Integral Membrane Enzymes in Eicosanoid Metabolism: Structures, Mechanisms and Inhibitor Design.

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.

journal_name

J Mol Biol

authors

Thulasingam M,Haeggström JZ

doi

10.1016/j.jmb.2020.07.020

subject

Has Abstract

pub_date

2020-08-21 00:00:00

pages

4999-5022

issue

18

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(20)30475-7

journal_volume

432

pub_type

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