Kühn Lab: Lipoxygenase Research

Inflammatory processes play a key role in the pathogenesis of many diseases. Understanding the mechanisms of inflammation is an important part for future therapeutic interventions. Our group is especially interested in an enzyme, 15-lipoxygenase, which is involved in the biosynthesis of pro- and anti-inflammatory mediators. We are investigating the role of this enzyme in different biological models and with respect to its evolution in mammals. Another topic of our research is the interplay of lipoxygenases and Gpx4 on regulating the redox homeostasis of the cell.

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Research Areas

  • Investigation of the reaction mechanism of different LOX isoforms.
  • The phylogenetic development of ALOX15 as lipid peroxidizing enzyme.
  • The physiological and pathophysiological role of different LOX-isoforms, which is investigated in animal models and in man.
  • The role of Gpx4 in regulation of the cellular redox homeostasis in cellular models and in genetically modified animal models.

Lipoxygenase (LOX)

molecule Modell of  Lipoxygenase
Molecule model (PDB ID: 2P0M)

Lipoxygenases (LOX’s) are a heterogeneous group of lipid peroxydizing enzymes, which play an important role in cell differentiation, inflammatory and hyperproliferative diseases (1,2). Different isoforms are present in all higher developed animals and plants. LOX isoforms are classified according to their reaction specificity with polyunsaturated fatty acids as substrate. Within the human genome six different functional LOX genes are present, which encode for six different LOX isoforms. Although the crystal structure of different LOX isoforms were solved (1,2), the structural cause of different catalytic characteristics of LOX isoforms and their evolutionary relationships are widely unknown.

Main focus of our research is the investigation of the reaction mechanism of different LOX isoforms, phylogenetic aspects of LOX as lipid peroxidising enzymes and the physiological and patho-physiological relevance of LOX isoforms, which is investigated in different animal models of disease as well as in humans.

 

 

1. HaeggstroemJZ, FunkCD. Chem. Rev.111(2011)5866-5898.

2. IvanovI, HeydeckD, HofheinzK, RoffeisJ, O'DonnellVB, KuhnH, WaltherM. Arch. Biochem. Biophys. 503(2010)161-174.

 

 

 

Glutathioneperoxidases (Gpx)

Crystal structure of the Sec46Cys Mutant of human phospholipid hydroperoxide glutathione peroxidase
Molecule model of GPx4 (PDB ID: 2OBI)

Glutathioneperoxidases form a heterogenous family of peroxide reducing enzymes and utilize glutathione as electron donor (3). Intracellularly, they constitute the functional counterpart of lipoxygenases, which form fatty acid hydroperoxides. The human Genome contains several GPx-genes, some of which encode for selenocystein containing isoenzymes. The different GPx-isoforms differ from each other with respect to their cellular and subcellular lokalisation but also regarding their substrate specificity. Among the GPx-isoforms GPx4 is unique since it constitutes the only GPx-isoenzyme capable of reducing complex lipid hydroperoxides (phospholipid hydroperoxides, cholesterol ester hydroperoxides) even if these substrate are incoprporated within complex lipid-protein assemblies such as biomembranes, lipoproteins (4). Beside its role as peroxide reducing enzyme GPx4 also functions as structural protein because the mid-piece of sperms contains high amounts of GPx4 polymers.

3. Brigelius-FlohéR, MaiorinoM. Biochem Biophys Acta.1830(2013)3289-3303.
4. SchnurrK, BelknerJ, UrsiniF, ScheweT, KuehnH. J. Biol. Chem. 271(1996)4653-4658.