Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Functional effects of mutations in cytochrome c oxidase related to prostate cancer
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2011 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1807, no 10, 1336-1341 p.Article in journal (Refereed) Published
Abstract [en]

A number of missense mutations in subunit I of cytochrome c oxidase (CytcO) have previously been linked to prostate cancer (Petros et al. (2005) PNAS, 102, 719). To investigate the effects of these mutations at the molecular level, in the present study we prepared four different structural variants of the bacterial Rhodobacter sphaeroides CytcO (cytochrome aa3), each carrying one amino-acid residue replacement corresponding to the following substitutions identified in the above-mentioned study: Asn11Ser, Ala122Thr, Ala341Ser and Val380Ile (residues Asn25, Ser168, Ala384 and Val423 in the R. sphaeroides oxidase). This bacterial CytcO displays essentially the same structural and functional characteristics as those of the mitochondrial counterpart. We investigated the overall activity, proton pumping and internal electron- and proton- transfer reactions in the structural variants. The results show that the turnover activities of the mutant CytcOs were reduced by at most a factor of two. All variants pumped protons, but in Ser168Thr, Ala384Ser and Val423Ile we observed slight internal proton leaks. In all structural variants the internal electron equilibrium was slightly shifted away from the catalytic site at high pH (10), resulting in a slower observed ferryl to oxidized transition. Even though the effects of the mutations were relatively modest, the results suggest that they destabilize the proton-gating machinery. Such effects could be manifested in the presence of a transmembrane electrochemical gradient resulting in less efficient energy conservation.

Place, publisher, year, edition, pages
2011. Vol. 1807, no 10, 1336-1341 p.
Keyword [en]
Respiration, Proton pumping, Electron transfer, Cytochrome aa3, Mitochondria, Membrane protein
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-65338DOI: 10.1016/j.bbabio.2011.02.005ISI: 000294513600011OAI: oai:DiVA.org:su-65338DiVA: diva2:465860
Available from: 2011-12-15 Created: 2011-12-07 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Cytochrome c Oxidase dysfunction in cancer: Exploring the molecular mechanisms
Open this publication in new window or tab >>Cytochrome c Oxidase dysfunction in cancer: Exploring the molecular mechanisms
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mutations in genes encoding the mitochondrial enzyme Cytochrome c Oxidase (CytcO) have lately been found in connection to various types of cancer. Some mutations result in substitutions of highly conserved amino-acid residues. As CytcO is an essential enzyme in oxidative phosphorylation, the substitutions are likely to have deleterious effects on the cellular energy metabolism. There is, however, a lack of data on the functional consequences of the pathogenic substitutions. In the publications on which this thesis is based, we investigated the effects of the substitutions on a molecular level. This was done using the validated bacterial model organism Rhodobacter sphaeroides which has a CytcO that is both structurally and functionally similar to the mammalian CytcO. For the functional studies, we used spectroscopic techniques to investigate the overall activity of the enzyme as well as the proton-pumping efficiency and the internal proton and electron transfers. We found that most of the CytcO substitutions observed in connection to cancer, resulted in a decreased catalytic activity. The impaired activity was due to defects in specific electron- or proton-transfer processes. Moreover, in several cases the substitutions resulted in an impaired proton-pumping activity. This thesis deals with the relevance of using R. sphaeroides CytcO as a model system for investigating human disease, as well as the possible links between the defective enzyme and the development of cancer.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2012. 65 p.
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-65303 (URN)978-91-7447-424-4 (ISBN)
Public defence
2012-02-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2012-01-12 Created: 2011-12-06 Last updated: 2012-01-05Bibliographically approved

Open Access in DiVA

fulltext(103 kB)140 downloads
File information
File name FULLTEXT01.pdfFile size 103 kBChecksum SHA-512
d11196433c90d5e3a344a9934518610d097011a1ba0eb3891be94a3f5cc55f7329f28218e8c7adb84a99e715416d87097c4e4f21201b28ce2531dc8acbe2ff81
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Namslauer, IdaBrzezinski, Peter
By organisation
Department of Biochemistry and Biophysics
In the same journal
Biochimica et Biophysica Acta - Bioenergetics
Biological Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 140 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 59 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf