L, Wikstrom M (2009) The chemistry of the CuB site in cytochrome c oxidase and the importance of its unique His-Tyr bond. Biochim Biophys Acta 1787:221–233PubMedCrossRefGoogle Scholar
  46. Kaila VR, Sharma V, Wikstrom M (2011) The identity of the transient proton loading site of the proton-pumping mechanism of cytochrome c oxidase. Biochim Biophys Acta 1807:80–84PubMedCrossRefGoogle Scholar
  47. Kannt A, Lancaster CR, Michel H (1998a) The coupling of electron transfer and proton translocation: electrostatic calculations on Paracoccus denitrificans cytochrome c oxidase. Biophys J 74:708–721PubMedPubMedCentralCrossRefGoogle Scholar
  48. Kannt A, Soulimane T, Buse G, Becker A, Bamberg E, Michel H (1998b) Electrical current generation and proton pumping catalyzed by the ba 3-type cytochrome c oxidase from Thermus thermophilus. FEBS Lett 434:17–22PubMedCrossRefGoogle Scholar
  49. Kim YC, Wikstrom M, Hummer G (2007) Kinetic models of redox-coupled proton pumping. Proc Natl Acad Sci U S A 104:2169–2174PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kim YC, Wikstrom M, Hummer G (2009) Kinetic gating of the proton pump in cytochrome c oxidase. Proc Natl Acad Sci U S A 106:13707–13712PubMedPubMedCentralCrossRefGoogle Scholar
  51. Koepke J, Olkhova E, Angerer H, Muller H, Peng G, Michel H (2009) High resolution crystal structure of Paracoccus denitrificans cytochrome c oxidase: new insights into the active site and the proton transfer pathways. Biochim Biophys Acta 1787:635–645PubMedCrossRefGoogle Scholar
  52. Kozuch J, von der Hocht I, Hilbers F, Michel H, Weidinger IM (2013) Resonance Raman characterization of the ammonia-generated oxo intermediate of cytochrome c oxidase from Paracoccus denitrificans. Biochemistry 52:6197–6202PubMedCrossRefGoogle Scholar
  53. Kulajta C, Thumfart JO, Haid S, Daldal F, Koch HG (2006) Multi-step assembly pathway of the cbb 3-type cytochrome c oxidase complex. J Mol Biol 355:989–1004PubMedCrossRefGoogle Scholar
  54. Lee HJ, Ojemyr L, Vakkasoglu A, Brzezinski P, Gennis RB (2009) Properties of Arg481 mutants of the aa 3-type cytochrome c oxidase from Rhodobacter sphaeroides suggest that neither R481 nor the nearby D-propionate of heme a 3 is likely to be the proton loading site of the proton pump. Biochemistry 48:7123–7131PubMedPubMedCentralCrossRefGoogle Scholar
  55. Lee HJ, Gennis RB, Adelroth P (2011) Entrance of the proton pathway in cbb 3-type heme-copper oxidases. Proc Natl Acad Sci U S A 108:17661–17666PubMedPubMedCentralCrossRefGoogle Scholar
  56. Lubben M, Morand K (1994) Novel prenylated hemes as cofactors of cytochrome oxidases. Archaea have modified hemes A and O. J Biol Chem 269:21473–21479PubMedGoogle Scholar
  57. Luna VM, Chen Y, Fee JA, Stout CD (2008) Crystallographic studies of Xe and Kr binding within the large internal cavity of cytochrome ba 3 from Thermus thermophilus: structural analysis and role of oxygen transport channels in the heme-Cu oxidases. Biochemistry 47:4657–4665PubMedCrossRefGoogle Scholar
  58. Lyons JA, Aragao D, Slattery O, Pisliakov AV, Soulimane T, Caffrey M (2012) Structural insights into electron transfer in caa 3-type cytochrome oxidase. Nature 487:514–518PubMedPubMedCentralCrossRefGoogle Scholar
