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2024-03-17 09:57:49

20-羟-二十烷四烯酸_百度百科

-二十烷四烯酸_百度百科网页新闻贴吧知道网盘图片视频地图文库资讯采购百科百度首页登录注册进入词条全站搜索帮助首页秒懂百科特色百科知识专题加入百科百科团队权威合作下载百科APP个人中心收藏查看我的收藏0有用+1020-羟-二十烷四烯酸播报讨论上传视频化学物质本词条缺少概述图，补充相关内容使词条更完整，还能快速升级，赶紧来编辑吧！20-羟-二十烷四烯酸(20-hydroxyeicosatetraenoic acid,20-HETE)是花生四烯酸的细胞色素P-450代谢途径的一个重要代谢产物·近年来研究发现20-HETE对血管内皮细胞发挥重要的生理和病理生理作用·20-HETE可激活内皮细胞烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶系统和核因子-кB(nuclear factor-кB,NF-кB)通路发挥氧化应激和促炎作用；20-HETE可介导血管内皮细胞内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的解离、降低NO的生物利用度及诱导血管紧张素转换酶，调节血管的舒张和收缩功能；20-HETE还可促进内皮细胞的增生而促进血管新生 [1-2]中文名20-羟-二十烷四烯酸 [2]外文名20-hydroxyeicosatetraenoic acid,20-HETE [1]性质化学物质目录1涵义220-HETE对血管内皮细胞的作用和机制▪20-HETE调节血管收缩和舒张功能▪促进血管内皮细胞的增殖3综合涵义播报编辑花生四烯酸代谢网络调节着机体的细胞分化、增殖、激素分泌、凝血及纤溶系统动态平衡、体温及血压等生理过程，还在炎症、心血管系统疾病及糖尿病等疾病的病理生理过程中发挥重要作用。以往研究认为 AA主要经过环氧酶途径和脂氧酶途径代谢，分别产生前列腺素、前列环素、血栓素 A2，氢过氧化二十烷四烯酸。近十余年来研究发现AA的“第三条代谢途径”细胞色素 P450途径产生表氧二十碳三烯酸（EETs）和 20羟二十烷四烯酸，在体内的生理和病理生理过程中也发挥着重要的作用20-HETE对血管内皮细胞的作用和机制播报编辑20-HETE对血管内皮细胞的氧化应激损伤和促炎作用20-HETE可激活MAPK/ERK通路，继而激活NF-кB促进血管内皮细胞的炎症反应。而NF-кB是对氧化还原状态敏感的转录因子。NADPH氧化酶系统可激活NF-кB。NF-кB又可诱导gp91phox的表达，因此氧化应激激活NF-кB可导致正反馈循环，进一步激活NADPH氧化酶产生更多的自由基。20-HETE则因为可激活NADPH和NF-кB而成为炎症和氧化应激正反馈反应的驱动力以维持内皮细胞的持续激活。20-HETE调节血管收缩和舒张功能以往研究主要认为20-HETE对血管功能的调节与其抑制血管平滑肌细胞高电导钙激活钾通道，引起去极化和细胞内Ca2+浓度的升高有关，因此20HETE可提高动脉对收缩性刺激，如压力、氧、苯肾上腺素和内皮素的反应性。而新近研究表明CYP4A——20-HETE通路还可通过引起血管内皮细胞功能失调，导致动脉收缩和舒张功能障碍而参与高血压的发生和发展。促进血管内皮细胞的增殖20-HETE可激活血管内皮细胞、调节血管的收缩和舒张功能外，还可促进血管内皮细胞的增殖，进而促进血管的新生。综合播报编辑总之，是机体调节不同生理功能的重要物质之一。作为第二信使，对调节血管平滑肌、肾功能、肺血管舒张和冠脉循环发挥着关键作用。它的生成与很多疾病的发生、发展有关，例如：脑血管疾病、肾病、冠心病、高血压、妊娠毒血症等。那些能够调节生成或者抑制其活性的药物，对于治疗某些人类疾病具有广阔的开发价值。因此，研究必然对人类的健康带来福音。 [1]20-HETE做为 AA第三条代谢通路的主要产物，近十余年来逐渐得到了关注。由于其对血管内皮细胞的上述作用（图 1），已被认为是高血压等心血管疾病治疗的靶点。因此研究20-HETE对心血管系统的作用和机制具有重要的基础和临床意义，对开发新药也具有重要的指导意义。 [2]新手上路成长任务编辑入门编辑规则本人编辑我有疑问内容质疑在线客服官方贴吧意见反馈投诉建议举报不良信息未通过词条申诉投诉侵权信息封禁查询与解封©2024 Baidu 使用百度前必读 | 百科协议 | 隐私政策 | 百度百科合作平台 | 京ICP证030173号京公网安备110000020000

干货 | 氧化脂质在CVD中的分子机制 - 知乎

干货 | 氧化脂质在CVD中的分子机制 - 知乎切换模式写文章登录/注册干货 | 氧化脂质在CVD中的分子机制迈维代谢已认证账号一、心血管病理生理学概述心血管疾病是反映了许多影响血管和心脏功能的病理生理学问题，这些问题通常会导致心肌梗死、心力衰竭和中风等疾病。影响心血管疾病发展的风险因素既有可控的，也有不可控的，如年龄、高血压、血脂异常、肥胖、糖尿病和吸烟，所有这些因素都包括多器官系统，这些系统康复后会导致心血管结构、功能、代谢和生物能发生显著变化。许多心血管疾病患者的终点是心力衰竭，其特征是心输出量减少。心力衰竭不是一个单一的疾病实体，而是一个明确的发病机制，其累积表现为收缩和/或舒张功能衰竭，导致心脏无法满足身体的能量需求。心血管病理生理学发展概况Oxylipins氧化脂质是多不饱和脂肪酸（PUFAs）氧化产生的生物活性脂质。自他们被发现以来，已与许多生物学功能联系在一起，许多其他功能仍在阐明中。检测和定量技术的进步激发了人们使用先进的质谱仪对Oxylipins氧化脂质进行精确检测的研究兴趣。尽管如此，研究Oxylipins氧化脂质的生物学功能仍然受到Oxylipins氧化脂质数量的挑战，迄今为止，已鉴定出超过100种Oxylipins氧化脂质，并且各种Oxylipins氧化脂质功能重叠且相互联系。心血管疾病（CVD）病理包括高脂血症、高血压、血栓形成、止血和糖尿病等过程，这些都与异常的Oxylipins氧化脂质信号传导有关。二、氧化脂质的合成氧化脂质合成受到严格调节并以旁分泌或自分泌的方式发挥作用。游离的PUFA被三个酶家族：环氧合酶（COX）、脂氧合酶（LOX）和细胞色素P450（CYP）分解成氧化脂质。环氧合酶（COX）酶将花生四烯酸（AA）转化为类前列腺素（PG和血栓烷）。同样，COX酶可以产生一些羟基代谢物，例如将AA转化为11-HETE和将油酸LA 转化为 9-HODE。脂加氧酶（LOXs）催化羟基脂肪酸的形成，包括：白三烯，脂类毒素、RESOLVIN，保护素，Maresin，hepoxilins和eoxins。LOX酶也代谢AA形成中链（5-，8、9、11、12和15-）HETE。细胞色素P450（CYP）酶最初因其在异源生物代谢中的作用而闻名，可能具有环氧合酶或ω-羟化酶活性。ω-羟化酶（CYP4A和CYP4F）代谢AA并生成ω-端（16-，17-，18-，19-和20-）HETE，而具有环氧酶活性的CYP（CYP2C和CYP2J）则代谢AA和产生环氧二十碳三烯酸（EETs），其通过可溶性环氧化物水解酶（sEH）进一步代谢为二羟基二十碳三烯酸（DHETs）。AA也可以从LA代谢产生。LA的代谢包括上述相同的酶家族；例如，CYP环氧酶会代谢LA形成LA的环氧化合物EpOMEs。EpOMEs被sEH水合形成DiHOMEs，即EpOMEs 的二羟基形式。LOX酶形成LA的羟基代谢产物HODEs。下图举例说明了一些来自AA和LA的氧化脂质以及涉及其生成和分解的主要酶，例如脂氧化酶、CYP环氧酶，ω-羟化酶和环氧化酶。花生四烯酸和亚油酸衍生的氧化脂质以及涉及其生成和分解的主要酶氧化脂质具有广泛的生物学功能，其中许多仍在研究中。它们通过激活PPAR或GPCR产生作用。靶向sEH影响了其催化活性直接影响氧化脂质的水平，例如：EET，DHET，EpOMEs和DiHOMEs，间接影响了其他PUFA途径，例如；HODE和HETE。后者的观察结果可以解释为：由于EET的积累，在sEH -/-小鼠体内通过AA代谢发生的转变，表明不同的脂蛋白途径相互影响。此外，与n-6多不饱和脂肪酸相比，补充膳食的n-3多不饱和脂肪酸在降低炎症介质（类花生酸，细胞因子和ROS）和粘附分子的表达具有多种对抗心血管疾病的健康益处。此外，Lorente-Cebrian 等人在其综述中已充分讨论了n-3 PUFA的有益作用。包括增强的血管功能，心脏保护功能，减少心肌梗塞，心律不齐，心源性猝死，中风等。下图说明氧化脂质参与心血管调节。氧化脂质参与心血管调节三、氧化脂质在CVD中的分子机制1.环氧二十碳三烯酸（EET）EET是花生四烯酸（AA）的20碳代谢产物，具有多种生理作用。它们是通过细胞色素P450环氧合酶途径从AA产生的。产生四种不同的异构体：5，6-EET、8，9-EET、11，12-EET和14，15-EET。在心脏中，EET在缺血/再灌注损伤中发挥心脏保护作用。EET被归类为EDHF。它们在内皮细胞中通过Ca2 +和K + 通道（BK Ca）诱导血管平滑肌细胞的超极化。EET通过水解酶迅速代谢为相应活性较低的DHET，而sEH是负责EET分解的主要分解代谢途径。并非所有的EETs异构体都是sEH的底物。5,6-EET是sEH的不良底物。实际上，该EET异构体（5,6-EET）和8,9-EET都是环氧合酶（COX）途径的底物。14,15-EET的半衰期为7.9-12.3分钟。EET的其他分解代谢途径包括ω-氧化，β-氧化和链延长。当主要途径（sEH的水解酶）被抑制时，后两种途径变得更加重要。EET产生减少的多态性变体，例如CYP2J2表达降低（变体G-50T）或EETs分解增加， sEH活性增加（变体K55R），增加了冠心病的风险。一些研究人员推测，EET通过特定的细胞表面受体发挥其作用，即EET的不同立体异构体和区域异构体引起不同的反应。许多报道都将EET的信号传导途径与蛋白激酶A（PKA）和cAMP联系起来。2.中链羟基二十碳四烯酸（HETE）中链HETEs是AA通过脂氧合酶（LOX）的烯丙基氧化产生。15-HETE可以转化为氧化脂质（LXs），它们在消炎中起着重要作用。不像EET在肾脏血管中起着扩张作用，12-HETE在肾动脉引起血管收缩。原发性高血压中中链HETE的生成增加，这表明它们可能参与了其发病机理。这些报道指出EET与HETE在血管生物学中具有相反作用。Maayah 等人报道，中链HETE阻断了RL-14细胞中EET的合成并增加了它们向DHET的转化。此外，尽管sEH不直接参与中链HETE的产生或分解，但已发现sEH对于中链HETE介导的细胞肥大诱导至关重要。因此，EET和中链HETE不仅具有相反的作用，而且似乎相互影响。3.环氧十八碳烯酸（EpOMEs）EpOMEs和DiHOMEs被报道提高血管内皮细胞中的氧化应激；DiHOMEs对肾近端肾小管细胞有毒性，静脉注射9,10-EpOME对狗心脏有抑制作用。用12,13-EpOME预处理可保护兔肾近端肾小管原代培养细胞免受缺氧/复氧损伤。此外，通过使用AUDA抑制sEH引起的EpOME / DiHOME比的影响，可改善C57BL / 6小鼠缺血/再灌注损伤的肾脏恢复率。可溶性环氧水解酶改变EpOME / DiHOME和EET / DHET比例4.9-，13-羟基十八碳二烯酸（9-，13-HODEs）亚油酸（LA）还通过CYP环氧酶经羟基化作用代谢，从而形成称为羟基十八碳二烯酸（HODEs）的羟基LA代谢产物。13-HODE通过其作为PPARγ激动剂的作用在炎症性疾病中具有抗炎作用。13-HODE增加了前列环素（PGI2）的生物合成，这与犬的平滑肌细胞中的脾脏和冠状动脉舒张有关。9-HODE在大鼠的实验伤口愈合模型描述为促炎性，而13-HODE可防止血小板在人血管内皮细胞粘附。5.前列腺素前列腺素包括前列腺素和血栓烷。前列腺素G2和H2，它们是由COX同工型（1和2）形成的AA代谢物，获得转换成4个主要生物活性的前列腺素PG（D2，E2，I2和F2α）和血栓烷（TXA2和TXB2）。大多数前列腺素PG具有促炎作用。然而发现PGE2也具有抗炎作用，通过上调cAMP并诱导抗炎IL-10的分泌。同样，PGD2可减轻胸膜炎和结肠炎实验模型中的炎症反应。6-酮-PGF1α是一种稳定的代谢产物和PGI2的标记物，可通过环氧合酶（COX）产生。6-酮-PGF1α在人类中是与心血管和高血压事件负相关。PGF2α诱导牛，犬和人冠状动脉的血管收缩。PGF2α与心脏功能障碍和心脏肥大相关联。TXA2诱导血管收缩和血小板的聚集。发布于 2020-10-14 08:47干货心血管赞同添加评论分享喜欢收藏申请

