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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

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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 3

Metabolism of polyunsaturated fatty acids into leukotrienes and resolvins.

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Metabolism of polyunsaturated fatty acids into leukotrienes and resolvin...
The scheme illustrates the interconnections between the pathways for synthesis of proinflammatory leukotrienes and antiinflammatory lipoxins and resolvins from arachidonic, eicosapentaenoic, and docosahexaenoic acids. For D- and E-series resolvins, the respective fatty acid substrate is first oxygenated by 15-LOX or cytochrome P450. Inhibition of 5-LOX attenuates leukotriene formation and may interfere with synthesis of pro-resolving molecules. Inhibition of LTA4H and/or LTC4S will block leukotrienes, shunt LTA4 into lipoxin synthesis, and spare 5-LOX activity for generation of other pro-resolving molecules.
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