Leukotrienes Synthesis
Eicosanoids

Author: daniele viarisio
Date: 10/01/2008

Description

Leukotriene are synthesized mostly in of myeloid origin cells, like basophils, eosinophils, macrophages, monocytes, stem cells...

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The initial step in the synthesis of leukotrienes is the cleavage of an arachidonoyl ester bond of a glycerophospholipid through the action of a PLA2 in a hydrolysis reaction that yields lysophospholipid and free arachidonic acid. Cellular levels of arachidonic acid and lysophospholipid are tightly regulated; one of the main mechanism that the cell use to mantain the right equilibrium is the so called Lands cycle. In this cycle arachidonic acid is conjugated with CoA through an acyl-CoA ligase and then is esterified to a lysophospholipid by a LAT (lysophospholipid-acylCoA acyltransferase). Inhibition of this enzyme with organo-mercury compound, like thimerosal, leads to a dramatic increase of LTB4 released by PMNs cells (link).
Leukotriene biosynthesis begins with the specific oxidation of arachidonic acid by a free radical mechanism as a consequence of interaction with 5-LO. A second enzymatic step is also catalysed by 5-LO and involves removal of a hydrogen atom from C-10, resulting in formation of the conjugated triene epoxide LTA4.

Comments
2011-12-11T12:16:55 - chiara brusa

CysLT RECEPTORS

Cysteinyl leukotrienes and their receptors: molecular and functional characteristics, 2010 PubMed

CysLTs exert their effect through cell surface receptors.
According to the International Union of Pharmacology, the CysLT receptor nomenclature was originally based on the sensitivity to the so-called ‘classical’ antagonists, which include montelukast, zafirlukast, pranlukast, pobilukast and MK571.
Accordingly, CysLT receptors have been mainly divided into two classes: CysLT 1 that is sensitive to the classical antagonists and CysLT 2 which mediates several effects that are not inhibited by the classical antagonists.

CysLT 1 receptor

The CysLT 1 receptor gene was localized to the X chromosome. Human CysLT 1 receptor is a member of the superfamily of G protein-coupled receptors. It possesses 4 potential N-glycosylation sites, 1 in the extracellular N-tail, 2 in the second and 1
in the third extracellular loop, in addition to many potential protein kinase A and C phosphorylation sites, mostly located in the third intracellular loop and carboxyl terminal.
The hypothesis that the CysLT 1 receptor is expressed by a variety of airway mucosal inflammatory cells in asthma and that the numbers of cells expressing CysLT 1 receptor are increased in asthma, either stably or in association with an exacerbation, has been confirmed by
results obtained from normal subjects which indicate that bronchial mucosal eosinophils, neutrophils, mast cells, macrophages, B lymphocytes and plasma cells, but not T lymphocytes, express the CysLT 1 receptor.

CysLT 2 receptor

The gene encoding the human CysLT 2 receptor is on chromosome. The CysLT 2 receptor has always been pharmacologically less defined than CysLT 1, mainly because of the lack of a selective antagonist. Human CysLT 1 and CysLT 2 receptors share only 38% amino acid identity with very low homology in the extreme carboxyl terminal.
Human CysLT 2 receptor is a member of the superfamily of G protein-coupled receptors. It possesses 4 potential N-glycosylation sites, 3 in the extracellular N-tail and 1 in the second extracellular loop, in addition to many potential protein kinase A and C phosphorylation sites mostly located in the third intracellular loop and carboxyl terminal.
The human CysLT 2 expression pattern is substantially different from that of human CysLT 1. It is highly expressed in the spleen and peripheral blood leukocytes, but expression in the heart, adrenal gland and brain appears unique to this subtype.

LTB4 RECEPTORS

Leukotriene B4 receptors: novel roles in immunological regulations, 2011 PubMed

Leukotriene B4 (LTB4) is a well known chemoattractant for phagocytes. It exerts its effect through cell surface receptors.

One is LTB4 receptor BLT1 highly expressed in granulocytes,

and the other is LTB4 receptor BLT2

In humans, BLT2 is expressed ubiquitously in sharp contrast to BLT1 that is expressed only in leukocytes. Both BLT1 and BLT2 mainly couple to inhibitory Gi protein, inhibit adenylate cyclase, activate phospholipase C to increase intracellular calcium concentration, and induce robust chemotaxis.

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