5-HPETE 5-hydroperoxyeicosatetraenoic

Figure 23-7. Conversion of arachidonicacid to leukotrienesand lipoxins of series 4 via the lipoxygenase pathway. Some similar conversions occur in series 3 and 5 leukotrienes. (HPETE, hydroperoxyeicosatetraenoate HETE, hydroxyeicosatetraenoate , peroxidase (2), leukotriene A4 epoxide hydrolase , glutathione S-transferase ...

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. 

Fig. 2. Biosynthetic pathways of polyunsaturated fatty acid and eicosanoid synthesis. The terminology used indicates first the number of carbons in the acyl chain, then the number of double bonds, and then the number of carbons from the methyl terminus at which the most distal double bond is located (e.g., 20 4n-3). HPETEs hydroperoxyeicosatetraenoic acids HETEs hydroxyeicosa-tetraenoic acids.

FIGURE 33-3. Metabolism of arachidonic acid after its release from membrane phospholipids. ASA, aspirin HPETE, hydroperoxyeicosatetraenoic acid NSAlDs, nonsteroidal antiinflammatory drugs PC, prostaglandin. Broken arrow indicates inhibitory effects. 

Fig. 35.11. Formation of leukotrienes and their glutathione (GSH) derivatives. HPETE = hydroperoxyeicosatetraenoic acids LT = leukotriene (thus, LTA4 is leukotriene A4).

Fig. 5. Generation of 155-hydroxyeicosatetraenoic acid (HETE) and 13-hydroxyoctadecadienoic acid (HODE) by 15-lipoxyge-nase (LOX)-1 and -2. HPETE, hydroperoxyeicosatetraenoic acid HPODE, hydroperoxyoctadecadienoic acid.

Figure 7. Eicosanoid synthesis from arachidonic acid. COX, cyclooxygenase. HETE, hydroxyeicosatetraenoic acid. HPETE, hydroperoxyeicosatetraenoic acid. LOX, lipoxygenase. LT, leukotriene. LX, lipoxin. PG, prostaglandin. TX, thromboxane.

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 . ... 

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... 

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). 

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. 

LTs are produced in the 5-lipoxygenase pathway (Figure 18-25). Their synthesis begins with arachidonic acid obtained from cleavage of the membrane phospholipid pool due to the action of phospholipase A2. Arachidonic acid is converted in a catalytic sequence by 5-lipoxygenase complex and its activating protein to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and... 

Fig. 6. Biochemical pathway of the metabolism of arachidonic acid into the biologically active leukotrienes. Arachidonic acid released from phospholipids by cytosolic (c) phospholipase Aja is metabolized by 5-lipoxygenase to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) and leukotriene A4 (LTA4) which is then enzymatically converted into leukotriene B4 (LTB4) or conjugated by glutathione to yield leukotriene C4 (LTC4).

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.

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