Untangling the web of 5-lipoxygenase-derived products from a molecular and structural perspective: The battle between pro- and anti-inflammatory lipid mediators

Arachidonic acid (AA) is the precursor to leukotrienes (LT), potent mediators of the inflammatory response. In the 35 + years since cysteinyl-LTs were reported to mediate antigen-induced constriction of bronchi in tissue from asthma patients, numerous cellular responses evoked by the LTs, such as chemoattraction and G protein-coupled receptor (GPCR) activation, have been elucidated and revealed a potential for 5-lipoxygenase (5-LOX) as a promising drug target that goes beyond asthma. We describe herein early work identifying 5-LOX as the key enzyme that initiates LT biosynthesis and the discovery of its membrane-embedded helper protein required to execute the two-step reaction that transforms AA to the progenitor leukotriene A4 (LTA4). 5-LOX must traffic to the nuclear membrane to interact with its partner and undergo a conformational change so that AA can enter the active site. Additionally, the enzyme must retain the hydroperoxy-reaction intermediate for its final transformation to LTA4. Each of these steps provide a unique target for inhibition. Next, we describe the recent structures of GPCRs that recognize metabolites of the 5-LOX pathway and thus provide target alternatives. We also highlight the role of 5-LOX in the biosynthesis of anti-inflammatory lipid mediators (LM), the so-called specialized pro-resolving mediators (SPM). The involvement of 5-LOX in the biosynthesis of LM with opposing functions undoubtedly complicates the continuing search for 5-LOX inhibitors as therapeutic leads. Finally, we address the recent discovery of how some allosteric 5-LOX inhibitors promote oxygenation at the 12/15 carbon on AA to generate mediators that resolve, rather than promote, inflammation.

Automated summary

Arachidonic acid (AA) serves as the precursor for leukotrienes (LT), potent mediators of the inflammatory response. The discovery of 5-lipoxygenase (5-LOX) as a key enzyme in LT synthesis and recent structures of GPCRs recognizing 5-LOX metabolites offer promising drug target alternatives. The involvement of 5-LOX in both pro-inflammatory and anti-inflammatory lipid mediator biosynthesis complicates the search for therapeutic leads, while allosteric 5-LOX inhibitors promoting resolution of inflammation add a new dimension to potential treatments.