  59. Lyubenova S, Siddiqui MK, Vries MJ, Ludwig B, Prisner TF (2007) Protein-protein interactions studied by EPR relaxation measurements: cytochrome c and cytochrome c oxidase. J Phys Chem B 111:3839–3846PubMedCrossRefGoogle Scholar
  60. Makhov DV, Popovic DM, Stuchebrukhov AA (2006) Improved density functional theory/electrostatic calculation of the His291 protonation state in cytochrome c oxidase: self-consistent charges for solvation energy calculation. J Phys Chem B 110:12162–12166PubMedCrossRefGoogle Scholar
  61. Maklashina E, Cecchini G (2010) The quinone-binding and catalytic site of complex II. Biochim Biophys Acta 1797:1877–1882PubMedPubMedCentralCrossRefGoogle Scholar
  62. Maneg O, Ludwig B, Malatesta F (2003) Different interaction modes of two cytochrome-c oxidase soluble CuA fragments with their substrates. J Biol Chem 278:46734–46740PubMedCrossRefGoogle Scholar
  63. Maneg O, Malatesta F, Ludwig B, Drosou V (2004) Interaction of cytochrome c with cytochrome oxidase: two different docking scenarios. Biochim Biophys Acta 1655:274–281PubMedCrossRefGoogle Scholar
  64. Marechal A, Iwaki M, Rich PR (2013) Structural changes in cytochrome c oxidase induced by binding of sodium and calcium ions: an ATR-FTIR study. J Am Chem Soc 135:5802–5807PubMedCrossRefGoogle Scholar
  65. Michel H (1999) Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping—a discussion. Biochemistry 38:15129–15140PubMedCrossRefGoogle Scholar
  66. Mills DA, Hosler JP (2005) Slow proton transfer through the pathways for pumped protons in cytochrome c oxidase induces suicide inactivation of the enzyme. Biochemistry 44:4656–4666PubMedCrossRefGoogle Scholar
  67. Mills DA, Florens L, Hiser C, Qian J, Ferguson-Miller S (2000) Where is ‘outside’ in cytochrome c oxidase and how and when do protons get there? Biochim Biophys Acta 1458:180–187PubMedCrossRefGoogle Scholar
  68. Mills DA, Tan Z, Ferguson-Miller S, Hosler J (2003) A role for subunit III in proton uptake into the D pathway and a possible proton exit pathway in Rhodobacter sphaeroides cytochrome c oxidase. Biochemistry 42:7410–7417PubMedCrossRefGoogle Scholar
  69. Moser CC, Chobot SE, Page CC, Dutton PL (2008) Distance metrics for heme protein electron tunneling. Biochim Biophys Acta 1777:1032–1037PubMedPubMedCentralCrossRefGoogle Scholar
  70. Muresanu L, Pristovsek P, Lohr F, Maneg O, Mukrasch MD, Ruterjans H, Ludwig B, Lucke C (2006) The electron transfer complex between cytochrome c 552 and the CuA domain of the Thermus thermophilus ba 3 oxidase. A combined NMR and computational approach. J Biol Chem 281:14503–14513PubMedCrossRefGoogle Scholar
  71. Ogura T, Kitagawa T (2004) Resonance Raman characterization of the P intermediate in the reaction of bovine cytochrome c oxidase. Biochim Biophys Acta 1655:290–297PubMedCrossRefGoogle Scholar
  72. Orii Y, Okunuki K (1963) Studies on cytochrome a. X. Effect of hydrogen peroxide on absorption spectra of cytochrome a. J Biochem 54:207–213PubMedGoogle Scholar
  73. Ostermeier C, Harrenga A, Ermler U, Michel H (1997) Structure at 2.7 Å resolution of the Paracoccus denitrificans two-subunit cytochrome c oxidase complexed with an antibody FV fragment. Proc Natl Acad Sci U S A 94:10547–10553PubMedPubMedCentralCrossRefGoogle Scholar
