Leukotriene LTA

Leukotrienes (LTA, LTB LTC, LTD, and LTE ) are synthesized from arachi-donic acid by a cascade of enzymes that include 5-lipoxygenase (5-LOX), 5-lipoxy-genase-activating protein (FLAP), and leukotriene C4 synthase (LTC synthase) (79,80). The leukotriene LTA is synthesized by 5-LOX in the first step and is an unstable precursor that is then enzymatically converted to LTB or LTC (80,81), which can subsequently be metabolized to LTD and LTE. LTC, LTD, and LTE are the components of the slow-reacting substance of anaphylaxis. These moieties, particularly LTC and LTD, are active forms of CysLTs that interact with the G protein-coupled cysteinyl leukotriene receptors (CysLtrl and CysLtr2) (70,81,82). Once engaged, the activated CysLtrs receptors stimulate the secretion of mucus and induce edema and bronchoconstriction (81). 

As shown in Figure 1, 5-LOX, via a double catalytic step, transforms arachidonic acid into the first of the leukotrienes, LTA [5(6)-epoxy-7,9-rrans-... 

The first step in the formation of the leukotrienes is cleavage of arachidonic add from membrane phospholipids. 5-I.ipoxygcnasp, which is a calcium-dependent enzyme, catalyzes the introductionof Oi into the arachidonic add and the conversion of the resulting hydroperoxide to an epoxide. Leukotriene A, contains an epoxide group. Leukobiene (LTA ) can be converted to leukotriene B (LTB4) by enzymatic hydrolysis. LTB is a dihydroxy fatty acid it regulates the functions... 

Penning TD, Chandrakumar NS, Chen BB et al (2000) Structure-activity relationship studies on l-[2-(4-phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. J Med Chem 43 721-735... 

Besides, DEC also exerts antiinflammatory activity which action is caused solely due to the bockade occurring at cyclooxygenase and LTA synthase (leukotriene synthesis), whereby two predominant activity takes place ... 

Figure 1. Pathways and chemical structures for leukotriene and lipoxin biosynthesis. Enzymes responsible for known catalytic steps are noted in italics. AA, arachidonicacid.5-, 15-LOX, 5-, 15-lipoxygenase. 5-, 15-HETE, 5(5 )-, 15(5)-hydroxyeicosatetraenoicacid.5-, 15-HPETE, 5(5 )-, 15(5 )-hydroperoxyeicosatetraenoic acid. 5(6)-Epoxytetraene, 15(5)-hydroxy-5(6)-epoxy-7,9,13- ra. -ll-c/5-eicosatetraenoic acid. LTA, leukotriene A 5(6)-epoxy-7,9- rafZ5-ll,14-cw-eicosatetraenoic acid. LTB, leukotriene 5(5 ),12(/ )-dihydroxy-6,14-cw-8,10- rfl .y-eicosatetraenoic acid. LTC, peptido-leukotriene C 5(5)-hydroxy-6(/ )-5 -glutathione-7,9-fra 5-ll,14-cw-eicosatetraenoic acid. LTD, peptido-leukotriene D 5(5)-hydroxy-6(/ )-( S-cysteinylglycinyl)-7,9-rra 5-11,14-cA-eicosatetraenoic acid. LTE, peptido-leukotriene E 5(5)-hydroxy-6(/ )-( S-cysteinyl)-7,9-rra 5-ll,14-cw-eicosatetraenoic acid. LXA, lipoxin A 5(5 ),6(/ ), 15(5)-trihydroxy-7,9, 3-trans-11 -cA-eicosatetraenoic acid.

Contrary to the expected limitations dictated by the short half-hfe of LTA in aqueous solutions, a complex transcellular metabolism is achieved by the stabilization that occurs when LTA is associated with phospholipids and/or albumin (Fitzpatrick et al, 1982 Fiore and Serhan, 1989). Such half-life extension proves critical to the synthesis of peptido-leukotrienes by platelets, or to the synthesis of LTB by red blood cells, since both these cell types are devoid of 5-LOX activity and caimot synthesize the necessary LTA by themselves (Maclouf and Murphy, 1988 Fukai et al, 1996). 

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