Arachidonate 15-lipoxygenase

Goodman JE, Bowman ED, Chanock SJ, Alberg AJ, Harris CC. (2004) Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. Carcinogenesis. 25, 2467-2472. 

Kohyama, N., T. Nagata, S. I. Fuji-moto, and K. Sekiya. Inhibition of arachidonate lipoxygenase activities by 2-(3-4-dihydroxyphenyl) ethanol, a OE066 phenolic compounds from olives. Bio-sci Biotech Biochem 1997 61(2) ... 

Tang DG, Chen YQ, Honn KV (1996) Arachidonate lipoxygenases as essential regulators of ceh survival and apoptosis. Proc Natl Acad Sci USA 93 5241-5246... 

Tang, D.G., Chen, Y.Q.. and Honn, K.V. (1996) Arachidonate Lipoxygenases as Essential Regulators of Cell Survival and Apoptosis, Proc. Natl. Acad. Sci. USA 93,5241-5246. 

Nugteren DH. Arachidonate lipoxygenase in blood platelets. Biochim Biophys Acta 1975 380 299-307. 

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages. Newer drugs are designed to either inhibit the enzyme 5-lipoxygenase, which acts on arachidonic acid in the first stage of leukotriene biosynthesis, or to block leukotriene receptors. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Any of the collection of oxygenated metabolites of arachidonic acid that are the product of cyclooxygenase, cytochrome P450, or lipoxygenase pathways. 

In cell free systems or isolated cells, some enzymes of the arachidonate cascade can also recognize AEA and 2-AG as substrates, thereby producing the corresponding lipoxygenase and cyclooxygenase-2 derivatives. However, these metabolites have not yet been isolated from tissues and their biological relevance is still unknown. 

Applications of peroxide formation are underrepresented in chiral synthetic chemistry, most likely owing to the limited stability of such intermediates. Lipoxygenases, as prototype biocatalysts for such reactions, display rather limited substrate specificity. However, interesting functionalizations at allylic positions of unsaturated fatty acids can be realized in high regio- and stereoselectivity, when the enzymatic oxidation is coupled to a chemical or enzymatic reduction process. While early work focused on derivatives of arachidonic acid chemical modifications to the carboxylate moiety are possible, provided that a sufficiently hydrophilic functionality remained. By means of this strategy, chiral diendiols are accessible after hydroperoxide reduction (Scheme 9.12) [103,104]. 

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

Williams, JH and Bliss, TV (1989) An in vitro study of the effect of lipoxygenase and cyclooxygenase inhibitors of arachidonic acid on the induction and maintenance of long-term potentiation in the hippocampus. Neurosci. Lett. 107 301-309. 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

Payne, A.N., Garland, L.G., Lees, I.W. and Salmon, J.A. (1988). Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids effects on bronchial anaphylaxis in anaesthetised guinea-pigs. Br. J. Pharmacol. 94, 540-546. 

There is some evidence that in cells with low anandamide amidase activity, such as platelets and neutrophils, anandamide is inactivated by an oxidative pathway involving 12(5)-lipoxygenase (Edgemond, 1998). Metabolism of anandamide by enzymes of the arachidonic acid cascade... 

Leukotrienes Arachidonic acid/ damaged cells Lipoxygenase Sensitization ... 

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