羟基二十碳四烯酸（HETEs）分析 - 知乎

羟基二十碳四烯酸（HETEs）分析 - 知乎首发于百泰派克代谢组学服务切换模式写文章登录/注册羟基二十碳四烯酸（HETEs）分析百泰派克生物科技已认证账号已知花生四烯酸可以通过几种酶途径被氧化，包括前列腺素H2合酶、5-脂氧合酶和细胞色素P450依赖的环氧合酶反应。这些酶促途径需要游离花生四烯酸作为底物，并产生大量有生物活性的脂质介质，包括前列腺素、血栓烷、白三烯和环氧二十碳四烯酸。血液和血管中主要的花生四烯酸代谢产物是羟基二十碳四烯酸（HETEs）。羟基二十碳四烯酸HETEs与生理反应有关，例如聚集、细胞迁移和细胞增殖。高效液相色谱分离后的GC/选定离子监测通常被用作HETEs的灵敏和特异分析。百泰派克生物科技基于高稳定性、可重复和高灵敏度的分离、表征、鉴定和定量分析系统，结合LC-MS/MS提供可靠、快速且经济高效的羟基二十碳四烯酸HETEs及其异构体的分析服务。百泰派克可提供以下HETEs的分析HETEs（5-、8-、9-、11-、12-、15-、20-HETE），HEPEs和HDoHEs相关服务靶向脂质组学非靶向脂质组学脂质代谢组学研究How to order?联系我们：扫码立刻咨询点击咨询：http://i.biotech-pack.com/3联系方式：19182150730网址：http://i.biotech-pack.com/4地址：北京市经济技术开发区科创六街88号院发布于 2021-05-14 10:30生物化学与分子生物学分子生物学生物化学赞同添加评论分享喜欢收藏申请转载文章被以下专栏收录百泰派克代谢组

12-HETE (12-羟基二十碳四烯酸) - 仅供科研 | 血管功能调节剂 | MCE

— Master of Bioactive Molecules

花生四烯酸衍生的羟基二十碳四烯酸（HETE）和羟基二十碳四烯酸（oxo-ETE）的生物合成，生物学作用和受体,Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids - X-MOL

花生四烯酸衍生的羟基二十碳四烯酸（HETE）和羟基二十碳四烯酸（oxo-ETE）的生物合成，生物学作用和受体,Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids - X-MOL

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花生四烯酸衍生的羟基二十碳四烯酸（HETE）和羟基二十碳四烯酸（oxo-ETE）的生物合成，生物学作用和受体

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

(

4.8

)

Pub Date : 2014-10-29

, DOI:

10.1016/j.bbalip.2014.10.008

William S. Powell

Joshua Rokach

花生四烯酸可以被多种不同的酶氧化，包括脂氧合酶，环加氧酶和细胞色素P450，并且由于脂质的过氧化作用，可以转化为氧化产物的复杂混合物。这些反应的初始产物是氢过氧二十碳四烯酸（HpETE）和羟基二十碳四烯酸（HETE）。氧代二十碳四烯酸（oxo-ETE）可以通过HETE上各种脱氢酶的作用或HpETE的脱水来形成。尽管已鉴定出许多不同的HETE和oxo-ETE，但本综述主要侧重于5-oxo-ETE，5S-HETE，12S-HETE和15S-HETE。其他相关的花生四烯酸代谢物也将不那么详细地讨论。5-Oxo-ETE是通过选择性酶将5-脂氧合酶产物5S-HETE氧化而合成的，5-羟基类花生酸脱氢酶。它的作用是由选择性OXE受体介导的，该受体在嗜酸性粒细胞上高度表达，表明它在嗜酸性疾病如哮喘中可能很重要。5-Oxo-ETE也似乎刺激肿瘤细胞增殖，也可能与癌症有关。高选择性和有效的OXE受体拮抗剂最近已经可用，可以帮助阐明其病理生理作用。12-脂氧合酶产物12S-HETE由GPR31受体起作用，并促进肿瘤细胞增殖和转移，因此可能成为癌症治疗中有希望的靶标。它也可能作为糖尿病的促炎介质。相反，15S-HETE可能在癌症中具有保护作用。除了GPCR，较高浓度的HETE和OXO-ETE可以激活过氧化物酶体增殖物激活受体（PPAR），并可能通过该机制调节多种过程。本文是名为“ PUFA的氧合代谢：分析和生物学相关性”的特刊的一部分。

"点击查看英文标题和摘要"

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.

更新日期：2014-10-29

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12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 中华危重病急救医学

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12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展

程倩

田李星

梁华平

罗艳

中华危重病急救医学, 2019,31(12)

: 1555-1558. DOI: 10.3760/cma.j.issn.2095-4352.2019.12.027

摘要12-羟基二十碳四烯酸（12-HETE）是花生四烯酸（AA）的代谢产物。12-HETE主要由活化的磷脂酶A2（PLA2）释放AA后经12 -脂氧合酶（LOX）催化AA代谢生成。12-HETE在癌症、糖尿病和高血压等多种疾病中扮演着重要角色，参与炎症、氧化应激等病理过程的发生发展，目前研究表明它参与炎症反应过程中的变质、渗出。本文通过对12-HETE在炎症及氧化应激中的作用及其调节策略进行综述，以提高对12-HETE的认识。

引用本文:

程倩,

田李星,

梁华平,

等.

12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展

[J]

. 中华危重病急救医学,2019,31

(12): 1555-1558.

DOI: 10.3760/cma.j.issn.2095-4352.2019.12.027

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Hydroxyeicosatetraenoic acids (HETE), oxylipins, epoxides, docosanoids, octadecanoids, lipoxygenases, CYP450 oxidases - composition and biochemistry

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Hydroxyeicosatetraenoic Acids and RelatedMono-Oxygenated Oxylipins

The oxygenated metabolites or oxylipins derived from arachidonic and related fatty acids are produced

through a series of complex, interrelated biosynthetic pathways often termed the 'eicosanoid cascade'.

Here, the linear hydroxyeicosatetraenes and related mono-oxygenated metabolites are described,

together with octadecanoids produced from linoleate and comparable oxylipins from eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids.

While these are relatively simple in structure, they are precursors for families of more complex molecules, such as the

leukotrienes and lipoxins and the protectins, resolvins and maresins

(or 'specialized pro-resolving mediators').

