Cysteinyl-leukotrienes

Cysteinyl leukotriene is a compound synthesized from arachidonic acid in inflammatory cells that contains an amino-acid side chain. 

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... 

In a third study the time course of the effects of intravenous and intracoronary injections of cysteinyl leukotrienes on metabolic parameters and systemic and coronary hemodynamics was examined in patients with normal coronary arteries [32]. LTD4 (3 nmol, injected into the left coronary artery) induced an early (20 s), transient fall in mean arterial pressure paralleled by rises in heart rate and plasma levels of epinephrine and norepinephrine, all of which had returned to baseline by 10 min. CVR rose at 10 and 15 min and myocardial oxygen extraction at 15 min. Thus, small doses of cysteinyl leukotrienes may induce both an early, transient fall in mean arterial pressure, with secondary sympathoadrenergic activation, and a later increase in small coronary arteriolar resistance. 

Cysteinyl leukotrienes can induce an early, transient fall in arterial pressure associated with sympathoadrenergic activation, plus a late rise in small coronary arteriolar resistance [32]. Using specific antagonists of CysFTi and CysFT2 [63] it will be possible to assess the each receptor s contribution to the cardiovascular effects of these vasoactive mediators. 

J mohara M, Takasaki J, Matsumoto M> Matsumoto S-I, Saito X Soga X Matsushime H, Furuichi K Functional characterization of cysteinyl leukotriene CysLT2 receptor on human coronary artery smooth muscle cells. Biochem Biophys Res Commun 2001 287 1088. 

N. Miyazaki E, Kumamoto T. Akiyama K Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis. Chn Exp Allergy 2009 39 72-80. SO... 

Compound 508 (PNRI-299), a small molecule /3-strand mimetic template compound, is active as an inhibitor of the multifunctional activating protein factor 1 (AP-1). PNRI-299 has demonstrable effects on the reduction of API-driven transcription and beneficial pharmacological effects in a mouse asthma model. The compound affects the expression of leukotriene C4 (LTC4) synthase, a crucial enzyme for the formation of the cysteinyl leukotrienes <2003PNA1169, 2004MI211>. 

Although there are data on the variability of the treatment response for each of these classes of agents, there are no systematic studies on the reasons for variance in the treatment response to steroids or theophylline. Therefore, this chapter will focus on the specific pharmacogenomics of /1-agonists and inhibitors of the cysteinyl-leukotriene pathway [18, 30] and on general considerations related to pharmacogenomic mechanisms. 

Lam BK, Austen KF. Leukotriene C-4 synthase - a pivotal enzyme in the biosynthesis of the cysteinyl leukotrienes. Am J Respir Crit Care Med 2000 161 16-19. 

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. 

The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible for production of cysteinyl leukotrienes. Leukotrienes C4, D4, and E4 are released during inflammatory processes in the lung and produce broncho-spasm, mucus secretion, microvascular permeability, and airway edema. 

Spinozzi, F. et al., Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes, Clin. Exp. Allergy, 34, 1876, 2004. 

Ishikawa, T., Muller, M., Klunemann, C., Schaub, T. and Keppler, D. (1990) ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates. Journal of Biological Chemistry, 265, 19279-19286. 

Scheuber, P.H., Denzlinger, C., Wilker, D., Bed Keppler, G. and Hammer, D.K., Staphylococcal enterotoxin B as a nonimmunological mast cell stimulus in primates the role of endogenous cysteinyl leukotriens, Int. Arch. Allergy Appl. Immunol., 82, 289-291, 1987. 

These receptors share several common features, some of which are illustrated in our example, the cysteinyl leukotriene 2 (CysLT ) receptor (see Fig. 6.1) (11). These features include (1) insertion into the membrane and targeting to the plasma membrane of the cell (2) the presence of seven conserved transmembrane domains (3) three extracellular and three intracellular loops (4) an extracellular amino terminus and (5) an intracellular carboxyl terminus (1,2). 

Fig. 6.1 Schematic representation of the cysteinyl leukotriene 2 (CysLT ) receptor. Ribbon model of this family A G protein-coupled receptor (GPCR) is pictured in its heptahelical configuration. The extracellular amino terminus of the receptor, the transmembrane domains, and the intracellular carboxyl tail extend behind the intracellular palmitoylation site. The putative binding pocket for cysteinyl leukotriene ligands is derived from a rhodopsin model...

Figueroa, D. J., Breyer, R. M., Defoe, S. K., et al. (2001) Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am. J. Resp. Crit. Care Med. 163, 226-233. 

Mellor, E. A., Frank, N., Soler, D., et al.. (2003) Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells functional distinction from CysLTlR. Proc. Natl. Acad. Sci. U. S. Am. 100,11589-11593. 

Sjostrom, M., Johansson, A. S., Schroder, O., Qiu, H., Palmblad, J., and Haeggstrom, J. Z. (2003) Dominant expression of the CysLT(2) receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells. Arterioscler. Thromb. Vase. Biol. 23, E37-E41. 

Fig. 8.2 Alignment of the protein structure of the cysteinyl leukotriene 1 (CysLTj) and 2 (CysLT ) receptors in relation to rhodopsin. The amino acids conserved between these family A receptors are shown. The consensus is greater than 50%. These data formed the basis of the model predicting the CysLTj and CysLT transmembrane domains (helices 1-7), the four [3-sheets, and the putative cysteinyl leukotiiene-binding domain. The amino acid variants that are associated with atopy or asthma, the G300S CysLTj variant, and the M201V CysLT variant are each boxed and noted with arrows...

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