Untangling the web of 5-lipoxygenase-derived products from a molecular and structural perspective: The battle between pro- and anti-inflammatory lipid mediators.
Untangling the web of 5-lipoxygenase-derived products from a molecular and structural perspective: The battle between pro- and anti-inflammatory lipid mediators.
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DOI：
10.1016/j.bcp.2021.114759
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发表时间：
2021-11
影响因子：
5.8
通讯作者：
Werz O
中科院分区：
文献类型：
--
作者：
Gilbert NC;Newcomer ME;Werz O
花生四烯酸（AA）是白三烯（LT）的前体，LT是炎症反应的有效介质。自从半胱氨酰-LT被报道介导哮喘患者组织中抗原诱导的支气管收缩以来的35年多时间里，已经阐明了由LT诱发的许多细胞反应，如化学吸引和G蛋白偶联受体（GPCR）活化，并揭示了5-脂氧合酶（5-LOX）作为超越哮喘的有希望的药物靶标的潜力。我们在此描述了早期的工作，确定5-LOX作为启动LT生物合成的关键酶，并发现了其膜包埋的辅助蛋白，该辅助蛋白需要执行将AA转化为祖细胞白三烯A4（LTA 4）的两步反应。5-LOX必须运输到核膜与它的伙伴相互作用，并经历构象变化，以便AA可以进入活性位点。此外，酶必须保留过氧化氢反应中间体，以最终转化为LTA 4。这些步骤中的每一个都提供了独特的抑制靶标。接下来，我们描述了GPCR的最新结构，其识别5-LOX途径的代谢物，从而提供靶向替代物。我们还强调了5-LOX在抗炎脂质介质（LM），即所谓的专门促消退介质（SPM）的生物合成中的作用。5-LOX参与LM的生物合成，具有相反的功能，这无疑使继续寻找5-LOX抑制剂作为治疗先导变得复杂。最后，我们讨论了最近发现的一些变构5-LOX抑制剂如何促进AA上12/15碳的氧合，以产生解决而不是促进炎症的介质。
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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影响因子：
3.3
作者：
Bair AM;Turman MV;Vaine CA;Panettieri RA Jr;Soberman RJ
通讯作者：
Soberman RJ
影响因子：
5.8
作者：
Gerstmeier, Jana;Kretzer, Christian;Pace, Simona
通讯作者：
Pace, Simona
炎性关节炎需要中性粒细胞的白细胞B4。
DOI：
10.1084/jem.20052371
发表时间：
2006-04-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
DAHLEN, SE;HEDQVIST, P;SAMUELSSON, B
通讯作者：
SAMUELSSON, B
影响因子：
4.1
作者：
Esser, Julia;Rakonjac, Marija;Radmark, Olof
通讯作者：
Radmark, Olof