The two main enzymatic pathways for production of these eicosanoids utilize lipoxygenases (LOXs) and oxidases of the cytochrome P-450 family,

although some are produced as minor by-products of cyclooxygenases or when cyclooxygenase 2 is inhibited by aspirin,

as discussed in our web page on prostanoids,

which have distinctive ring structures in the centre of the molecule and are discussed on their own web page.

Hydroperoxides can also be formed non-enzymatically (autoxidation) as discussed in our web page dealing with

isoprostanes.

1. Lipoxygenases and Hydroxyeicosatetraenoic Acids

Lipoxygenases are a family of enzymes that are characterized as non-heme iron proteins or dioxygenases, which

catalyse the abstraction of hydrogen atoms from bis-allylic positions (1Z,4Z-pentadiene groups) of polyunsaturated

fatty acids followed by stereospecific addition of dioxygen to generate hydroperoxides.

They occur widely in plants, fungi, a few prokaryotes (cyanobacteria and proteobacteria) and animals, but not in the archaea and most insects.

The plant lipoxygenases have distinctive substrates and products, and they are described in our web page dealing with

plant oxylipins rather than here, although interesting parallels can be drawn with the mechanisms

and functions of the animal enzymes.

Animal

lipoxygenases that utilize arachidonic acid as substrate are of great biological and medical relevance

because of the functions of the products in signalling or in inducing structural or metabolic changes in the cell.

They react with arachidonic acid per se to produce specific hydroperoxides and thence by downstream processing

the plethora of eicosanoids, each with distinctive functions, which are described in this and other web pages and include lipoxins, trioxilins,

leukotrienes, hepoxilins, eoxins and specialized pro-resolving mediators, but only the primary lipoxygenase products are discussed here.

These enzymes can react to some extent directly with phospholipids in membranes to produce hydroperoxides and further metabolites that

perturb the membranes to induce structural changes in the cell as in the maturation of red blood cells.

Beyond their role in oxylipin production, lipoxygenases and lipid hydroperoxides have a more general function in cellular redox homeostasis

and can stimulate the formation of secondary products, which, for example, can attack low-density lipoproteins directly with major implications

for the onset of atherosclerosis.

General mechanisms: The nomenclature of animal lipoxygenases is based on the specificity of the enzymes with

respect to the products of the reaction with arachidonate (not the initial point of hydrogen abstraction); for example, 12-LOX oxygenates

arachidonic acid at carbon-12, and the stereochemistry of the reaction can be specified, e.g., 12R-LOX or 12S-LOX,

although the most enzymic hydroperoxides have the S‑configuration.

Where more than one enzyme has the same specificity, it may be named after the tissue in which it is found, and there are platelet,

leukocyte and epidermal types of 12‑LOX.

As the research in this area has developed, this simplistic nomenclature has become confusing as some enzymes can oxygenate more than one

position and this can vary with the chain-length of the polyunsaturated substrate and the positions of the double bonds.

Enzymes with specificities for four different positions in arachidonic acid occur in animal tissues, i.e., 5‑LOX, 8-LOX, 12-LOX and

15‑LOX, although some of these have dual specificities, while many iso-forms exist depending on species.

In humans, there are now considered to be six main lipoxygenase family members (5‑LOX, 12‑LOX, 12/15‑LOX (15‑LOX type 1),

15‑LOX type 2, 12(R)-LOX and epidermal LOX (eLOX-3) with seven in mice.

Orthologues of the same gene have different reaction specificities in different species, and mice do not express a distinct 15‑LOX but rather

a leukocyte-derived 12-LOX with some 15‑LOX activity, so it can be difficult to extrapolate from animal experiments to human conditions;

the human enzymes only are discussed at length here.

Each of the lipoxygenase proteins in animal tissues has a single polypeptide chain with a molecular mass of 75-80 kDa.

They have an N‑terminal 'β‑barrel' or 'PLAT' domain, which is believed to function in the acquisition of the substrate,

and a larger α-helical catalytic domain containing a single atom of non-heme iron,

which is bound to four conserved histidine residues and to the carboxyl group of a conserved isoleucine at the C-terminus of the protein.

The PLAT domain anchors the otherwise cytosolic protein to membranes in response to intracellular calcium levels.

For catalysis, the iron component of the enzymes must be oxidized to the active ferric state.

All the enzymes appear to include the fatty acid substrate within a tight channel with smaller channels

that direct molecular oxygen toward the selected carbon to facilitate the formation of specific hydroperoxy-eicosatetraenes (HPETEs).

In other words, the regiospecificity is regulated by the orientation and depth of substrate entry into the active site,

while stereospecificity is controlled by switching the position of oxygenation on the reacting pentadiene

of the substrate at a single active enzyme site,

which is conserved as an alanine residue in S‑lipoxygenases and a glycine residue in the rarer R‑lipoxygenases.

There is evidence that two amino acids opposite the catalytic iron ion determine

the orientation of the substrate for entry into the enzyme channel.

With 5‑LOX and 8‑LOX, the carboxyl group of arachidonic acid enters the active site first,

while with 12-LOX and 15-LOX, the ω‑terminus enters the site and facilitates the activity.

It should be noted that the specificities of the enzymes are not always absolute and can differ between species.

The N-terminal domains function in membrane binding and regulation and are not required for the catalytic activity.

Lipoxygenase action is believed to proceed in four steps - hydrogen abstraction (1),

radical rearrangement (2), oxygen insertion (3) and peroxy radical

reduction (4), all occurring under strict steric control, as illustrated.

For example, in the action of 5-LOX, the first and rate-limiting step is the abstraction of a hydrogen atom from carbon 7 of arachidonic acid

by non-heme ferric iron (Fe(III)), involving a proton-coupled electron transfer in which the electron is transferred directly to the iron and

the proton is acquired simultaneously by the hydroxide ligand in a concerted mechanism to produce a substrate radical,

while the iron atom is reduced to the ferrous form (Fe(II)).

The cis-double bond in position 5 migrates to position 6 to form a more stable conjugated diene with a change to the

trans-configuration before dioxygen is introduced opposite to the removed hydrogen (antarafacially) to generate a lipid peroxyl radical.

Finally, the lipid peroxyl radical is reduced by Fe(II) and protonated to form a lipid hydroperoxide in another concerted reaction.

In the process, the iron atom is re-oxidized to its ferric form for another round of catalysis.

The oxylipin produced in the reaction illustrated is 5S‑hydroperoxy-6t,8c,11c,14c-eicosatetraenoic acid

(5‑HPETE).

HPETE in general have a short half-life and are rapidly metabolized to hydroxy-eicosatetraenes (HETE)

with the same stereochemistry, often via reduction by the abundant and ubiquitous glutathione peroxidases (step 5).

While their primary function is to act as intermediates in the biosynthesis of other eicosanoids,

HPETE have some biological activities of their own.

Alternatively, isomerization reactions of hydroperoxides can occur to produce leukotrienes and lipoxins via epoxy intermediates.

Simplistically, the Fe2+ in the lipoxygenase cleaves the O-O bond in the hydroperoxide with transfer of the hydroxyl group to form

Fe3+‑OH, before the residual alkoxyl radical is cyclized to form an epoxy fatty acid.

Enzyme specificities: 5-LOX (ALOX5) is found only in cells derived from bone marrow

(leukocytes, macrophages, etc.), and it is of particular interest as the product is the primary precursor for the

leukotrienes and lipoxins and for resolvins.

It is a cytosolic protein when intracellular calcium levels are low, but it becomes associated with the nuclear membrane when they are high

or after phosphorylation.

In contrast to other lipoxygenases, it requires the presence of a specific activator protein on the perinuclear membrane, lipoxygenase-activating

protein (FLAP), which facilitates the transfer of arachidonic acid to the active site on 5-LOX and is believed to accomplish the functional

coupling of phospholipase A2 (cPLA2) to 5-LOX at the membrane.

It is noteworthy that both cPLA2 and 5-LOX are Ca2+‑dependent.

The activities of 5-LOX and related enzymes are regulated by several factors that include the concentration and availability

of the substrates, the redox state, intracellular Ca2+ concentrations and phosphorylation-dephosphorylation

by means of various protein kinases.

8-, 12-

and 15-LOX operate in the same way to give analogous products and associate with membranes in a calcium-dependent process,

although they do not require accessory proteins.

15‑LOX exists in two forms, but the more active has a broader specificity somewhat dependent on the animal

source, hence the superfluity of names, and is expressed primarily in reticulocytes and macrophages on stimulation by interleukins 4 and 13

(12S-LOX of mice, leukocyte-type 12S-LOX of rabbits, reticulocyte-type 15S-LOX of rabbits and human

reticulocyte-type 15S-LOX).

The main product of 15-LOX in in humans is 15S-HPETE, and this form of the enzyme is then best termed

15‑LOX‑1 (alternatively, ALOX15 or 12/15‑LOX), but it can produce some 12‑HETE,

8,15‑diHETE and eoxin A4 from arachidonic acid.

It can oxidize linoleate to 13‑hydroperoxy-octadecadienoate (and in part to the 9-isomer), as well as oxidizing

α‑linolenic, γ‑linolenic, eicosapentaenoic and docosahexaenoic (DHA) acids.

15S‑HPETE is induced by the action of cytokines and is the precursor of the pro-resolution

lipoxins, while with DHA, 15-LOX produces

17(S)‑HPDHA, a precursor of resolvins and protectins.

Uniquely, 15‑LOX‑1 synthesises both pro- and anti-inflammatory molecules, and molecular genetics studies show that this broad

reactivity is seen only in higher ranked primates and not in mammals ranked in evolution lower than gibbons, where the enzyme has

12‑lipoxygenating specificity with arachidonate.

The second human arachidonate 15‑lipoxygenase has 40% homology with the first and is termed 15‑LOX‑2

(or ALOX15B).

