Leukotriene biosynthetic enzymes as therapeutic targets
Jesper Z. Haeggström
Jesper Z. Haeggström
Published July 2, 2018
Citation Information: J Clin Invest. 2018;128(7):2680-2690. https://doi.org/10.1172/JCI97945.
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Review Series

Leukotriene biosynthetic enzymes as therapeutic targets

Abstract

Leukotrienes are powerful immune-regulating lipid mediators with established pathogenic roles in inflammatory allergic diseases of the respiratory tract — in particular, asthma and hay fever. More recent work indicates that these lipids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, and metabolic diseases as well as cancer. Biosynthesis of leukotrienes involves oxidative metabolism of arachidonic acid and proceeds via a set of soluble and membrane enzymes that are primarily expressed by cells of myeloid origin. In activated immune cells, these enzymes assemble at the endoplasmic and perinuclear membrane, constituting a biosynthetic complex. This Review describes recent advances in our understanding of the components of the leukotriene-synthesizing enzyme machinery, emerging opportunities for pharmacological intervention, and the development of new medicines exploiting both antiinflammatory and pro-resolving mechanisms.

Authors

Jesper Z. Haeggström

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Figure 2

Crystal structure of the key enzymes and proteins in leukotriene biosynthesis.

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Crystal structure of the key enzymes and proteins in leukotriene biosynt...
(A) Structure of 5-LOX at 2.4 Å resolution depicting the N-terminal β-barrel domain (yellow) and the catalytic domain (magenta). (B) Structure of FLAP at 4 Å resolution. It is a trimer with each monomer (yellow, green, and magenta) composed of four transmembrane α-helices. FLAP inhibitors are bound in the intermonomeric cleft. (C) Structure of LTA4H at 1.9 Å resolution. The protein is folded into three domains, an N-terminal (yellow), a catalytic (green), and a C-terminal (magenta), between which the catalytic center is located. A molecule of LTA4 is indicated in the center of the interdomain cavity. (D) Structure of LTC4S. It is a trimer with each monomer (yellow, green, and magenta) composed of 4 transmembrane α-helices. Three molecules of the cosubstrate GSH are bound between two monomers toward the cytosolic side of the protein. Figures were derived from the following Protein Data Bank IDs: 5-LOX 3O8Y; FLAP 2Q7R; LTA4H 5NI6; LTC4S 2UUH.