Skip to main content
SpringerLink
Log in

Reaction Mechanism of Mammalian Mitochondrial Cytochrome c Oxidase

  • Chapter
  • First Online:
Mitochondrial Oxidative Phosphorylation

Part of the book series: Advances in Experimental Medicine and Biology ((volume 748))

Abstract

Cytochrome c oxidase (COX) is the terminal oxidase of the mitochondrial respiratory system. This enzyme reduces molecular oxygen (O2) to water in a reaction coupled with the pumping of protons across the mitochondrial inner membrane. Progress in investigating the reaction mechanism of this enzyme has been limited by the resolution of its X-ray structure. Bovine heart COX has provided the highest resolution (1.8 Å) X-ray structure presently available among the terminal oxidases. The reaction mechanism of the bovine heart enzyme has been the most extensively studied, particularly with respect to (1) the reduction of O2 to water without release of reactive oxygen species, (2) the mechanism of coupling between the O2 reduction process and proton pumping, (3) the structural basis for unidirectional proton transfer (proton pumping), and (4) the effective prevention of proton leakage from the proton-pumping pathway to the proton pathway used for generation of water molecules. In this chapter, we will review recent structural studies of bovine heart COX and discuss the mechanisms described earlier in context of the structural data.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aoyama H, Muramoto K, Shinzawa-Itoh K, Hirata K et al (2009) A peroxide bridge between Fe and Cu ions in the O2 reduction site of fully oxidized cytochrome c oxidase could suppress the proton pump. Proc Natl Acad Sci USA 106:2165–2169

    Article  PubMed  CAS  Google Scholar 

  • Arnold S, Kadenbach B (1997) Cell respiration is controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase. Eur J Biochem 249:350–354

    Article  PubMed  CAS  Google Scholar 

  • Caughey WS, Smythe GA, O’Keefe DH, Maskasky JE, Smith ML (1975) Heme A of cytochrome c oxidase. J Biol Chem 250:7602–7622

    PubMed  CAS  Google Scholar 

  • Caughey WS, Wallace WJ, Volpe JA, Yoshikawa S (1976) Cytochrome c oxidase. In: Boyer PD (ed) The enzymes, volume XIII. Oxidation-reduction, Part C, 3rd edn. Academic, New York

    Google Scholar 

  • 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 USA 106:16169–16173

    Article  PubMed  CAS  Google Scholar 

  • Fabian M, Skultety L, Brunel C, Palmer G et al (2001) Cyanide stimulated dissociation of chloride from the catalytic center of oxidized cytochrome c oxidase. Biochemistry 40:6061–6069

    Article  PubMed  CAS  Google Scholar 

  • Fiamingo FG, Altshuld RA, Moh PP, Alben JO (1982) Dynamic interactions of CO with a3Fe and CuB in cytochrome c oxidase in beef heart mitochondria studied by Fourier transform infrared spectroscopy at low temperatures. J Biol Chem 257:1639–1650

    PubMed  CAS  Google Scholar 

  • Frank V, Kadenbach B (1996) Regulation of the H+/e− stoichiometry of cytochrome c oxidase from bovine heart by intramitochondrial ATP/ADP ratios. FEBS Lett 382:121–124

    Article  PubMed  CAS  Google Scholar 

  • Gilderson G, Salomonson L, Aagaard A, Gray J et al (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 42:7400–7409

    Article  PubMed  CAS  Google Scholar 

  • Hemp J, Han H, Roh JH, Kaplan S et al (2007) Comparative genomics and site-directed mutagenesis support the existence of only one input channel for protons in the C-family (cbb 3 oxidase) of heme-copper oxygen reductases. Biochemistry 46:9963–9972

    Article  PubMed  CAS  Google Scholar 

  • Isaacs NS (1995) Physical organic chemistry, 2nd edn. Longman, Essex

    Google Scholar 

  • Kadenbach B, Ungibauer M, Jarausch J, Buge U, Kuhn-Nentwig L (1983) The complexity of respiratory complexes. Trends Biochem Sci 8:398–400