The human form of 15‑LOX‑2 produces 15-HETE exclusively from arachidonate and is expressed constitutively in macrophages, where it

has been associated with cellular cholesterol homeostasis and is induced by hypoxia, and in the prostate gland, lung, skin and cornea.

Further, like 15-LOX-1, it differs from the other lipoxygenases in that it can utilize most polyunsaturated fatty acids as substrates, both in

unesterified form and bound to intact lipids, including phospholipids and cholesterol esters in biomembranes and lipoproteins.

Hence the interest in the role of the enzyme in autophagy, membrane disruption and disease states (asthma, psoriasis and atherosclerosis).

Mouse skin produces a lipoxygenase (8‑LOX) that is structurally related to 15-LOX-2,

but generates 8S-HETE and 8S,15S-diHPETE from arachidonic acid.

Some 15(R)-HETE is produced by the action of COX-2 and aspirin.

12(S)-LOX (ALOX12) from human platelets and leukocytes was one of the first lipoxygenases to be characterized,

but a rather different enzyme is present in the epidermis.

Although lipoxygenase metabolites generally have a hydroperoxide moiety in the S‑configuration,

lipoxygenases in mammalian skin can produce the R‑form.

Indeed, 12R‑HETE was first characterized as a component of psoriatic lesions.

One of the enzymes responsible is a second form of the human 15‑lipoxygenase (15-LOX-2), but there is also a 12R-LOX (ALOX12B)

with quite specific functions in keratinocytes and certain other tissues in relation to linoleate metabolism and the formation

of essential ceramides in the corneocyte envelope.

Thus, eLOX3 exhibits a hydroperoxide isomerase activity (lipohydroperoxidase activity) and transforms hydroperoxides to epoxy-alcohols

and ketones.

Enzymes related to the last are common in aquatic invertebrates.

Hydroxy fatty acids produced by lipoxygenases can be further oxidized to their keto analogues (cf., 5-oxo-eicosatetraenoic acid below)

or to dihydroxy derivatives that include the leukotrienes discussed in a separate web page;

some form glutathione conjugates.

2. Cytochrome P450 Oxidases and Hydroxy-/Epoxy-Eicosatetraenoic Acids

Arachidonic acid can be oxidized by several cytochrome P450 mixed-function oxidases to produce various HETE isomers

(the name was coined to describe the first such enzyme to be characterized and was based on an unusual absorbance peak at 450 nm

from its carbon monoxide-bound form).

These enzymes are a superfamily of membrane-bound hemoproteins that catalyse the scission of the dioxygen bond in molecular oxygen and

transfer a single atomic oxygen to a substrate carbon atom, i.e., they are monooxygenases

(with the release of the other oxygen atom as water).

The result is the introduction of either a hydroxyl or an epoxyl group into the molecule.

The catalytic turnover of the reaction is NADPH-dependent, requiring transfer of electrons from NADPH to the P450 heme iron

(lipoxygenases use non-heme iron) for which a membrane-bound enzyme partner, NADPH-cytochrome P450 reductase, is essential in the endoplasmic

reticulum (or functionally related enzymes in mitochondria).

Cytochrome P450 oxidases are found in all mammalian cell types and indeed appear to be ubiquitous in all living organisms,

although the number and distribution of each form of the enzymes are specific both to cell type and species.

They are located in the endoplasmic reticulum with a limited expression in mitochondria (and perhaps plasma membrane and nucleus)

and predominantly in the liver but with significant levels in some other extrahepatic tissues, including brain, kidney and lung.

As well as generating HETE isomers, enzymes of this kind have a more general function as part of the eicosanoid

cascade in the metabolism of prostanoids, and they are involved in cholesterol and steroid metabolism as well as detoxification of lipophilic

xenobiotics, including drugs and chemical carcinogens.

Their nomenclature starts with the root 'CYP', followed by a number allocated to the family, a letter for subfamily and

a gene-identifying number for isoforms.

CYP450s have two key domains: a β-sheet-rich N-terminal domain and a larger helix-rich C-terminal catalytic domain.

Those enzymes in the endoplasmic reticulum have a transmembrane helix in the N-terminal domain that is required for membrane anchoring,

but this feature is not present in mitochondrial CYPs, which rely upon hydrophobic regions on the surface to bind to membranes.

The catalytic domain contains the heme prosthetic group in a deep cavity, where variability in the structure of the active site

in each form explains the flexibility for substrates and products.

Access channels permit entry of substrates, and exit channels allow egress of the product.

Three types of reaction have been observed in animal cells that lead to the formation of three distinct families of eicosanoids,

all requiring unesterified arachidonic acid as substrate, although appreciable amounts of the products can be found in esterified form.

Mid-chain HETE: Synthesis of mid-chain HETEs is accomplished by CYP1B1, CYP4A or CYP2B members in reactions

at bis‑allylic centres and is lipoxygenase-like in the nature of the ultimate HETE products, although hydroperoxy intermediates

are not involved.

Thus, these microsomal cytochrome P450 oxidases can react with arachidonic acid to produce six regioisomeric

cis,trans-conjugated dienols, i.e., with the hydroxyl group in positions 5, 8, 9, 11, 12 or 15.

The mechanism is believed to involve bis-allylic oxidations at either carbon-7, 10 or 13,

followed by acid-catalysed rearrangement to the cis,trans-dienol (two of the possible products are illustrated).

12(R)-HETE as opposed to the 12(S)-isomer is a major product of the reaction,

and this was at one time though to be a distinguishing feature, but some other lipoxygenases are now known to produce the former enantiomer.

Omega-hydroxylated HETE: Secondly, there are ω- and (ω-1)-hydroxylases that introduce a

hydroxyl group into positions 20 and 19, respectively, of arachidonic acid mainly, although other enzymes can react at positions 16, 17 and 18.

The reaction was first observed with medium-chain saturated fatty acids, such as lauric (12:0), where it may play a role in oxidative catabolism.

Some isoenzymes are specific for laurate, others for arachidonate, and some will utilize both fatty acids as substrates.

In humans, the iso-forms CYP4A and CYP4F are the main enzymes involved in ω‑hydroxylation

of polyunsaturated fatty acids, including both arachidonic and eicosapentaenoic acids,

while the CYP1A1, CYP2C19, and CYP2E1 forms perform (ω‑1)-hydroxylations.

Both R- and S-forms of the sub-terminal HETE with differing biological activities can be produced.

20-HETE is metabolized by cyclooxygenases into a hydroxy analogue of prostaglandin H2 (20-OH PGH2),

a vasoconstrictor that is further converted by isomerases into 20-OH PGE2 and 20-OH PGI2 (vasodilator/diuretic metabolites)

and 20‑OH thromboxane A2 and 20-OH PGF2α (vasoconstrictor-antidiuretic metabolites).

Some CYP450 enzymes can introduce hydroxyl groups into positions 2 and 3 of fatty acids,

while others can catalyse decarboxylation or form terminal alkenes, properties that have biotechnology potential.

Epoxyeicosatrienoic acids: The third series of reactions of P450 arachidonic acid monooxygenases

involves the formation of epoxytrienoic acids (‘EET’) from arachidonic acid,

i.e., four cis-epoxyeicosatrienoic acids (14,15-, 11,12-, 8,9- and 5,6-EETs).

Apart from the 5,6-isomer, they are relatively stable molecules.

Several iso-enzymes of the cytochrome P450 epoxygenase exist, with CYP2C and CYP2J as the most active,

and they can produce all four EET regioisomers, although one isomer tends to predominate in each tissue usually.

For example, epoxygenases that produce 14,15-EET as the main isomer synthesise a significant amount of 11,12‑EET and a little 8,9-EET.

The epoxygenase attaches an oxygen atom to one of the carbons of a double bond of arachidonic acid,

and as the epoxide forms, the double bond is reduced.

The enzymes are located both in the cytosol and the endoplasmic reticulum of endothelial cells, and they make use of arachidonic acid

that is hydrolysed from phospholipids when the Ca2+-dependent phospholipase A2

is activated and translocated from the cytosol to intracellular membranes.

The proportions of the various isomers depend on tissue and species, although the 11,12- and 14,15‑EET generally tend to predominate.

In the rat, 14,15‑EET amounts to about 40% of those produced in the heart, while 11,12-EET represents 60% of those produced in the kidney.

To add to the complication, each of these regioisomers is a mixture of

R,S- and S,R-enantiomers, and each iso-enzyme produces variable proportions, differing even among regioisomers.

Eight isomers can be formed, therefore, each with somewhat different biological activities.

By the same means, adrenic acid (22:4(n-6)) can be converted to epoxy metabolites with 16,17‑epoxydocosatrienoic acid as the most

abundant isomer in liver.

The epoxygenases require the fatty acid substrate to be in the unesterified form, but the products can be esterified later.

Thus, significant amounts of epoxyeicosatrienes are found esterified to position sn-2 of phospholipids, including phosphatidylcholine,

phosphatidylethanolamine and phosphatidylinositol, perhaps as a storage form that is available when a rapid response is required.

Free epoxyeicosatrienes can then be released following activation of phospholipase A2 by neuronal, hormonal or chemical stimuli,

although it is possible that esterified epoxy-eicosanoids may have a biological function within membranes.

The presence of esterified EETs in plasma suggests that some exchange between tissues is likely, although most are believed to be

produced close to the site of action.

In many tissues, the esterified epoxy-eicosanoids are almost identical in composition to those in the free form, so the conclusion must be that

they are entirely products of enzyme action.

On the other hand, non-enzymic lipid epoxidation has been observed in erythrocytes in vitro, and some EETs with the epoxide group

in both the cis- and trans-configurations may arise by this route.

EETs are rapidly metabolized in vivo to the corresponding dihydroxyeicosatrienoic acids (DHET) by epoxide hydrolases, of which at

least five forms are known with different cellular locations and preferred substrates.

The cytosolic (EPHX2) and membrane-bound (EPHX1) enzymes are of special importance, both in terms of lipoxin metabolism

and for detoxification of xenobiotic epoxides.

