Integral Membrane Enzymes in Eicosanoid Metabolism: Structures, Mechanisms and Inhibitor Design. Issue 18 (21st August 2020)

• Record Type: Journal Article
• Authors: Thulasingam, Madhuranayaki; Haeggström, Jesper Z.
• Is Part Of: Journal of molecular biology. Volume 432:Issue 18(2020)
• Page Start: 4999
• Page End: 5022
• Publication Date: 2020-08-21
• Subjects: eicosanoids -- MAPEG -- mPGES-1 -- LTC4S -- FLAP; AA arachidonic acid -- COX cyclooxygenase -- PG prostaglandin -- TX thromboxane -- LOX lipoxygenase -- 5-LO 5-lipoxygenase -- FLAP five-lipoxygenase-activating protein -- LTA4 leukotriene A4 -- LTC4S leukotriene C4 synthase -- GSH glutathione -- cys-LTs cysteinyl leukotrienes -- MAPEG membrane-associated proteins in eicosanoid and glutathione metabolism -- mPGES-1 microsomal prostaglandin E synthase 1 -- MGST1/2/3 microsomal glutathione S-transferase 1/2/3 -- ER endoplasmic reticulum -- DDM dodecyl maltoside -- LXA4 lipoxin A4 -- NSAID non-steroidal anti-inflammatory drug -- CDNB 1-chloro-2, 4-dinitro benzene; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.07.020
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: 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. Graphical Abstract: Unlabelled Image