5- Hydroperoxyeicosatetraenoic acid 5-HPETE

The metabolism of AA by the 5-, 12-, and 15-lipoxygenases (LOX) results in the production of hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs) and leukotrienes (Figure 18-3). The most actively investigated leukotrienes are those produced by the 5-LOX present in leukocytes (neutrophils, basophils, eosinophils, and monocyte-macrophages) and other inflammatory cells such as mast cells and dendritic cells. This pathway is of great interest since it is associated with asthma, anaphylactic shock, and cardiovascular disease. Stimulation of these cells elevates intracellular... 

Lipid hydroeicosatetraenoic (HETE) and hydroperoxyeicosatetraenoic acids (HPETE) are important products of both enzymatic processes and autooxidation of polyunsaturated fatty acids. They appear to exhibit biological activity in disease processes and in ageing. 

In the first step, oxygen is added by lipoxygenases, and a family of linear molecules, hydroperoxyeicosatetraenoic acids (HPETEs), is formed. 

Fig. 11. Metabolism of arachidonic acid by 12- and 15-lipoxygenase pathways with corresponding stereospecific formation of hydroperoxyeicosatetraenoic acids (HpETE). Subsequent reduction of these hydroperoxides leads to the corresponding HETE at either carbon-12 or -15, which are thought to mediate biological activities of these enzymatic pathways.

As shown in figure 35.11, the synthesis of the leukotrienes begins with the formation of hydroperoxyeicosatetraenoic acids (HPETEs). This product is either reduced to the corresponding hydroxy metabolites, HETEs (see Eig. 35.10), or it is metabolized to form leukotrienes or lipoxins (see Eigs. 35.11 and 35.12). The major leukotrienes are produced by 5-lipoxygenase. 

Metabolism of arachidonic acid by COX-2, 15-LO, or oxidation by ROS all lead to the formation of 15(A)-hydroperoxyeicosatetraenoic acid (HPETE). 15(A)-HPETE undergoes homolytic decomposition to form HPNE (Blair, 2008). It is also important to note that 15-LO-derived 13(A)-hydroperoxy-9Z,1 lii-octadecadienoic acid (HPODE) from linoleic acid (LA) also undergoes decomposition to form HPNE (Blair, 2008). A formal loss of water (2-electron oxidation) converts HPNE to ONE, whereas a 2-electron reduction results in the formation of HNE (Blair, 2008). ONO is formed enzymatically from ONE through reduction by aldo-keto reductases (AKRs). ONE is highly reactive, and upon translocation to the nucleus it readily forms HedGuo adducts. ONE... 

One of the key functional roles of PUFA is as precursors to eicosanoids. Eicosanoids are a family of bioactive mediators that are oxygenated derivatives of the 20-carbon PUFA dihomo-y-linolenic, arachidonic and eicosapentaenoic acids. Eicosanoids include prostaglandins (PG) and thromboxanes (TX), which together are termed prostanoids, and leukotrienes (LT), lipoxins (LX), hydroperoxyeicosatetraenoic acids (HPETE) and hydroxyeicosatetraenoic acids (HETE). In most conditions the principal precursor for these compounds is arachidonic acid, and the eicosanoids produced from arachidonic acid sometimes have more potent biological functions than those released from dihomo-y-linolenic or eicosapentaenoic acids. The precursor PUFA is released from membrane diacylglycerophospholipids by the action of phospholipase A or from membrane phosphatidylinositol-4,5-bisphosphate by the actions of phospholipase C and a diacylglycerol (DAG) lipase (Figure 7). 

The first reaction catalyzed by all lipoxygenase enzymes is the addition of a hydroperoxide group to a select carbon atom in the arachidonate molecule, to form a chiral hydroperoxyeicosatetraenoic acid (HPETE). Thus, the primary product of mammalian 5-lipoxygenase is 5(S)-HPETE, that of sea-urchin 12-lipoxygenase,... 

HPETE, 12(.S)-hydroperoxyeicosatetraenoic acid 15-HPETE, 15(S)-hydropcroxycicosatctracnoic acid 4-HPNE, 4-hydroperoxy-2-nonenal... 

LO catalyses the stereospecific conversion of arachidonic acid (1) to a 5-hydroperoxyeicosatetraenoic acid (5-HPETE) (2). The enzyme contains... 

The hydroperoxides obtained on thermal oxidation of cholesteryl acetate (191e) can be selectively separated by SPE and elution with a polar solvent. After reduction to the corresponding alcohols by NaBH4 and further derivatization to the trimethylsilyl ether, the products can be subjected to GLC with ion-trap MS detection. It can be thus demonstrated with the aid of standards that under the oxidation conditions (160 °C for 90 min) only the 7-position is attacked, leading to the la- and 7/3-hydroperoxy derivatives, while the plausible 4-position remains unscathed . Treatment of erythrocite ghosts with t-BuOOH causes a manyfold content increase of 5-hydroxyeicosatetraenoic acid (5-HETE), 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and 5-oxoeicosatetraenoic acid (5-oxo-ETE) residues of phospholipids. These acids can be separated by HPLC, identified and quantitized by tandem MS . ... 

After liberation, AA is converted into prostaglandin endoperoxides by the action of the enzyme cyclooxygenase. Endoperoxides are rapidly converted into either stable prostaglandins, PGE2, PGF2a, and PGD2, or thromboxane A2. AA can also be converted into lipoxygenase-dependent products such as 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 12-hydroxyeicosatet-raenoic acid (12-HETE). 

Pathways of arachidonate metabolism in eicosanoid synthesis and their inhibitors. HPETE = Hydroperoxyeicosatetraenoic acid HETE = hydroxyeicosatetraenoic acid PG = prostaglandin PGI = prostacyclin TX = thromboxane. Conversions of arachidonic acid by various enzymes can be inhibited by analogues of the natural fatty acid, e g., the acetylenic analogue 5,8,11,14-eicosatetraynoic acid. 

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