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.

leukotrienes+and+iron (Pubmed)

leukotrienes+and+glutathione. (Pubmed)

leukotrienes+and+asthma. (Pubmed)

The role of leukotrienes in asthma, 2003

TREATMENT OF ASTHMA WITH DRUGS MODIFYING THE LEUKOTRIENE PATHWAY, 1999

Fish or Chips?, 2003

AA percentage of relevant proteins

CLTR1_HUMAN
Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma. Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4.

CLTR2_HUMAN
Receptor for cysteinyl leukotrienes. The response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Stimulation by BAY u9773, a partial agonist, induces specific contractions of pulmonary veins and might also have an indirect role in the relaxation of the pulmonary vascular endothelium. The rank order of affinities for the leukotrienes is LTC4 = LTD4 >> LTE4.

LT4R1_HUMAN (LBT4R)
Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response.

LT4R2_HUMAN (LBT4R2)
Low-affinity receptor for leukotrienes including leukotriene B4. Mediates chemotaxis of granulocytes and macrophages. The response is mediated via G-proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTB4 > 12-epi-LTB4 > LTB5 > LTB3.

Comments
2023-11-20T18:39:30 - Gianpiero Pescarmona

curcumin+and+leukotriene

curcumin+and+histamine

2022-04-19T21:41:15 - Gianpiero Pescarmona

leukotrienes+and+proctitis

leukotrienes+and+asthma

Relevant for Parkinson's Disease

Phospholipase iPLA 2 β averts ferroptosis by eliminating a redox lipid death signal, 2021
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal.

2021-07-25T17:35:26 - Gianpiero Pescarmona

CLTR2

CLTR2+and+vitamin

The regulatory actions of retinoic acid on M2 polarization of porcine macrophages. 2019

Twenty-three genes associated with M2a markers in other species were independently upregulated by both IL-4 and ATRA, including the adenosine receptor A2B (ADORA2B), cysteinyl leukotriene receptor 2 (CYSLTR2) and the vitamin D receptor (VDR).

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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