Integral Membrane Enzymes in Eicosanoid Metabolism: Structures, Mechanisms and Inhibitor Design
| Autor: | Madhuranayaki Thulasingam, Jesper Z. Haeggström |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Lipoxygenase 0302 clinical medicine Structural Biology Humans Lipid bilayer Molecular Biology Integral membrane protein 030304 developmental biology 0303 health sciences Arachidonic Acid biology Eicosanoid metabolism Chemistry Endoplasmic reticulum Cell Membrane Membrane Proteins Glutathione Lipid signaling Eicosanoid Biochemistry Drug Design biology.protein Eicosanoids lipids (amino acids peptides and proteins) Oxidation-Reduction 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Journal of Molecular Biology. 432:4999-5022 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2020.07.020 |
| Popis: | Eicosanoids are potent lipid mediators involved in central physiological processes such as hemostasis, renal function and parturition. When formed in excess, eicosanoids become critical players in a range of pathological conditions, in particular pain, fever, arthritis, asthma, cardiovascular disease and cancer. Eicosanoids are generated via oxidative metabolism of arachidonic acid along the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Specific lipid species are formed downstream of COX and LOX by specialized synthases, some of which reside on the nuclear and endoplasmic reticulum, including mPGES-1, FLAP, LTC4 synthase, and MGST2. These integral membrane proteins are members of the family "membrane-associated proteins in eicosanoid and glutathione metabolism" (MAPEG). Here we focus on this enzyme family, which encompasses six human members typically catalyzing glutathione dependent transformations of lipophilic substrates. Enzymes of this family have evolved to combat the topographical challenge and unfavorable energetics of bringing together two chemically different substrates, from cytosol and lipid bilayer, for catalysis within a membrane environment. Thus, structural understanding of these enzymes are of utmost importance to unravel their molecular mechanisms, mode of substrate entry and product release, in order to facilitate novel drug design against severe human diseases. |
| Databáze: | OpenAIRE |
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