  74. Paco L, Galarneau A, Drone J, Fajula F, Bailly C, Pulvin S, Thomas D (2009) Catalase-like activity of bovine met-hemoglobin: interaction with the pseudo-catalytic peroxidation of anthracene traces in aqueous medium. Biotechnol J 4:1460–1470PubMedCrossRefGoogle Scholar
  75. Pawate AS, Morgan J, Namslauer A, Mills D, Brzezinski P, Ferguson-Miller S, Gennis RB (2002) A mutation in subunit I of cytochrome oxidase from Rhodobacter sphaeroides results in an increase in steady-state activity but completely eliminates proton pumping. Biochemistry 41:13417–13423PubMedCrossRefGoogle Scholar
  76. Pereira MM, Santana M, Soares CM, Mendes J, Carita JN, Fernandes AS, Saraste M, …, Teixeira M (1999) The caa 3 terminal oxidase of the thermohalophilic bacterium Rhodothermus marinus: a HiPIP:oxygen oxidoreductase lacking the key glutamate of the D-channel. Biochim Biophys Acta 1413:1–13Google Scholar
  77. Pereira MM, Santana M, Teixeira M (2001) A novel scenario for the evolution of haem-copper oxygen reductases. Biochim Biophys Acta 1505:185–208PubMedCrossRefGoogle Scholar
  78. Pereira MM, Sousa FL, Verissimo AF, Teixeira M (2008) Looking for the minimum common denominator in haem-copper oxygen reductases: towards a unified catalytic mechanism. Biochim Biophys Acta 1777:929–934PubMedCrossRefGoogle Scholar
  79. Popovic DM, Leontyev IV, Beech DG, Stuchebrukhov AA (2010) Similarity of cytochrome c oxidases in different organisms. Proteins 78:2691–2698PubMedPubMedCentralGoogle Scholar
  80. Qin L, Hiser C, Mulichak A, Garavito RM, Ferguson-Miller S (2006) Identification of conserved lipid/detergent-binding sites in a high-resolution structure of the membrane protein cytochrome c oxidase. Proc Natl Acad Sci U S A 103:16117–16122PubMedPubMedCentralCrossRefGoogle Scholar
  81. Qin L, Mills DA, Buhrow L, Hiser C, Ferguson-Miller S (2008) A conserved steroid binding site in cytochrome c oxidase. Biochemistry 47:9931–9933PubMedPubMedCentralCrossRefGoogle Scholar
  82. Qin L, Liu J, Mills DA, Proshlyakov DA, Hiser C, Ferguson-Miller S (2009) Redox-dependent conformational changes in cytochrome c oxidase suggest a gating mechanism for proton uptake. Biochemistry 48:5121–5130PubMedPubMedCentralCrossRefGoogle Scholar
  83. Rauhamaki V, Baumann M, Soliymani R, Puustinen A, Wikstrom M (2006) Identification of a histidine-tyrosine cross-link in the active site of the cbb 3-type cytochrome c oxidase from Rhodobacter sphaeroides. Proc Natl Acad Sci U S A 103:16135–16140PubMedPubMedCentralCrossRefGoogle Scholar
  84. Reincke B, Perez C, Pristovsek P, Lucke C, Ludwig C, Lohr F, Rogov VV, …, Ruterjans H (2001) Solution structure and dynamics of the functional domain of Paracoccus denitrificans cytochrome c(552) in both redox states. Biochemistry 40:12312–12320 Google Scholar
  85. Rich PR, Marechal A (2013) Functions of the hydrophilic channels in protonmotive cytochrome c oxidase. J R Soc Interface 10:20130183PubMedPubMedCentralCrossRefGoogle Scholar
  86. Richter OM, Durr KL, Kannt A, Ludwig B, Scandurra FM, Giuffre A, Sarti P, Hellwig P (2005) Probing the access of protons to the K pathway in the Paracoccus denitrificans cytochrome c oxidase. FEBS J 272:404–412PubMedCrossRefGoogle Scholar