    Article  CAS  Google Scholar 

  • Kamiya K, Boero M, Tateno M, Shiraishi K, Oshiyama A (2007) First-principles molecular dynamics study of proton transfer mechanism in bovine cytochrome c oxidase. J Am Chem Soc 129:9663–9673

    Article  PubMed  CAS  Google Scholar 

  • Kitagawa T, Ogura T (1997) Oxygen activation mechanism at binuclear site of heme-copper oxidase superfamily as revealed by time-resolved resonance Raman spectroscopy. Prog Inorg Chem 45:431–479

    Article  CAS  Google Scholar 

  • Konstantinov A, Siletsky S, Mitchell D, Kaulen A, Gennis RB et al (1997) The roles of the two proton input channels in cytochrome c oxidase from Rhodobacter sphaeroides probed by the effects of site-directed mutations on time-resolved electrogenic intraprotein proton transfer. Proc Natl Acad Sci USA 94:9085–9090

    Article  PubMed  CAS  Google Scholar 

  • Lee I, Bender E, Arnold S, Kadenbach B (2001) New control of mitochondrial membrane potential and ROS formation–a hypothesis. Biol Chem 382:1629–1636

    Article  PubMed  CAS  Google Scholar 

  • Mochizuki M, Aoyama H, Shinzawa-Itoh K, Usui T et al (1999) Quantitative reevaluation of the redox active sites of crystalline bovine heart cytochrome c oxidase. J Biol Chem 274:33403–33411

    Article  PubMed  CAS  Google Scholar 

  • Muramoto K, Ohta K, Shinzawa-Itoh K, Kanda K et al (2010) Bovine cytochrome c oxidase ­structures enable O2 reduction with minimization of reactive oxygens and provide a proton-pumping gate. Proc Natl Acad Sci USA 107:7740–7745

    Article  PubMed  CAS  Google Scholar 

  • Napiwotzki J, Shinzawa-Itoh K, Yoshikawa S, Kadenbach B (1997) ATP and ADP bind to cytochrome c oxidase and regulate its activity. Biol Chem 378:1013–1021

    Article  PubMed  CAS  Google Scholar 

  • Oliveberg M, Malmstrom BG (1992) Reaction of dioxygen with cytochrome c oxidase reduced to different degrees: indications of a transient dioxygen complex with copper-B. Biochemistry 31:3560–3563

    Article  PubMed  CAS  Google Scholar 

  • Pawate AS, Morgan J, Namslauer A, Mills D et al (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 41:13417–13423

    Article  PubMed  CAS  Google Scholar 

  • Potter WT, Tucker MP, Houtchens RA, Caughey WS et al (1987) Oxygen infrared spectra of oxyhemoglobins and oxymyoglobins. Evidence of two major liganded O2 structures. Biochemistry 26:4699–4707

    Article  PubMed  CAS  Google Scholar 

  • Sakaguchi M, Shinzawa-Itoh K, Yoshikawa S, Ogura T (2010) A resonance Raman band assignable to the O-O stretching mode in the resting oxidized state of bovine heart cytochrome c oxidase. J Bioenerg Biomembr 42:241–243

    Article  PubMed  CAS  Google Scholar 

  • Sasaroli M, Ching Y-C, Dasgupta S, Rousseau DL (1989) Cytochrome c oxidase: evidence for interaction of water molecules with cytochrome a. Biochemistry 28:3128–3132

    Article  Google Scholar 

  • Shimokata K, Katayama Y, Murayama H, Suematsu M et al (2007) The proton pumping pathway of bovine heart cytochrome c oxidase. Proc Natl Acad Sci USA 104:4200–4205

    Article  PubMed  CAS  Google Scholar 

  • Shinzawa-Itoh K, Aoyama H, Muramoto K, Terada H et al (2007) Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J 26:1713–1725

