Journal
BIOCHEMICAL PHARMACOLOGY
Volume 193, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114759
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Funding
- NIH [P50AT002776, HL107887]
- AHA [16GRNT31000010]
- Deutsche Forschungsgemeinschaft. (DFG, the German Research Foundation) [316213987, SFB 1278 PolyTarget, CRC 1127]
- Free State of Thuringia
- European Social Fund [2016 FGR 0045]
- Louisiana Governor's Biotechnology Initiative
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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.
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.
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