  87. Riistama S, Puustinen A, García-Horsman A, Iwata S, Michel H, Wikström M (1996) Channelling of dioxygen into the respiratory enzyme. Biochim Biophys Acta 1275:1–4PubMedCrossRefGoogle Scholar
  88. Roberts VA, Pique ME (1999) Definition of the interaction domain for cytochrome c on cytochrome c oxidase. J Biol Chem 274:38051–38060PubMedCrossRefGoogle Scholar
  89. Sharma V, Karlin KD, Wikstrom M (2013) Computational study of the activated O(H) state in the catalytic mechanism of cytochrome c oxidase. Proc Natl Acad Sci U S A 110:16844–16849PubMedPubMedCentralCrossRefGoogle Scholar
  90. Sharpe MA, Ferguson-Miller S (2008) A chemically explicit model for the mechanism of proton pumping in heme-copper oxidases. J Bioenerg Biomembr 40:541–549PubMedPubMedCentralCrossRefGoogle Scholar
  91. Sharpe MA, Krzyaniak MD, Xu S, McCracken J, Ferguson-Miller S (2009) EPR evidence of cyanide binding to the Mn(Mg) center of cytochrome c oxidase: support for Cu(A)-Mg involvement in proton pumping. Biochemistry 48:328–335PubMedPubMedCentralCrossRefGoogle Scholar
  92. Soulimane T, Buse G, Bourenkov GP, Bartunik HD, Huber R, Than ME (2000) Structure and mechanism of the aberrant ba (3)-cytochrome c oxidase from Thermus thermophilus. EMBO J 19:1766–1776PubMedPubMedCentralCrossRefGoogle Scholar
  93. Sousa FL, Alves RJ, Ribeiro MA, Pereira-Leal JB, Teixeira M, Pereira MM (2012) The superfamily of heme-copper oxygen reductases: types and evolutionary considerations. Biochim Biophys Acta 1817:629–637PubMedCrossRefGoogle Scholar
  94. Stryer L, Berg JM, Tymoczko JL (2002) Biochemistry. W.H. Freeman & Co. Ltd, New YorkGoogle Scholar
  95. Svensson-Ek M, Abramson J, Larsson G, Tornroth S, Brzezinski P, Iwata S (2002) The X-ray crystal structures of wild-type and EQ(I-286) mutant cytochrome c oxidases from Rhodobacter sphaeroides. J Mol Biol 321:329–339PubMedCrossRefGoogle Scholar
  96. Thomas JW, Puustinen A, Alben JO, Gennis RB, Wikstrom M (1993) Substitution of asparagine for aspartate-135 in subunit I of the cytochrome bo ubiquinol oxidase of Escherichia coli eliminates proton-pumping activity. Biochemistry 32:10923–10928 PubMedCrossRefGoogle Scholar
  97. Thornstrom PE, Brzezinski P, Fredriksson PO, Malmstrom BG (1988) Cytochrome c oxidase as an electron-transport-driven proton pump: pH dependence of the reduction levels of the redox centers during turnover. Biochemistry 27:5441–5447 PubMedCrossRefGoogle Scholar
  98. Tiefenbrunn T, Liu W, Chen Y, Katritch V, Stout CD, Fee JA, Cherezov V (2011) High resolution structure of the ba3 cytochrome c oxidase from Thermus thermophilus in a lipidic environment. PLoS One 6:e22348PubMedPubMedCentralCrossRefGoogle Scholar
  99. Toledo-Cuevas M, Barquera B, Gennis RB, Wikstrom M, Garcia-Horsman JA (1998) The cbb 3-type cytochrome c oxidase from Rhodobacter sphaeroides, a proton-pumping heme-copper oxidase. Biochim Biophys Acta 1365:421–434PubMedCrossRefGoogle Scholar
  100. Tomson FL, Morgan JE, Gu G, Barquera B, Vygodina TV, Gennis RB (2003) Substitutions for glutamate 101 in subunit II of cytochrome c oxidase from Rhodobacter sphaeroides result in blocking the proton-conducting K-channel. Biochemistry 42:1711–1717PubMedCrossRefGoogle Scholar
