Lipoxygenase competitive inhibition

The alteration of lipid mediators by PUFA has been reviewed in great detail (Stulnig, 2003) and is mentioned only briefly here. The function of cells of the immune system can be exquisitely sensitive to lipid mediators such as prostaglandins and leukotrienes. Those mediators are normally produced by the action of specific enzyme systems on the AA substrate that is released from membrane phospholipids pools. Thus, cyclooxygenase (COX-1 or COX-2) converts AA to prostaglandins, and lipoxygenase (e.g., 5-LOX) converts AA to HETEs and leukotrienes. The amount of substrate, the activity of the enzymes, and the amount and potency of the lipid mediators appear to be regulated by FA composition and, thus, the dietary intake of PUFA. Specifically, EPA is and DHA is not a substrate for COX and LOX and can competitively inhibit AA metabolism. In addition, DHA can inhibit... 

Important in this respect is that 18 2, n-6 18 3, n-3 20 3, n-9 FA and varions cis-trans isomers show competitive inhibition with 20 3, n-6 20 4, n-6 and 20 5, n-3, which are the precursors for the known biologically active prostaglandins and lencotrienes. Administration of an EFA-deficient diet leads to partial replacement of AA by 20 3, n-9, which is a substrate for lipoxygenase bnt not for cyclooxygenase. Feeding a diet high in PUFA of the n-3 type (e.g., linseed oil, fish oil) resnlts in an enrichment of membrane phospholipids with EPA and docosahexaenoic acid (DHA). This may explain why the FA composition of tissue lipids, including membrane PF, can be modified to some extent by the amount of each class of FA in the diet. 

In an in vitro study involving alkamides from Echinacea angustifolia and several Achillea species, 20 compounds tested were relatively potent inhibitors of cyclooxygenase, while a few also inhibited 5-lipoxygenase (Muller-Jakic et al. 1994). The two enzymes are involved in the metabolism of arachidonic acid, the major pathway to inflammation. Considering the structural similarities to arachidonic acid, the authors propose the alkamides act as analogues, competitively inhibiting the enzymes. 

Leukotriene modifiers either inhibit 5-lipoxygenase (zileuton) or competitively antagonize the effects of leukotriene D4 (montelukast and zafirlukast). These agents improve FEV, and decrease asthma symptoms, rescue drug use, and exacerbations due to asthma. Although these agents offer the convenience of oral therapy for asthma, they are significantly less effective than low doses of inhaled corticosteroids.2,33... 

There are multiple pathways that are currently known to inactivate lipoxygenases, ranging from competitive to allosteric to reductive inhibition. The competitive pathways have been studied by Zherebtsov, Popova, and Zyablova (2000). The allosteric process has been studied by Mogul Johansen, and Holman (2000). Reductive inhibition has been studied by Kemal Louis-Flamberg, Krupinski-Olsen, and Shorter (1987). (57 words)... 

Multiple pathways are currently known to inactivate lipoxygenases, ranging from competitive to allosteric to reductive inhibition. (16 words)... 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

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