In humans, EPHX2 is widely expressed throughout the body and is a 62kDa enzyme composed of two domains

separated by a short proline-rich linker in which the N‑terminal domain has phosphatase activity towards lipid phosphates,

while the C-terminal domain has the epoxide hydrolase activity.

The reaction is illustrated below for the conversion of 14,15-EET to 14,15-DHET.

This enzyme metabolizes 8,9-, 11,12- and 14,15-EET efficiently, but 5,6-EET is a poor substrate.

It displays some enantioselectivity, and this may be a factor in determining the stereochemistry of the circulating epoxides.

11,12- and 14,15-EET can undergo partial β‑oxidation to form C16 epoxy-fatty acids, or they can be elongated to

C22 products, and 5,6- and 8,9-EET are substrates for cyclooxygenase.

While DHETs were once believed to be merely deactivation products of EETs, they are now known to have appreciable biological effects

of their own.

3. Oxo-Eicosatetraenoic Acids

5-Oxo-6t,8c,11c,14c-eicosatetraenoic acid

(5-oxo-ETE) is a metabolite of 5S-hydroxy-6t,8c,11c,14c-eicosatetraenoic acid (5‑HETE),

produced by oxidation by NADP+-dependent 5-hydroxy-eicosanoid dehydrogenase,

an enzyme found in the microsomal membranes of white blood cells (leukocytes), platelets, eosinophils and neutrophils.

The enzyme requires the presence of a 5S‑hydroxyl group and a

trans-6 double bond in the eicosanoid, and NADP+ is a cofactor.

Synthesis of the metabolite is stimulated during periods of oxidative stress, but some 5-oxo-ETE may be formed directly from

5‑hydroperoxyeicosatetraenoic acid, possibly by a non-enzymic route.

It can be produced by transcellular biosynthesis from inflammatory cell-derived 5S-HETE.

In neutrophils, a high proportion is rapidly incorporated into triacylglycerols.

It appears that 5-hydroxyeicosanoid dehydrogenase can catalyse the reverse reaction, i.e., the reduction of 5-oxo-ETE,

and this seems to be of special relevance in platelets.

The biological activity of 5-oxo-ETE is of course changed by this reverse reaction,

and alternative deactivation can occur by reduction of the double bond in position 6,

or by further oxidation either by lipoxygenases or by cytochrome P450 enzymes, the latter in positions 19 or 20.

All the HETE isomers can be converted to oxo-metabolites by specific hydroxy-eicosanoid dehydrogenases,

and the 11-, 12- and 15‑isomers possess appreciable biological activity.

15(S)-HETE and 11(R)-HETE are substrates for 15‑hydroxyprostaglandin dehydrogenase,

the enzyme involved in the first step of prostaglandin catabolism,

to yield 15-oxo-ETE and 11‑oxo‑ETE, respectively, which mediate anti-proliferative properties in endothelial cells.

They can also form CoA esters, which can undergo up to four double bond reductions.

14‑Hydroxy-docosahexaenoic acid is a good substrate for the enzyme to yield the 14-oxo analogue.

It is now recognized that α,β-unsaturated keto-eicosanoids generated in this way

are electrophilic and have the potential to interact with nucleophilic centres in proteins and other molecules to modify their activities.

4. Mono-oxygenated Metabolites of EPA and DHA

Lipoxygenases and cytochrome P450 oxidases interact with the other essential polyunsaturated fatty acids of

the omega-3 and omega-6 families, especially the former, to give comparable series of metabolites.

Lipoxygenases have much the same positional specificity with eicosapentaenoic acid (EPA or 20:5(n-3)) as with arachidonic acid

to produce hydroxy-eicosapentaenoic acids (HEPE), such as 5- and 12‑HEPE, but 18‑HEPE is produced by aspirin-acetylated

COX-2 or by CYP2C8/CYP2J2.

5-Lipoxygenase generates 4- and 7‑hydroxy metabolites from docosahexaenoic acid (22:6(n‑3) or DHA),

while 12-lipoxygenase generates 11- and 14-hydroxy metabolites, and 15‑lipoxygenase (15-LOX-2) introduces a 17‑hydroxyl group.

These can react further to produce the protectins, resolvins and maresins or 'specialized pro-resolving

mediators', which have special importance in the resolution of inflammation and have their own web page

The products of the lipoxygenases with arachidonate were soon documented, but it has taken longer to recognize the occurrence and activities

of the metabolites of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, e.g., the epoxides,

produced by the activities of various cytochrome P450 oxidases.

Indeed, it is now evident that these n-3 polyunsaturated fatty acids, rather than arachidonic acid,

are the preferred substrates for some of the enzyme isoforms, specifically the CYP1A, CYP2C, CYP2J and CYP2E subfamily members,

which then exhibit very different regio- and stereo-specificities.

Human CYP1A1 acts mainly as a subterminal hydroxylase with arachidonate to produce four different isomers, but with EPA it generates

mainly 17(R),18(S)-epoxy-eicosatetraenoate with almost absolute regio- and stereo-selectivity, and with DHA, it epoxidizes

the n-3 double bond and produces 19,20‑epoxydocosapentaenoate.

Other isoforms of the cytochrome P450 enzymes produce epoxides by reaction with an n‑3 double bond in the same manner,

some much more rapidly than with arachidonate as substrate, but CYP2C9 is an exception and oxidizes EPA to 14,15-epoxy-ETE mainly and

DHA to 10,11‑epoxy‑DPE.

The CYP4A/CYP4F subfamilies generate 20-hydroxy-eicosatetraenoic acid from arachidonate in mammals, and they hydroxylate the terminal

methyl group in EPA and DHA at the same rate.

In addition, human endothelial cells with upregulated COX-2 and treated with aspirin convert EPA to 18R-hydroxyeicosapentaenoic acid

with anti-inflammatory properties.

4‑Oxo‑DHA is present in plasma of rats fed DHA and has potent anti-tumour effects against breast cancer, possibly because it can

undergo the Michael reaction, although details of its fine structure and biosynthesis are awaited.

By competing with arachidonate, EPA and DHA may modify the action of the various HETE metabolites,

but the oxygenated EPA and DHA compounds have biological properties of their own.

For example, 17,18-epoxyeicosatetraenoic acid generated in the gut is an anti-allergic molecule, while significant amounts of DHA epoxides,

mainly 7,8‑epoxydocosapentaenoic acid, are present in the central nervous system of rats, where they ameliorate the effects

of inflammatory pain.

It has been suggested that such EPA and DHA metabolites may be responsible for some of the beneficial effects

associated with dietary n‑3 fatty acid intake.

5. Octadecanoids

Linoleate hydroperoxides are produced in animal tissues by all the enzymes involved in eicosanoid formation, including

lipoxygenases, cyclooxygenases and cytochrome P450 enzymes, with production of octadecanoids or 'HODEs', and they can be catabolized by

the same enzyme, i.e., 15-hydroxyprostaglandin dehydrogenase, to form keto derivatives.

In the gut, bacteria produce 12(Z)-10- and 11(E)-10-hydroxyoctadecamonoenoic acids (HOME) by enzymatic oxidation

of linoleic acid.

While similar reactions occur with both α- and γ‑linolenic acids in vitro and their metabolites have been detected in plasma

and some other tissues at low levels, relatively little appears to be known of their biological significance in vivo.

Autoxidation of linoleate produces the same types of products but with more variable stereochemistry.

The action of lipoxygenases upon linoleic acid in plant tissues is discussed in the web page on

plant oxylipins, but this fatty acid is acted upon by lipoxygenases in animal tissues in the same

way to produce 9- and 13-hydroperoxy- and thence hydroxy-octadecadienoic acids of defined stereochemistry.

13(S)‑Hydroperoxy-9Z,11E-octadecadienoic acid (13S‑HPODE) is generated by the action

of 15‑lipoxygenase (15‑LOX‑1) on linoleic acid, and this is reduced to the hydroxy compound, while oxo-, epoxy- and

epoxy-keto-octadecenoic acids can be formed in further reactions, as illustrated.

12R-LOX reacts readily with linoleate (9,12-18:2) to produce 9R‑HPODE.

Enzymes of the cytochrome P450 family make a further contribution, and linoleic acid is a substrate for CYP epoxygenases, e.g.,

CYP2C9 in human liver, to yield the linoleic epoxides 9,10- and 12,13‑epoxyoctadecenoic acids, which are sometimes termed

leukotoxins (although this name has been applied also to very different microbial metabolites).

Epoxide hydrolase can then metabolize them to the 9,10- and 12,13‑diols, respectively.

Epoxy-octadeca-monoenoic acids are produced by insects where they are believed to be involved in the resolution of cellular and

humoral immune reactions.

Linoleate metabolites were first found in patients with burns and inflammatory diseases, adult respiratory distress syndrome and chronic

obstructive pulmonary disease (COPD), and the diols can cause mitochondrial-mediated cell death, although they can be detoxified

by conversion to the glucuronides.

On the other hand, 12,13-dihydroxy-9Z-octadecenoate (12,13-diHOME) synthesised in adipose tissue has beneficial properties (see below).

As linoleic acid is a major unsaturated fatty acid in animal tissues, appreciable amounts of these hydroxy and hydroperoxy metabolites

can accumulate and influence inflammatory diseases.

Indeed, linoleate metabolites are by far the most abundant oxygenated fatty acids in both free and esterified form in human plasma

and in the brain of rat pups.

A further interesting observation is that one of the unique ceramides of skin,

O‑linoleoyl-ω-hydroxyacyl-sphingosine, is a substrate for 12R‑LOX with

9R‑hydroperoxy-linoleoyl-ω-hydroxyceramide as the product.

This in turn can be converted to hepoxilin-like compounds,

i.e., with an epoxyl group, by an enzyme epidermal lipoxygenase 3 (eLOX-3), while trihydroxy compounds,

e.g., octadec-9R,10S,13R-trihydroxy-11E-enoate (tri-HOMEs) may be formed subsequently by the action of an epoxide

hydrolase, such as the human soluble enzyme.

9R,10S,13R-Trihydroxy-11E-octadecenoate is an important oxylipin formed

in porcine and human epidermis, where it interacts with the ceramides to aid formation of the waterproof barrier.

