15-hydroperoxy-arachidonic acid

Boonprab K, Matsui K, Akakabe Y, YotsukuraN, Kajiwara T (2003) Hydroperoxy-arachidonic acid mediated n-hexanal and (Z)-3- and (E)-2-nonenal formation in Laminaria angustata. Phytochemistry 63 669-678... 

P lg 1 A. Inhih it ion of AUP-induaed platelet aggregation by rabbit intra-pulmonary artery (i.p.a.) incubated in tris buffer. B. stability of the inhibitory activity at 0 C and ambient temperature note loss of activity at ambient temperature. C. Inhibition of the formation of the anti-aggregatory activity from i.p.a. by prior incubation of the tissue with 15-hydroperoxy-arachidonic acid (15-HPAA). D. Reduction of the inhibitory activity of i.p.a. by addition of anti-PGI serum (Ab) to the platelet-rich plasma. 

The synthesis of the compounds was also inhibited by incubation of the tissue with 15-hydroperoxy-arachidonic acid (15-HPAA a relatively specific inhibitor of prostacyclin synthetase (8) (Fig. 1C). 

Standards prostaglandins, prostacyclin and thromboxane Ba were generous gifts from Dr J.E. Pike of Upjohn, Kalamazoo. Endothelial cell micro-somes used to inhibit platelet aggregation were obtained from human umbilical cord and their inhibiting activity was completely abolished by 15-hydroperoxy arachidonic acid or tranylcypromine. 

Beetens, J. R., and Herman, A. G., 1983, Vitamin C increases the formation of prostacyclin by aortic rings from various species and neutralizes the inhibitory effect of 15-hydroperoxy-arachidonic acid, Br. J. Pharmacol. 80 249-254. 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoidpreclavulone-A via 8-( f )-hydroperoxy-5,ll,14( Z), QfEj-eicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

Lipoxygenation is the major pathway of dioxygenation of arachidonic acid in blood platelets and leads to the 12-5-hydroperoxy acid 12-HPETE and the corresponding 12-hydroxy acid 12-HETE. Several pathways for the synthesis of 12-HETE have been developed. However, despite the availability of this substance, its biological role remains undetermined. 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

Additional hypotheses concerning prostaglandin biosynthesis in P. homomalla resulted from isolation of 11R-HETE (76) from the polar lipid fraction [95]. Apparently, 11R-HETE (76) is also a minor product of incubations of arachidonic acid with acetone powder preparations of P. homomalla [95], In this alternate hypothesis (Scheme 8), an 11-hydroxy or 11-hydroperoxy-8,9-allene oxide intermediate is formed from a sequence of oxidations at C8 and Cll. Opening of the allene oxide to a transient C8 earboeation induces eycli-zation with a consequent addition of water to C15. This proposed pathway leads initially to formation of PGE2 (16 or 38), which following acetylation, elimination of acetic acid from Cl 1-12, and esterification, forms the observed major natural product in the coral, 15-acetoxy methyl PGA2 (36 or 54). Notably, if... 

Figure 7. Dependence of BP oxidation by ram seminal vesicle micro-somes on the concentration of different hydroperoxides. Abbreviations used are 20 4, arachidonic acid 15-HPEA, 15-hydroperoxy-eicosatetraenoic acid t-BuOOH, t-butyl hydroperoxide. The structure is PGG2 is given in Figure 1.

Schnurr et al. [22] showed that rabbit 15-LOX oxidized beef heart submitochondrial particles to form phospholipid-bound hydroperoxy- and keto-polyenoic fatty acids and induced the oxidative modification of membrane proteins. It was also found that the total oxygen uptake significantly exceeded the formation of oxygenated polyenoic acids supposedly due to the formation of hydroxyl radicals by the reaction of ubiquinone with lipid 15-LOX-derived hydroperoxides. However, it is impossible to agree with this proposal because it is known for a long time [23] that quinones cannot catalyze the formation of hydroxyl radicals by the Fenton reaction. Oxidation of intracellular unsaturated acids (for example, linoleic and arachidonic acids) by lipoxygenases can be suppressed by fatty acid binding proteins [24]. 

Figure 6.17. Leukotriene formation in neutrophils. Arachidonic acid, which is released from membrane phospholipids by the action of either phospholipase A2 or diacylglycerol lipase (see Fig. 6.13), is oxygenated by 5-lipoxygenase to yield 5 hydroperoxy-6,8,11,14 eicosa-tetraenoic acid (5-HPETE). This is then converted into 5 hydroxy-6,8,11,14 eicosatetra-enoic acid (5-HETE) and leukotriene (LT) A4. LTA4 may then be enzymically converted into LTC4 and LTB4. LTB4 is the major product in activated neutrophils.

Arachidonic acid Hydroperoxy endoperoxide prostaglandin G2 (PGG2) Prostaglandin H2 (PGH2)... 

The lipoxygenase system also competes for released arachidonic acid in a way that seems to be tissue-selective, giving rise to hydroperoxy fatty acids (HPETE) which can be converted into leukotrienes or reduced to hydroxy fatty acid (HETE) products [115]. The basic scheme for these metabolic conversions involving arachidonic acid is presented in Figure 5.2. Both of the main enzymatic pathways of arachidonic acid metabolism are thought to involve free-radical-mediated reactions [108] and the antioxidant capacity of vitamin E could therefore allow the vitamin to modify the products of these pathways. 

The other metabolic pathway derived from arachidonic acid is through the activity of the lypoxygenase-12 (2-LOX) (Fig. 5). 2-LOX converts arachidonic acid (AA) to 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) that is rapidly reduced by peroxidases to the stable 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). In... 

Lipoxygenase 5 converts arachidonic acid into 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), which is the precursor of leukotrienes. Leukotrienes... 

Lipoxygenases (LOs) are nonheme, mononuclear iron enzymes that catalyze the regio- and stereoselective conversion of polyunsaturated fatty acids with a di.di-1,4-diene functionality into products having a l-hydroperoxy-tra 5, cM-2,4-diene functionality. The mammalian LOs typically act on arachidonic acid and produce alkyl hydroperoxides that are converted into leukotrienes and lipoxins, which are involved as messengers in the inflammatory response. Plant enzymes act on linoleic acid, but the role of the product alkyl hydroperoxide is less well understood. 

Arachidonic acid is also metabolised by lipoxygenase to straight-chain hydroperoxy acids and then to leukotrienes which cause increased vascular permeability, vasoconstriction, bronchoconstriction, as well as chemotactic activity for leucocytes (whence their name). Inhibitors of lipoxygenase, e.g. zileuton, and leukotriene receptor antagonists, e.g. montelukast, zafirlukast, have found a place in the therapy of asthma (see p. 559). 

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