  101. Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, …, Yoshikawa S (1996) The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 Å. Science 272:1136–1144Google Scholar
  102. Turrens JF (1997) Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17:3–8PubMedCrossRefGoogle Scholar
  103. Tuukkanen A, Verkhovsky MI, Laakkonen L, Wikstrom M (2006) The K-pathway revisited: a computational study on cytochrome c oxidase. Biochim Biophys Acta 1757:1117–1121PubMedCrossRefGoogle Scholar
  104. van Dijk AD, Ciofi-Baffoni S, Banci L, Bertini I, Boelens R, Bonvin AM (2007) Modeling protein-protein complexes involved in the cytochrome c oxidase copper-delivery pathway. J Proteome Res 6:1530–1539PubMedCrossRefGoogle Scholar
  105. Verkhovsky MI, Jasaitis A, Verkhovskaya ML, Morgan JE, Wikstrom M (1999) Proton translocation by cytochrome c oxidase. Nature 400:480–483PubMedCrossRefGoogle Scholar
  106. Voicescu M, El Khoury Y, Martel D, Heinrich M, Hellwig P (2009) Spectroscopic analysis of tyrosine derivatives: on the role of the tyrosine-histidine covalent linkage in cytochrome c oxidase. J Phys Chem B 113:13429–13436PubMedCrossRefGoogle Scholar
  107. von der Hocht I, van Wonderen JH, Hilbers F, Angerer H, MacMillan F, Michel H (2011) Interconversions of P and F intermediates of cytochrome c oxidase from Paracoccus denitrificans. Proc Natl Acad Sci U S A 108:3964–3969PubMedPubMedCentralCrossRefGoogle Scholar
  108. Vygodina TV, Zakirzianova W, Konstantinov AA (2008) Inhibition of membrane-bound cytochrome c oxidase by zinc ions: high-affinity Zn2+ −binding site at the P-side of the membrane. FEBS Lett 582:4158–4162PubMedCrossRefGoogle Scholar
  109. Vygodina T, Kirichenko A, Konstantinov AA (2013) Direct regulation of cytochrome c oxidase by calcium ions. PLoS One 8:e74436PubMedPubMedCentralCrossRefGoogle Scholar
  110. Wikstrom M (1981) Energy-dependent reversal of the cytochrome oxidase reaction. Proc Natl Acad Sci U S A 78:4051–4054PubMedPubMedCentralCrossRefGoogle Scholar
  111. Wikstrom M (2000) Mechanism of proton translocation by cytochrome c oxidase: a new four-stroke histidine cycle. Biochim Biophys Acta 1458:188–198PubMedCrossRefGoogle Scholar
  112. Wikstrom M, Verkhovsky MI (2007) Mechanism and energetics of proton translocation by the respiratory heme-copper oxidases. Biochim Biophys Acta 1767:1200–1214PubMedCrossRefGoogle Scholar
  113. Xie H, Buschmann S, Langer JD, Ludwig B, Michel H (2014) Biochemical and biophysical characterization of the two isoforms of cbb 3-type cytochrome c oxidase from Pseudomonas stutzeri. J Bacteriol 196:472–482PubMedPubMedCentralCrossRefGoogle Scholar
  114. Yu MA, Egawa T, Shinzawa-Itoh K, Yoshikawa S, Guallar V, Yeh SR, Rousseau DL, Gerfen GJ (2012) Two tyrosyl radicals stabilize high oxidation states in cytochrome c oxidase for efficient energy conservation and proton translocation. J Am Chem Soc 134:4753–4761PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Joseph A. Lyons
    • 1
  • Florian Hilbers
    • 1
  • Martin Caffrey
    • 2
    Email author
  1. 1.Department of Molecular Biology and GeneticsAarhus UniversityAarhusDenmark
  2. 2.School of Medicine and School of Biochemistry and ImmunologyTrinity College DublinDublin 2Ireland

Personalised recommendations