In the lung, tri-HOMEs are produced by a mechanism that is believed to involve formation of a 13S‑hydroperoxide by the action

of 15-lipoxygenase and proceeds via an epoxide intermediate.

6. Esterified Oxylipins

Most eicosanoid-generating enzymes require free fatty acids as the substrate, and they are unable to oxidize intact phospholipids,

although 15‑LOX in human monocytes is an exception (as is murine 12/15-LOX).

However, free 5-, 12- and 15-HETEs can be esterified to phospholipids in tissues, often with some specificity, as can hydroxydocosahexaenoic acids

and hydroxyoctadecadienoic acids, and it has been established that all mammalian long-chain acyl-CoA synthetase isoforms have the capacity

to activate HETE for further esterification through the action of membrane-bound O‑acyltransferases (thromboxanes may be an exception).

The mechanisms for these esterification processes are discussed in our web page on

oxidized phospholipids.

It is evident that many of these reactions depend on specific cell types and lipids, and that cell compartmentalization is a significant factor,

since eicosanoids of exogenous origin and those generated endogenously appear to be sensed differently.

In contrast, non-enzymatic oxidation (autoxidation) of polyunsaturated fatty acids occurs when they are in esterified form by the initial steps

described in our web page on isoprostanes.

15-HETE is selectively esterified to phosphatidylinositol in lung and kidney epithelial cells and in aortic endothelial cells,

while 12-HETE occurs predominantly in phosphatidylcholine in microsomal membranes.

In neutrophils, 5-HETE is incorporated mainly into phosphatidylethanolamine plasmalogens and phosphatidylcholine,

while three 12‑hydroxyeicosatetraenoic acid phosphoinositides have been detected in thrombin-activated platelets.

More than 90% of the EETs in most plasma and organ tissues are esterified to position sn‑2 of glycerophospholipids, and

in aortic endothelial cells, 20‑HETE is present in esterified form in several phospholipid classes.

Many of these esterified lipoxygenase and oxidase products of phospholipids remain within the membranes where they are believed to serve

as storage forms to be released on appropriate stimulation, possibly into other cellular compartments with different biological roles

from their unesterified equivalents.

On the other hand, such oxidized lipids have the potential to perturb membrane structures and effect secondary oxygenations that could

induce unwanted changes in cells, such as ferroptosis (see our web page on

oxidized phospholipids), and their biological activities are discussed further below.

Oxidation of low-density lipoprotein by this means may be involved in the initiation of atherosclerosis, and

there are suggestions that cholesteryl arachidonate in the lipoprotein LDL is a good substrate

for 15‑LOX‑1 or oxidizing agents derived from it, and that the products are a causative factor in this disease

(see our web page on cholesterol).

Phospholipids containing EET are substrates for the production of lipid mediators such as

2-epoxyeicosatrienoyl-sn-glycerols, analogous to the endocannabinoid

2-arachidonoylglycerol (and discussed further under this topic).

Kidney and spleen, for example, synthesise sn-2-glycerol derivatives esterified with 11,12-EET or 14,15-EET,

which are endocannabinoids and exert biological effects by activating the CB1 and CB2 receptors, while

phospholipids containing EET are probable substrates for synthesis of EET-ethanolamide in the liver and kidney.

Endocannabinoids such as anandamide and synaptamide can be converted directly to

various oxygenated derivatives, which can have higher biological activities than their precursors.

7. Biological Activity

Numerous hydroxyeicosatetraenoic acids and related compounds have now been discovered and most of these have some form of biological activity,

in vitro at least, and primarily in signalling.

They modulate ion transport, vascular tone, renal and pulmonary functions, and growth and inflammatory responses

through both receptor and non-receptor mechanisms.

Their release is stimulated by the action of growth factors and cytokines, and they attain physiological concentrations in tissues that are

much higher than those of prostanoids.

This is a field that is still developing rapidly, and it is evident that the picture is complex and very far from complete.

A given eicosanoid of this kind can have differing functions in different cell types,

and its activity may be opposed or modified by another eicosanoid; the balance between them in a cell may be critical.

As animal models can have very different isoforms of enzymes,

it is often difficult to translate experiments with other species to human conditions.

It is not possible to give a comprehensive picture of these manifold biological activities here, as this would require a substantial tome,

and only a few of best known and studies are described briefly below.

HETEs: 5S-Hydroxy-6t,8c,11c,14c-eicosatetraenoic

acid (5(S)-HETE) is the precursor of the leukotrienes

and lipoxins, but it has some biological functions in its own right,

although these can be difficult to disentangle from those of its metabolites, which are more active.

Like its metabolite 5-oxo-HETE, 5(S)‑HETE activates neutrophils and monocytes, and it is known to stimulate proliferation of cancer cells

in a similar manner to certain leukotrienes with increased amounts formed in brain tumours; 5-LOX inhibitors have preventive effects.

5-Oxo-6t,8c,11c,14c-eicosatetraenoic acid is a chemo-attractant for eosinophils and

neutrophils and has many functions in such cells, including actin polymerization, calcium mobilization, integrin expression and degranulation.

Its signalling functions are mediated via a specific Gi/o-coupled receptor ('OXE'),

leading to increased intracellular calcium concentrations and inhibition of cAMP production.

By increasing the production of dermal fibroblasts, it promotes wound healing, but this is inhibited by the action of

ceramide 1-phosphate on its receptor (OXER1 in mice).

In contrast, it stimulates the proliferation of prostate tumour cells, and it is believed to be a mediator in asthma and other

allergic diseases

Efforts are underway to find inhibitors of the OXE receptor of potential clinical value.

Arachidonate

8(S)-lipoxygenase and its product 8S-hydroxy-5c,9t,11c14c-eicosatetraenoic

acid (8S-HETE) has only been found in the skin of mice.

It is a potent activator of the peroxisome proliferator-activated receptor PPARα, it is an anti-tumorigenic agent towards skin cancer,

and it promotes wound healing in the cornea.

In contrast, a human orthologue of this enzyme (15‑LOX‑2) is found in skin, sebaceous glands and prostate tissue but produces

15S-HETE.

12S-Hydroxy-5c,8c,10t,14c-eicosatetraenoic acid

(12S-HETE) is the precursor of the hepoxilins but has functions of its own.

In nervous tissue, it modulates membrane properties and stimulates melatonin synthesis, while together with 15(S)‑HETE,

it serves as a secondary messenger in synaptic transmission and is involved in learning and memory processes; increased levels are found

in Alzheimer's disease.

12S‑HETE can either stimulate or inhibit aggregation in platelets, depending on species and circumstances, and it can cause

constriction of blood vessels but inhibition of thromboxane (TxA2)-induced platelet aggregation while stimulating lipoxin synthesis.

The serum level of 12-HETE has been shown to be elevated in individuals with coronary heart disease, and in leukocytes, it promotes chemotaxis

and induces the synthesis of heat-shock protein.

Particular attention has been devoted to the effects of 12S‑HETE on inhibiting the adhesion of cancer cells to endothelial cells,

an activity that is linked to metastasis in cancer of the prostate and is mediated via cell surface signalling and activation

of protein kinase C; it promotes the proliferation of ovarian and other cancer cells by various mechanisms.

Extracellular vesicles derived from platelets promote tumour metastasis, and the explanation appears to be that they deliver 12‑lipoxygenase

to cancer cells where free and phospholipid-esterified 12S‑HETEs are generated.

The enantiomeric compound 12R-HETE is believed to be involved in the pathophysiology of

psoriasis and related skin diseases, although it is essential for the development of normal skin.

12R-HETE produced by cytochrome P450 enzymes may have a function in the eye.

12S‑Hydroxy-8,10,14-eicosatrienoic acid (12S‑HETrE), derived from dihomo-γ-linolenic acid (20:3(n‑6)),

has been shown to provide protection against thrombotic-mediated events in vivo and has a potential therapeutic role in providing

cardioprotection by activating the prostacyclin receptor (IP).

The hydroperoxide precursors of the various HETE isomers tend to be less studied, but 12S-hydroperoxy-ETE is reported to be

a key player in oxidative stress in platelets and is known to stimulate

the metabolism or arachidonate and other polyunsaturated fatty acids by activating phospholipase A2

(cPLA2) and cyclooxygenase (COX-1), the first enzymes required for prostanoid production.

15S-Hydroxy-5c,8c,11c,13t-eicosatetraenoic

acid (15S-HETE) is a precursor of the lipoxins

and is produced by two lipoxygenases in human tissues, one of which (15-LOX-1) is related structurally to the 12-lipoxygenase of leukocytes

and is unusual in that it produces some 12-HETE in addition to the 15‑isomer.

The second form of the enzyme was first found in the epidermis, although it is now known to exist in other tissues.

15S-HETE has been implicated in cell differentiation, inflammation, asthma and carcinogenesis.

In atherogenesis, there is an accumulation of 15-HETE in human carotid plaques, and this is believed to play a role in the induction

of atherothrombotic events by increasing platelet aggregation and thrombin generation.

15‑HETE appears to contribute to the development of Hodgkin lymphoma, colorectal and many other cancers,

but that produced by 15‑LOX‑2 activates PPARγ, a nuclear transcription factor involved in epithelial differentiation,

which may explain an anti-proliferative action on prostate cancer cells.

The activity of 15-LOX-1 is a feature of the processes of apoptosis, autophagy and ferroptosis, and reduced levels of this enzyme in some

cancers lead to decreased activity of PPARγ, resulting in a halt to apoptosis and enhanced cell proliferation.

Of the terminal and near-terminal HETE isomers (cytochrome P450 metabolites), 20-HETE has been considered to be

pro-inflammatory with largely detrimental functions in increasing hypertension, promoting systemic vasoconstriction and

tumour growth, while it may be a factor in rheumatoid arthritis.

It regulates vascular smooth muscle and endothelial cells by influencing their proliferation, migration, survival and tube formation,

acting via a specific G protein receptor (GPR75).

