Lipoxygenase reaction products leukotrienes

The fatty acid-like leukotrienes derived from the addition of glutathione to products of the lipoxygenase branch of the arachidonic cascade are closely associated with manifestations of asthma. Many compounds designed to antagonize leukotrienes at the receptor level incorporate long alkyl chains to mimic the leukotrienes backbone in addition to the sulfur-containing moieties that stand in for glutathione. The reaction... 

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. 

When a diet is rich in polyunsaturated fatty acids, the inflammatory response and production of free radicals appear to be strengthened. Arachidonic acid is held responsible for this reaction, as it is used by lipoxygenases of the immune system cells to produce, via biochemical transformations, leukotrienes, compounds which function as mediators and perform an important function in the immune system (Szponar and Respondek 1998, Fimmel and Zouboulis 2005). 

Many of the biological actions of essential fatty acids are the result of their metabolic products, the eicosanoids. These are oxidized derivatives of AA and include prostaglandins and thromboxanes that are formed via the cyclo-oxygenase (COX) pathway, as well as hydroxy fatty acids and leukotrienes that arise by means of the lipoxygenase pathway. Another series of AA-derived products, the epoxy fatty acids, are produced by the cytochrome P450 epoxygenase pathway. The AA that serves as precursor for these reactions... 

The mechanism of NSAID-induced respiratory reactions appears to be due to the redirection of arachidonic acid metabolism from the COX to the lipoxygenase synthetic pathway with associated production of cysteinyl leu-kotrienes. PGE2 normally helps to dampen the production of the leukotrienes. 

Oxygenation by SLO-1 is inhibited by various additives. Some of the reasons are (1) the reduction of active iron from the ferric form to the ferrous form, e,g, by N-alkylhydroxylamine [268], phenyldiazene [269], 2-benzyl-1-naphthol [270], diaryl-N-hydroxyurea [271] (2) oxidation of residues, e.g, methionine residues, by hexanal phenylhydrozone [272] (3) coordination to the active site, e.g. catechol [273], cysteine [274], hydroperoxy acids [275], chelating reagents [276], and Pt complex [277] (4) reaction with the active site, e.g. 12-iodo-ci5-9-octadecenoic acid [278]. In addition, it is reported that leukotriene A4, the electrophilic product of 5-lipoxygenases, irreversibly inactivates the enzyme [279]. 

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