    Article  PubMed  CAS  Google Scholar 

  • Suga M, Yano N, Muramoto K, Shinzawa-Itoh K et al (2011) Distinguishing between Cl− and O 2−2 as the bridging element between Fe3+ and Cu2+ in resting-oxidized cytochrome c oxidase. Acta Crystallogr D Biol Crystallogr D67:742–744

    Article  CAS  Google Scholar 

  • Thornstrom PE, Nilsson T, Malmstrom BG (1988) The possible role of the closed-open transition in proton pumping by cytochrome c oxidase: the pH dependence of cyanide inhibition. Biochim Biophys Acta 935:103–108

    Article  Google Scholar 

  • Tsukihara T, Aoyama H, Yamashita E, Tomizaki T et al (1996) The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 Å. Science 272:1136–1144

    Article  PubMed  CAS  Google Scholar 

  • Tsukihara T, Shimokata K, Katayama Y, Shimada H et al (2003) The low-spin heme of cytochrome c oxidase as the driving element of the proton-pumping process. Proc Natl Acad Sci USA 100:15304–15309

    Article  PubMed  CAS  Google Scholar 

  • Williams RJP (1995) Bioenergetics. Purpose of proton pathways. Nature 376:643

    Article  PubMed  CAS  Google Scholar 

  • Yakushiji E, Okunuki K (1941) Isolierung der a-Komponents des Cytochroms und ihre Eigenschaften. Proc Imp Acad Jpn 17:38–40

    Google Scholar 

  • Yamashita E, Aoyama H, Yao M, Muramoto K et al (2005) Absolute configuration of the hydroxyfarnesylethyl group of haem A, determined by X-ray structural analysis of bovine heart cytochrome c oxidase using methods applicable at 2.8 Angstrom resolution. Acta Crystallogr D Biol Crystallogr D61:1373–1377

    Article  CAS  Google Scholar 

  • Yoshikawa S, O’Keeffe DH, Caughey WS (1985) Investigations of cyanide as an infrared probe of hemeprotein ligand binding sites. J Biol Chem 260:3518–3528

    PubMed  CAS  Google Scholar 

  • Yoshikawa S, Mochizuki M, Zhao XJ, Caughey WS (1995) Effects of overall oxidation state on infrared spectra of heme a 3 cyanide in bovine heart cytochrome c oxidase. Evidence of novel mechanistic roles for CuB. J Biol Chem 270:4270–4279

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa S, Shinzawa-Itoh K, Nakashima R, Yaono R et al (1998) Redox-coupled crystal structural changes in bovine heart cytochrome c oxidase. Science 280:1723–1729

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa S, Muramoto K, Shinzawa-Itoh K (2011) Proton-pumping mechanism of cytochrome c oxidase. Annu Rev Biophys 40:205–223

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported in part by the Grant-in-Aid for Scientific Research 2247012 (S.Y.), the Targeted Protein Research Program, and the Global Center of Excellence Program, each provided by the Japanese Ministry of Education, Culture, Sports, Science and Technology. S.Y. is a Senior Visiting Scientist in the RIKEN Harima Institute.

Author information

Authors and Affiliations

  1. Department of Life Science, University of Hyogo, Hyogo, 678-1297, Japan

    Shinya Yoshikawa, Kazumasa Muramoto & Kyoko Shinzawa-Itoh

Authors
  1. Shinya Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazumasa Muramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyoko Shinzawa-Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinya Yoshikawa .

Editor information

Editors and Affiliations

  1. Philipps-Universitaet Marburg, Marburg, 35032, Germany

    Bernhard Kadenbach

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Yoshikawa, S., Muramoto, K., Shinzawa-Itoh, K. (2012). Reaction Mechanism of Mammalian Mitochondrial Cytochrome c Oxidase. In: Kadenbach, B. (eds) Mitochondrial Oxidative Phosphorylation. Advances in Experimental Medicine and Biology, vol 748. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3573-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation