Title:	Structural characterization of the leukotriene biosynthetic cascade
DNr:	NAISS 2024/6-47
Project Type:	NAISS Medium Storage
Principal Investigator:	Jesper Haeggstrom <Jesper.Haeggstrom@ki.se>
Affiliation:	Karolinska Institutet
Duration:	2024-02-29 – 2025-03-01
Classification:	10601 10605
Homepage:	https://ki.se/en/mbb/research-division-of-chemistry-ii
Keywords:

Abstract

Our group focuses on the structural elucidation of soluble as well as integral membrane proteins involved in leukotriene biosynthesis. Leukotrienes are potent pro-inflammatory and immune-modulating lipid mediators that play a central pathogenic role in different inflammatory diseases, including atherosclerosis, arthritis, asthma and allergy. Therefore, structural characterization of the leukotriene biosynthetic enzymes creates new therapeutic opportunities. More precisely, we are interested in the structural aspects of 5-lipoxygenase (5-LOX) and its molecular interactions with soluble coactosin-like protein (CLP) and membrane-bound 5-lipoxygenase-activating protein (FLAP) which are needed for the stability and activity of 5-LOX. 5-LOX is the key enzyme that gives rise to the important precursor molecule, leukotriene A4, for pro-inflammatory leukotrienes biosynthesized by leukotriene A4 hydrolase (LTA4H) or leukotriene C4 synthase (LTC4S). 5-LOX and FLAP are drug targets in many allergy and inflammatory related disorders. Native 5-LOX and FLAP are the focus of our project since there are no low-resolution structures available. The currently available structure of 5-LOX has been solved only for highly mutated “stable” 5-LOX at 2.4 Å. In addition, the structures of FLAP around 2.5 Å are available only at the presence of inhibitors. However, due to lack of wild-type 5-LOX and inhibitor-free FLAP, the structural details and molecular interactions are not well understood. In addition, integral membrane proteins in the leukotriene pathway, FLAP, LTC4S, and microsomal glutathione S-transferases (MGST1-3) belong to the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily. Our recent crystal structure of human microsomal glutathione S-transferase (MGST2) in complex with one of its hydrophilic substrates led to intriguing observations on its functional mechanism. To develop deeper understandings of the mechanism as well as its substrate entry and product release, we will be focusing on human MGST1, MGST2 and MGST3 protein in complex with its substrate. These structural studies will aid the development of novel drugs against asthma and other inflammatory disorders.