Leukotrienes synthesis

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Munoz NM, Kim YJ, Meliton AY et al (2003) Human gVPLA2 induces gIVA-PLA2 independent cysteinyl leukotriene synthesis in human eosinophils. J Biol Chem 278 38813-38820... 

Leukotrienes, synthesis of 735 Lewis acids 763, 764, 768, 807, 808 Linear free-energy relationship (LFER) 556, 559, 561... 

Zembowicz A, Mastalerz L, Setkowicz M, Radzis-zewski W, Szczeklik A Safety of cyclooxygenase-2 inhibitors and increased leukotriene synthesis in chronic idiopathic urticaria with sensitivity to nonsteroidal anti-inflammatory drugs. Arch Dermatol 2003 139 1577-1582. 

Sampson AP, Siddiqui S, Buchanan D et al. Variant LTC[4] synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000 55(Suppl 2) 28—31. 

Corticosteroids have antiinflammatory and immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation. 

Zileuton (Zyflo) is an inhibitor of leukotriene synthesis. The dose of zileuton tablets is 600 mg four times daily with meals and at bedtime. The recommended dose of zileuton extended-release tablets is two 600-mg tablets twice daily, within 1 hour after morning and evening meals (total daily dose 2,400 mg). 

A classic example of a biological pathway with implications for asthma pharmacogenetics is the leukotriene synthesis pathway. Cysteinyl leukotrienes... 

One key phenotype that may be associated with the leukotriene synthesis pathway is AIA. AIA patients have been found to produce increased quantities of CysLTs, which have been quantitated in both their urine and lung secretions (122). However, several association studies comparing the A-444C polymorphism and the risk of AIA have not been conclusive (117,121). 

Brock TG. (2005) Regulating leukotriene synthesis the role of nuclear 5-lipoxygenase. J Cell Biochem. 96, 1203-1211. 

Human Upoxygenase Inhibition of leukotriene synthesis by oximes of diphenyl sulfides with IC50 ca 50 nM 124... 

C) Enhancement of leukotriene synthesis at the expense of prostaglandin synthesis... 

D. Etanercept is a recombinant fusion protein consisting of two TNF receptor domains linked to one IgG Fc molecule. It binds to soluble TNF-a and TNF-(3 and forms inactive complexes. It does not directly affect cAMP phosphodiesterase, leukotriene synthesis, or autoantibody production. 

They also influence the inflammatory response by reducing the prostaglandin and leukotriene synthesis that results from activation of enzyme phospholipase A. ... 

Thromboxanes, like prostaglandins, contain a ring of five or six atoms the pathway from arachidonate to these two classes of compounds is sometimes called the cyclic pathway, to distinguish it from the linear pathway that leads from arachidonate to the leukotrienes, which are linear compounds (Fig. 21-16). Leukotriene synthesis begins with the action of several lipoxygenases that catalyze the incorporation of molecular oxygen into arachidonate. These enzymes, found in leukocytes and in heart, brain, lung, and spleen, are mixed-function oxidases that use cytochrome P-450 (Box 21-1). The various leukotrienes differ in the position of the peroxide... 

Peters-Golden M and Brock TG (2001) Intracellular compartmentalization of leukotriene synthesis unexpected nuclear secrets. FEBS Lett 487, 323-326. 

Leukotriene inhibitors, one leukotriene inhibitor blocks leukotriene synthesis by inhibiting the action of 5-lipooxygenase (Zileuton Zyflo). Another blocks leukotriene receptors on the surface of smooth-muscle cells and eosinophils (Montelukast Singulair). 

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