In contrast, 20-HETE has the potential to prevent septic shock and multi-organ failure induced by bacterial lipopolysaccharides.

It exerts a beneficial effect in terms of insulin secretion, and in the kidney, it has anti-hypertensive effects by blocking

re-absorption of sodium by inhibiting the Na+‑K+‑ATPase, although it has been implicated in the pathogenesis

of other kidney diseases.

Production of 20-HETE is increased after the onset of both ischemic and hemorrhagic strokes.

Although 20‑HETE may promote tumour growth, 8- and 11‑HETE have anti-tumour activities.

EPA and DHA are potent inhibitors of the biosynthesis of 20‑HETE, suggesting that this may be a partial explanation for

the physiological role of omega-3 fatty acids, although other HETE isomers appear to act in opposition to it, and 18- and 19‑HETE

induce vasodilatation by inhibiting the effects of 20‑HETE.

Together with 16- and 17‑HETE, they induce re-uptake of sodium in the kidney, and 16‑HETE inhibits neutrophil adhesion so may

be relevant to inflammation.

On the other hand, high 19-HETE concentrations have been correlated with cardiovascular events.

The 3-hydroxy-eicosanoids produced by pathogenic fungi may play a role in

the inflammatory processes associated with infections by such organisms, as they are strong pro-inflammatory lipid mediators.

As they are produced during the reproductive phase of yeast and fungal growth, they are presumably required for the organism per se.

Metabolites of EPA and DHA: The EPA lipoxygenase metabolite

5-hydroxy-eicosapentaenoic acid (5-HEPE) enhances the induction of regulatory T cells (Tregs) that modulate

the immune system and prevent autoimmune disease, and it can increase insulin secretion from pancreatic beta cells in mice.

Both 5- and 12-HEPE are induced in brown fat when exposed to cold and have been termed 'batokines'

or 'lipokines' that improve glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation

of an insulin-like intracellular signalling pathway.

Apart from its function as a precursor of E-series resolvins, 18‑HEPE per se has cardioprotective properties

and inhibits metastasis in a cancer model.

Various HEPE isomers have been detected in psoriatic arthritis, where that are believed to have anti-inflammatory effects.

It is noteworthy that while 17-hydroxy-DHA derived from the action of 15-LOX is often considered simply as

a precursor of the specialized pro-resolving mediators, there is evidence that it rather than the latter alleviates

the sensitivity to heat pain and osteoarthritis pain in humans.

In brain, 7(S)-HDHA is a high-affinity PPARα ligand that stimulates the growth of neurons and regulates the expression of genes

associated with their morphology.

In obese mice, 17‑HDHA attenuated inflammation in adipose tissue and improved insulin sensitivity and glucose tolerance.

Epoxyeicosatrienoic acids (EETs): The various EETs have major functions as autocrine and paracrine effectors

in the cardiovascular and renal systems that are believed to be anti-inflammatory and largely beneficial.

As the regioisomers and enantiomeric forms have many similar metabolic

and functional properties, epoxyeicosatrienoic acids have often been treated as a single class of compounds,

although as knowledge has expanded this view is no longer justifiable.

11,12-EET in particular has a number of distinctive activities.

Because of the anti-hypertensive, anti-fibrotic and anti-thrombotic properties of EETs, their presence in red blood cells has

implications for the control of circulation and the physical properties of the circulating blood.

Both cis- and trans-EETs are synthesised and stored in erythrocytes,

and they are produced and released in response to a low oxygen concentration as during exercise.

11,12‑EET enhances the process by which immature precursor cells develop into mature blood cells (hematopoiesis)

and in their further development (engraftment) in mice and zebrafish in vitro.

In the kidney, EETs modulate ion transport and gene expression to produce vasodilation, and in other tissues,

they exert beneficial effects on insulin resistance and obesity-associated diseases, they alleviate inflammatory pain, neuroinflammation

and neuroinflammatory diseases, and they improve lung function and wound healing.

By direct and indirect anti-inflammatory actions in the myocardium, they alleviate cardiomyopathy and cardiac remodelling.

There is a suggestion that signalling by 11,12-EET may be a factor in the regulation of the response to DNA damage,

and it is reported to beneficial towards pulmonary fibrosis.

Through interactions with specific binding pockets, fatty acid binding proteins (FABP3 and FABP5) modulate signalling of EETs

in synapses in the brain.

As significant amounts of EETs are incorporated into phospholipids from which they are rapidly released in the presence of Ca2+

ionophores, it has been suggested that they may be involved in those signal transduction processes mediated by phospholipases.

Some of the activities of epoxy-eicosanoids may require cell-surface receptors, and GPR132 has been identified as a potentially

low-affinity EET receptor with physiological relevance in hematopoiesis, but other activities involve intracellular mechanisms,

i.e., direct interaction with ion channels, signalling proteins or transcription factors.

In the central nervous system, epoxyeicosanoids may have additional functions such as the regulation of the release of neurohormones

and neuropeptides, and by reducing the long-term damage associated with central neurologic insults, they may have beneficial effects towards

neurologic diseases including Parkinson's disease, Alzheimer's disease and dementia.

Their concentrations are controlled by soluble epoxide hydrolases, and it is hoped that inhibitors of these will be developed

with therapeutic potential against several debilitating inflammatory diseases.

In non-failing human hearts, one isoform of phospholipase A (cPLA2ζ) channels arachidonic acid into protective EETs,

whereas in failing hearts, opening of the mitochondrial permeability transition pore increases the activity of a second isoform

of phospholipase A (cPLA2γ) that channels arachidonic acid into toxic HETEs.

17,18-Epoxyeicosatetraenoic acid is the main epoxide regio-isomer synthesised

from eicosapentaenoic acid and has anti-allergy and anti-inflammatory properties by activating the receptor GPR40;

it may have therapeutic properties in the skin and intestines.

In sensory neurons, it functions through the prostacyclin receptor (IP) to sensitize the transient receptor potential vanilloid 1 (TRPV1).

It is a vasodilator and may be responsible for some of the beneficial effects of dietary omega-3 fatty acids.

While 19,20-epoxy-docosapentaenoic acid derived from DHA has been shown to have many beneficial functions in tissues,

much less is known of the function of the other oxygenated metabolites of EPA and DHA, although they appear to act in opposition to HETE

isomers and may be important in the cardiovascular system and as anti-cancer agents.

Until recently, EETs were believed to be relatively benign molecules, but it has now been demonstrated in mice that they are

stimulants for the release of primary cancer tumours from dormancy, for promoting their growth and for triggering metastasis,

i.e., the spread of cancer to other organs; their dihydroxy metabolites have even stronger effects upon cancer progression.

The dihydroxyeicosatrienoic acids (DHET) produced by epoxide hydrolases are pro-inflammatory in general,

and they have been associated with colonic inflammation in obese mice and with osteoarthritis in the knee in humans.

Acting via ferroptosis, dihydroxy-metabolites of dihomo-γ-linolenic acid (20:3(n-6)) are reported to cause neurodegeneration,

while 19,20‑dihydroxydocosapentaenoic acid has a role in the development of diabetic retinopathy.

As dihydroxy metabolites may be involved in psychiatric and neurological disorders, the soluble epoxide hydrolase (EPHX1)

is a therapeutic target for such conditions as well as to assist in cardiac recovery after ischemia.

Inhibitors of the enzyme are undergoing clinical trials for several inflammatory conditions, including cancer.

Octadecanoids: The oxidized linoleate metabolites 13S-HODE and 9S-HODE are believed

to be atherogenic through the induction of pro-inflammatory cytokines and formation of foam cells from macrophages

by activation of PPARs, e.g., PPARγ, and other receptors.

9S‑HODE but not 13S-HODE is a high-affinity ligand of GPR132 and has proinflammatory effects, and the former is a marker for

oxidative stress and contributes to the process of pain perception.

In a Drosophila model, it functions by regulating FOXO family transcription factors.

HODE are found at increased levels in psoriatic skin, and they contribute to hepatic injury, including non-alcoholic steatohepatitis,

possibly by non-enzymatic formation of potentially toxic adducts with proteins.

As the actions of octadecanoids on the regulation of inflammation are of relevance to the metabolic processes associated

with atherogenesis and cancer, they are attracting special interest.

In contrast, there is evidence that a 15-LOX metabolite 13S-HPODE induces apoptosis in colon cancer cells.

13(S)-HODE is the brains of rat pups is reported to increase axonal outgrowth cortical neurons in male rat pups significantly,

but not in female pups where linoleic acid per se displayed this activity.

In general, in brain, HODE are involved in regulating pain thresholds, inflammation, neurotransmission and the response to ischemic brain

injury.

Epoxy-octadecenoic acids (epOMEs) are metabolites of linoleate from the cytochrome P450 monooxygenase pathway that have

cancer-promoting effects in the colon via mechanisms that involve the gut microbiota.

At high levels, the dihydroxy-metabolites (DiHOMEs) of these are vascular permeability and cytotoxic agents associated with multiple

organ failure, adult respiratory distress syndrome, and sepsis in burn patients, although they are not implicated in colon cancer.

In severe burn injury, DiHOMEs drive immune cell dysfunction through hyperinflammatory neutrophilic and impaired monocytic actions,

so inhibition of soluble epoxide hydrolase may be a promising therapeutic strategy.

12,13‑Dihydroxy-9Z-octadecenoic acid (12,13‑diHOME) causes increased sensitivity to inflammatory pain and has been

associated with the development of paediatric asthma, while both 9,10- and 12,13-diHOME are reported to be biomarkers for small versus

large vessel stroke, together with blood brain barrier and neurovascular-glial disruption and temporal lobe atrophy.

9,10-DiHOME produced by commensal bacteria in the intestines facilitates regulatory T cell differentiation and may be a biomarker for

colitis.

On the other hand, synthesis of 12,13‑diHOME is induced by cold with the effect of stimulating the activity of

brown adipose tissue by promoting the uptake of fatty acids.

