Structures of Leukotriene Biosynthetic Enzymes and Development of New Therapeutics

Abstract

Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Single-cell transcriptome analysis reveals the cellular atlas of human intracranial aneurysm and highlights inflammation features associated with aneurysm rupture

“…Neu.2 highly expressed immunoglobulin receptor FCGR3B and CXCR2, and had enriched pathways associated with migrating and serine/threonine activity (Figure 2B, Supplementary Figure 3B). Neu.3 highly expressed eicosanoid metabolizing enzyme encoding gene ALOX5AP (log2FC = 1.65, Pct.1 = 0.94, Pct.2 = 0.53) and chemokine CXCL8 (log2FC = 1.55, Pct.1 = 1, Pct.2 = 0.73) (Figure 2B, Supplementary Figure 3C), indicating a role in synergistically biosynthesis of leukotrienes 38 .…”

Substituted 1,2,4-Triazoles as Novel and Selective Inhibitors of Leukotriene Biosynthesis Targeting 5-Lipoxygenase-Activating Protein

“…These bioactive LTs exert their actions via distinct receptors such as BLT 1/2 for LTB 4 and CysLTRs for CysLTs (Figure 1). 3 LTB 4 is pro-inflammatory and acts as a chemoattractant for leukocytes and neutrophils, while cysLTs cause bronchoconstriction, airway edema, and vascular leakage. 1 To date, the most advanced drug class targeting this branch are cysLTR 1 antagonists as antiasthmatic drugs, i.e., montelukast, 4 but this drug class has limited clinical indication as it essentially blocks the action of LTD 4 in the lungs, resulting in decreased inflammation and relaxation of smooth muscle.…”

Theoretical Study of the Arachidonic Acid Conversion into Leukotriene A4 Catalyzed by Human 5-Lipoxygenase: Hydroperoxidation and Epoxidation Mechanisms and Arachidonic Acid Active Site Access

“…Massive efforts have been dedicated for many years to develop new therapeutics based on efficient 5-LOX inhibitors, specially facing the challenge of designing inhibitors that suppress the formation of LTs without lowering the production of lipoxins. 22 To this aim, the lack of a crystal structure of 5-LOX has been a big obstacle, thus preventing a complete understanding at the molecular level of the mechanism of the reactions catalyzed by 5-LOX. Several years ago, some of us used Stable-5-LOX to find the binding modes for AA inside the cavity of the enzyme.…”

“…When cells are stimulated to release intracellular Ca 2+ , the translocation of cytosolic phospholipase A 2 and 5-LOX to the nuclear membrane is triggered. Phospholipase A 2 mediates the release of AA from membrane phospholipids, and a small membrane protein, 5-lipoxygenase-activating protein (FLAP) transfers AA to 5-LOX. ,, It has been proposed , that the open conformation would increase the ability of 5-LOX to convert 5-HpETE into LTA 4 and that this conformation is likely the one presented by 5-LOX when interacting with membrane-embedded FLAP. On the other hand, human-5-LOX can also produce LTA 4 in vitro (in the absence of the membrane-embedded FLAP) from AA sequentially (hydroperoxidation + epoxidation) …”

“…As explained above, LTs are lipid mediators with a very important pathogenic role in inflammatory-based diseases. Massive efforts have been dedicated for many years to develop new therapeutics based on efficient 5-LOX inhibitors, specially facing the challenge of designing inhibitors that suppress the formation of LTs without lowering the production of lipoxins . To this aim, the lack of a crystal structure of 5-LOX has been a big obstacle, thus preventing a complete understanding at the molecular level of the mechanism of the reactions catalyzed by 5-LOX.…”