project

Brief description of selected projects:
5-LO: Principle investigator - Olof Rådmark. Here we study the impact of 5-LO phosphorylation on the regulation of enzyme activity, intracellular compartmentalization, and interaction with other proteins. Efforts to solve crystal structure are ongoing.
LTAH: For LTA4H we do structure-based inhibitor design, interaction with other proteins and gene regulation.
LTC4S:ases: We study the cellular expression, regulation and structure-function relationships of LTC4S:ases. They are also part of a program on “structural genomics”.
LT-receptors: We focus on the regulation of receptor expression and functional consequences of ligand binding in selected inflammatory cells, e.g. mast cells and endothelial cells. We also study structure-function relationships and regulation at the molecular level.
Translational topics: We are currently studying the role of eicosanoids in cardiovascular diseases and joint diseases. We employ animal models and unique collections of patient samples.
Gene discovery: Here, we look at the impact of eicosanoids on gene regulation as well as the reverse, i.e., influence of other inflammatory factors on the expression of eicosanoid related genes. It involves transcription profiling, IHC, gene isolation and functional genomics/proteomics.

References
Thunnissen, M.G.M., Nordlund, P. and Haeggström, J.Z.: Crystal structure of human leukotriene A4 hydrolase, an enzyme involved in inflammation. Nature Str. Biol. 8, 131-135, 2001.

Sjöström, M., Jakobsson, P.-J., Juremalm, M., Ahmed, A., Nilsson, G., Macchia, L., and Haeggström, J.Z.: Human mast cells express two leukotriene C4 synthase isoenzymes and the CysLT1 receptor, Biochim. Biophys. Acta (Mol. Cell Biol. Lipids) 1583, 53-62, 2002.

Rudberg, P.C., Tholander, F., Thunnissen, M.G.M., Samuelsson, B. and Haeggström, J.Z.: Leukotriene A4 hydrolase, selective abrogation of leukotriene B4 biosynthesis by mutation of aspartic acid 375, Proc. Natl. Acad. Sci. USA, 99, 4215-4220, 2002.

Sjöström, M., Johansson, A.-S., Schröder, O., Qiu, H., Palmblad, J., and Haeggström, J.Z.: Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl-leukotrienes in human umbilical vein endothelial cells., Arterioscler. Thromb. Vasc. Biol. 23, 37-41, 2003.

Schröder, O., Sjöström, M., Qiu, H., Stein, J., Jakobsson, P.-J. and Haeggström, J.Z. Molecular and catalytic properties of three rat leukotriene C4 synthase homologues, Biochem. Biophys. Res. Commun., 312, 271-276, 2003.

Rudberg, P., Tholander, F., Andberg, M., Thunnissen, M.G.M., and Haeggström, J.Z.: Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates., J. Biol. Chem., 279, 27376-27382, 2004.

Haeggström, J.Z. Leukotriene A4 hydrolase/Aminopeptidase, The gatekeeper of chemotactic leukotriene B4 biosynthesis. J. Biol. Chem. 279:50639-42, 2004.

Provost, P., Dishart, D., Doucet, J., Frendewey, D., Samuelsson, B. and Rådmark, O. Ribonuclease activity and RNA binding of recombinant human Dicer. EMBO J. 21, 5864-5874, 2002.

Werz O, Szellas D, Steinhilber D, Radmark O. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J. Biol. Chem. 277:14793-14800, 2002.

Fischer L, Szellas D, Radmark O, Steinhilber D, Werz O. Phosphorylation- and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox-type inhibitors. FASEB J. 17:949-951, 2003.

We are interested in a family of lipid mediators called the leukotrienes (LT) involved in a number of inflammatory and allergic diseases, in particular asthma, rheumatoid arthritis, and arteriosclerosis. Work in our laboratory is focused on biosynthetic and regulatory mechanisms involved in leukotriene formation at a cellular, enzyme, and genetic level with particular emphasis on 5-lipoxygenase (5-LO), LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S). These three enzymes catalyze the key steps in the biosynthesis of the proinflammatory compounds LTB4 and LTC4. Recently, we have also initiated molecular and cellular projects on leukotriene receptors, BLT1/BLT2 for LTB4 and CysLT1/CysLT2 for LTC4. In addition to increased knowledge about a class of physiologically important lipid mediators, we hope that our work will lead to the development of novel anti-inflammatory and anti-allergic drugs.