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Scavenging of superoxide by a membrane-bound superoxide oxidase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2018 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, p. 788-793Article in journal (Refereed) Published
Abstract [en]

Superoxide is a reactive oxygen species produced during aerobic metabolism in mitochondria and prokaryotes. It causes damage to lipids, proteins and DNA and is implicated in cancer, cardiovascular disease, neurodegenerative disorders and aging. As protection, cells express soluble superoxide dismutases, disproportionating superoxide to oxygen and hydrogen peroxide. Here, we describe a membrane-bound enzyme that directly oxidizes superoxide and funnels the sequestered electrons to ubiquinone in a diffusion-limited reaction. Experiments in proteoliposomes and inverted membranes show that the protein is capable of efficiently quenching superoxide generated at the membrane in vitro. The 2.0 Å crystal structure shows an integral membrane di-heme cytochrome b poised for electron transfer from the P-side and proton uptake from the N-side. This suggests that the reaction is electrogenic and contributes to the membrane potential while also conserving energy by reducing the quinone pool. Based on this enzymatic activity, we propose that the enzyme family be denoted superoxide oxidase (SOO).

Place, publisher, year, edition, pages
2018. Vol. 14, p. 788-793
National Category
Biological Sciences
Research subject
Biochemistry towards Bioinformatics; Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-156235DOI: 10.1038/s41589-018-0072-xISI: 000438970200013OAI: oai:DiVA.org:su-156235DiVA, id: diva2:1203601
Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2019-04-05Bibliographically approved
In thesis
1. Development and Application of Molecular Modeling Methods for Structure-Based Drug Discovery
Open this publication in new window or tab >>Development and Application of Molecular Modeling Methods for Structure-Based Drug Discovery
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Molecular modeling is increasingly being integrated into the drug discovery process. Although computational methods are already an essential part of the process today, these techniques have vast potential to evolve and refine drug design in the future. The integration of modeling is further catalyzed by the rapidly growing computational power available to both academia and pharmaceutical companies. These resources extend the reach of the computational methods to new time scales in physics-based simulations of biomolecular systems and increase the number of molecules that is possible to dock to a receptor by several orders of magnitude. However, there is also a need for further development of methods that utilize the increased computational power to increase the level of detail in modeling of molecular interactions. The work presented in this thesis has contributed to method development in two different areas and demonstrated how virtual screening can be applied to identify ligands of proteins. The first main project investigated modeling of ordered water molecules in protein binding sites to understand the role of water in molecular recognition and the impact of ligands on hydration networks. In a second project, an approach for discovery and optimization of fragment-sized ligands based on virtual screening was developed and used to identify inhibitors of a cancer drug target. Finally, molecular docking was applied to assess proposed substrates of cytochrome b561, a recently crystallized membrane protein.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2018. p. 56
National Category
Biochemistry and Molecular Biology Bioinformatics (Computational Biology)
Research subject
Biochemistry towards Bioinformatics
Identifiers
urn:nbn:se:su:diva-154977 (URN)978-91-7797-226-6 (ISBN)978-91-7797-227-3 (ISBN)
Public defence
2018-05-25, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: In press.

Available from: 2018-05-02 Created: 2018-04-09 Last updated: 2018-05-03Bibliographically approved
2. Structural and Functional Studies of Membrane Proteins: From Characterisation of a Fatty Acyl-CoA Synthetase to the Discovery of Superoxide Oxidase
Open this publication in new window or tab >>Structural and Functional Studies of Membrane Proteins: From Characterisation of a Fatty Acyl-CoA Synthetase to the Discovery of Superoxide Oxidase
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is divided into three parts; the first part describes a method for efficient screening of membrane proteins for crystallography. By utilising the properties of a folding reporter GFP it is possible to quickly and accurately screen the stability of a protein in a range of conditions without full purification. This allows rapid assessment of the suitability of a protein for crystallography and a parallel optimisation of purification conditions for subsequent large-scale protein production.

The second part describes the discovery of a membrane bound superoxide oxidase (SOO), a novel scavenger of membrane proximal superoxide. SOO is a kinetically perfect enzyme, reacting at rates close to the diffusion limit in a similar fashion to other superoxide scavengers, such as superoxide dismutase. We propose that SOO rescues electrons “lost” to superoxide and recycles them back into the respiratory chain, releasing oxygen. At the same time SOO contributes to the proton motive force by uptake of protons from the cytoplasmic side of the membrane.

The third part concerns the fatty acyl-CoA synthetase FadD13 from Mycobacterium tuberculosis (M. tuberculosis). It represents a critical node point in M. tuberculosis lipid metabolism and has been suggested to be a vital component of M. tuberculosis survival in host cell macrophages. FadD13 harbours a hydrophobic cavity that is unable to house the very-long-chain substrates the enzyme has preference for. We propose that FadD13 is a peripheral membrane protein, utilising the membrane to house the very-long-chain fatty acid substrates during the activation reaction.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2019. p. 74
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-167812 (URN)978-91-7797-648-6 (ISBN)978-91-7797-649-3 (ISBN)
Public defence
2019-05-29, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2019-05-06 Created: 2019-04-04 Last updated: 2019-05-02Bibliographically approved

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Lundgren, Camilla A. KSjöstrand, DanBennett, MatthewRudling, AxelBrzezinsk, Petervon Ballmoos, ChristophHögbom, Martin
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