As plasma levels are increased by exercise and the source is believed to be brown adipose tissue, 12,13-diHOME has been termed an

exercise-stimulated lipokine (or batokine), which produces an increase in fatty acid oxidation and uptake in skeletal muscle that results

in improved whole-body metabolic homeostasis and may be cardioprotective.

It has been detected in human milk where it is believed to influence infant adiposity.

In contrast, 12,13-diHOME (and noradrenaline) have been correlated with the occurrence of acute myocardial infarction and cognitive

decline in patients with type 2 diabetes mellitus.

Hepoxilin-like triHOMEs are important in skin, where they are vital for epidermal barrier formation (and some argue

for mammalian survival), but their levels are dysregulated in asthma and chronic obstructive pulmonary disease (COPD).

In psoriasis, 9,10‑epoxy-13-hydroxy-octadecenoate and 9,10,13-trihydroxy-octadecenoate contribute to itch and pain.

Oxidized phospholipids: Although studies are at a relatively early stage, it is apparent that esterified

HETEs have their own specific biological functions in relation to apoptosis, immune regulation, signalling and blood coagulation.

Oxidation of cardiolipin by a specific enzyme

of the cytochrome c family is an significant event in triggering mitochondrial apoptosis,

while phosphatidylserine containing oxidized fatty acids is externalized

to the surface of cells and is an effective signal for engulfment and digestion of apoptotic cells.

Phosphatidylethanolamines containing arachidonic and adrenic acids

that are oxidized by 15-LOX are believed to be pro-ferroptotic signals,

but oxidized phosphatidylcholine is reported to have anti-inflammatory and protective effects in the lung.

12(S)‑HETE-lysophospholipids react very specifically with certain human monocytes to generate tumour necrosis factor α (TNFα)

and thence initiate a key signalling pathway; they may serve as biomarkers for age-related diseases and could potentially be used as targets

for therapeutic intervention.

Indeed, dysregulation of the metabolism of any of these molecules may have implications for human health.

Further biological effects are discussed in our web page on oxidized phospholipids, including those

produced non-enzymatically.

8. Fungal and Bacterial Enzymes

Certain fungi and yeasts produce 3R- and/or 3S-HETE and 3,18-di-HETE, when supplied with exogenous arachidonic acid from

their animal hosts during infection.

The biochemical mechanism is unclear, and there are reports that implicate lipoxygenases, cyclooxygenases or mitochondrial β-oxidation.

With some pathogenic fungi, the 3-hydroxyeicosanoids produced in infected cells can be acted upon by

the host COX-2 enzyme to form a family of 3-hydroxy-prostaglandins, which are at least as active biologically as the normal compounds.

Aspergillus fumigatus has two lipoxygenase homologues of human ALOX15 and ALOX5, termed LoxA and LoxB,

of which the latter is secreted extracellularly and produces 13‑hydroxyoctadecadienoic acid (13‑HODE) from linoleate.

Some fungi produce peroxygenases that introduce oxygen atoms into non-activated carbon-hydrogen bonds of aliphatic and aromatic compounds.

As they only require H2O2 for their catalytic function and not cofactors and complex regeneration systems, they have

great biotechnological potential.

Prokaryotic LOX-encoding genes are best known from Pseudomonas aeruginosa (Gram-negative bacteria) with the capacity to produce

15S‑hydroxyeicosatetraenoic acid (15S‑HETE), but these are distant evolutionarily from human LOX.

This species has a cytochrome P450 enzyme, CYP168A1, which is a subterminal fatty acid hydroxylase that can produce 19-HETE from arachidonic

acid.

Many other bacterial species are now known to produce lipoxygenases, and some of these can utilize oleic, linoleic or polyunsaturated

fatty acids as substrates with high positional and stereochemical specificity, while others, including Rhodococcus sp.

and Bacillus megaterium, produce monooxygenases of the P450 family.

Fatty acid hydratases are present in bacteria but not in Eukaryotes, and these oxidize fatty acids by adding the elements of water to double

bonds, with flavin adenine dinucleotide (FAD) as a cofactor, presumably incidental to the detoxification of environmental toxins.

For example, oleate hydratases, such as that from Staphylococcus aureus, catalyse the hydroxylation of oleic acid to

10(R)-hydroxy-stearic acid, a reaction that may prove useful in industry.

9. Analysis

The remarkable array of eicosanoids and related oxygenated metabolites in animal tissues provides a daunting task for analysts, partly because

of their reactivity and low natural concentrations and partly because of a lack of suitable standards.

Selective extraction, concentration and derivatization steps are required,

followed by gas chromatography or high-performance liquid chromatography linked to mass spectrometry.

Of the many published procedures, the most comprehensive appears to be that of Wang, Y. et al. (2014) cited below,

who describe the analysis of 184 distinct eicosanoids in a single chromatographic run in only five minutes, with the use of deuterated internal

standards and tandem mass spectrometry to ensure accurate quantification (I have no personal experience in this area).

Equally authoritative for the analysis of octadecanoids is Quaranta, A. et al. (2022).

12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 百度学术

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摘要：

12-羟基二十碳四烯酸(12-HETE)是花生四烯酸(AA)的代谢产物。12-HETE主要由活化的磷脂酶A2(PLA2)释放AA后经12 -脂氧合酶(LOX)催化AA代谢生成。12-HETE在癌症、糖尿病和高血压等多种疾病中扮演着重要角色,参与炎症、氧化应激等病理过程的发生发展,目前研究表明它参与炎症反应过程中的变质、渗出。本文通过对12-HETE在炎症及氧化应激中的作用及其调节策略进行综述,以提高对12-HETE的认识。

展开

关键词：

12 -羟基二十碳四烯酸

炎症

氧化应激

调节

DOI：

10.3760/cma.j.issn.2095-4352.2019.12.027

年份：

2019

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Circ Res：20-HETE影响血管功能、触发高血压

2017-04-03 MedSci MedSci原创

20-HETE高血压GPCR

20-羟基二十碳四烯酸（20-HETE）是细胞色素P450类花生酸之一，是一种有效的血管活性脂质，其血管作用包括促进平滑肌细胞收缩，迁移和增殖，并与内皮细胞功能障碍和炎症相关。实验动物和人体中20-HETE水平升高与高血压，中风，心肌梗死和血管疾病等相关。近来来自纽约医科大学的学者发表研究型文章《20-羟基二十碳四烯酸信号通过G蛋白偶联受体GPR75（Gq）影响血管功能、触发高血压》于著名血管杂志Circ Res.。研究结果为高血压等血管疾病的进一步探索提供了新思路。迄今为止，20-HETE的受体/结合位点在特异性激动剂和拮抗剂中得到应用。本研究是为了鉴定20-HETE结合的受体，通过该受体激活级联信号信号通路，最终导致体外、体内多种后果。使用交联类似物，点击化学，结合实验和功能测定，我们确定了孤儿G蛋白偶联受体（GPCR）GPR75为20-HETE的特异性靶标。在培养的人内皮细胞中，20-HETE结合GPR75结合刺激Gαq/ 11蛋白解离、增加磷酸肌醇（IP-1）积累以及GPCR-激酶相互作用蛋白-1（GIT1）-GPR75的结合，进一步促进了c -Src介导的内皮内皮生长因子受体反式激活。这些导致下游信号通路及其诱导的血管紧张素转化酶（ACE）表达和内皮功能障碍。敲除GPR75或GIT1可阻止20-HETE介导的内皮生长因子受体磷酸化和ACE被诱导。在血管平滑肌细胞中，GPR75-20-HETE配对与Gαq/ 11和GIT1介导的蛋白激酶C刺激MaxiKβ磷酸化、激活GPR75、20-HETE介导血管收缩相关。在20-HETE依赖性高血压的小鼠模型中，敲除GPR75阻止血压升高和20-HETE介导的ACE表达、内皮功能障碍、平滑肌收缩和血管重构发现20-HETE-GPR75为20-HETE介导的高血压和心血管疾病信号传导和病理生理学功能提供了分子基础。原始出处：Garcia V1， Gilani A，et al. 20-HETE Signals Through G Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res. 2017 Mar 21. pii： CIRCRESAHA.116.310525.本文系梅斯医学（MedSci）原创编译整理，转载需授权！

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12-羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 中国生物医学文献服务系统

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12-羟基二十碳四烯酸在炎症及氧化应激中的研究进展

Research progress of 12-HETE in the inflammation and oxidative stress

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来源出版物：中华危重病急救医学卷：31期：12

关键词：

12-羟基二十碳四烯酸

炎症

氧化应激

调节

摘要：

12-羟基二十碳四烯酸(12-HETE)是花生四烯酸(AA)的代谢产物。12-HETE主要由活化的磷脂酶A2(PLA2)释放AA后经12-脂氧合酶(LOX)催化AA代谢生成。12-HETE在癌症、糖尿病和高血压等多种疾病中扮演着重要角色,参与炎症、氧化应激等病理过程的发生发展,目前研究表明它参与炎症反应过程中的变质、渗出。本文通过对12-HETE在炎症及氧化应激中的作用及其调节策略进行综述,以提高

查看主题词相同的文献，请选择：

*12-羟基-5,8,10,14-花生甲烯酸

*炎症

*氧化性应激

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20-羟-二十烷四烯酸_百度百科

干货 | 氧化脂质在CVD中的分子机制 - 知乎

羟基二十碳四烯酸（HETEs）分析 - 知乎

12-HETE (12-羟基二十碳四烯酸) - 仅供科研 | 血管功能调节剂 | MCE

花生四烯酸衍生的羟基二十碳四烯酸（HETE）和羟基二十碳四烯酸（oxo-ETE）的生物合成，生物学作用和受体,Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids - X-MOL

12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 中华危重病急救医学

Hydroxyeicosatetraenoic acids (HETE), oxylipins, epoxides, docosanoids, octadecanoids, lipoxygenases, CYP450 oxidases - composition and biochemistry

12 -羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 百度学术

Circ Res：20-HETE影响血管功能、触发高血压-MedSci.cn

12-羟基二十碳四烯酸在炎症及氧化应激中的研究进展 - 中国生物医学文献服务系统

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