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leukotriene signaling pathway

Definition

Target type: biologicalprocess

A G protein-coupled receptor signaling pathway initiated by leukotriene binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process. [GOC:dph, PMID:21771892]

Leukotriene signaling is a critical pathway in the inflammatory and immune responses. It is initiated by the enzymatic conversion of arachidonic acid, a fatty acid found in cell membranes, into leukotrienes. This conversion occurs via the 5-lipoxygenase (5-LOX) pathway.

The leukotrienes are potent lipid mediators that act through specific G protein-coupled receptors (GPCRs) on target cells, primarily leukocytes. There are three main types of leukotriene receptors:

1. CysLT1 receptor: This receptor binds to leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). Its activation leads to bronchoconstriction, mucus secretion, and vascular permeability, contributing to the development of asthma and allergic reactions.

2. CysLT2 receptor: This receptor is also activated by LTC4, LTD4, and LTE4, but its role in inflammation is less well understood compared to CysLT1. It may be involved in smooth muscle contraction, vascular permeability, and leukocyte migration.

3. BLT1 receptor: This receptor specifically binds to leukotriene B4 (LTB4), a potent chemoattractant for neutrophils and other immune cells. It induces the recruitment and activation of leukocytes, contributing to the inflammatory response.

The leukotriene signaling pathway is tightly regulated to prevent excessive inflammation. Several mechanisms are involved in regulating leukotriene production and signaling:

- Inhibition of 5-LOX activity: This can be achieved by inhibiting the enzyme's activity directly or by reducing the availability of its substrate, arachidonic acid.

- Inhibition of leukotriene receptor signaling: This can be accomplished by blocking the interaction between leukotrienes and their receptors or by interfering with downstream signaling pathways activated by receptor stimulation.

Leukotriene signaling plays a key role in various physiological and pathological processes, including:

- Asthma: Leukotrienes contribute to bronchoconstriction, mucus secretion, and airway inflammation, leading to asthma symptoms.

- Allergic reactions: Leukotrienes are involved in the allergic response by promoting vascular permeability, leukocyte recruitment, and mediator release.

- Inflammatory bowel disease: Leukotrienes contribute to the inflammatory process in the gut, promoting tissue damage and inflammation.

- Rheumatoid arthritis: Leukotrienes are implicated in the pathogenesis of rheumatoid arthritis by inducing inflammation and joint damage.

- Cardiovascular disease: Leukotrienes are involved in the development of atherosclerosis and thrombosis by promoting vascular inflammation and platelet aggregation.

Leukotriene signaling represents a valuable therapeutic target for inflammatory and immune diseases. Several drugs, including leukotriene receptor antagonists and 5-LOX inhibitors, have been developed to block this pathway and alleviate inflammatory symptoms.'
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Proteins (4)

ProteinDefinitionTaxonomy
Cysteinyl leukotriene receptor 1A cysteinyl leukotriene receptor 1 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q9Y271]Homo sapiens (human)
Cysteinyl leukotriene receptor 2A cysteinyl leukotriene receptor 2 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q9NS75]Homo sapiens (human)
Leukotriene B4 receptor 2A leukotriene B4 receptor 2 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q9NPC1]Homo sapiens (human)
Leukotriene B4 receptor 1A leukotriene B4 receptor 1 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q15722]Homo sapiens (human)

Compounds (60)

CompoundDefinitionClassesRoles
candesartancandesartan : A benzimidazolecarboxylic acid that is 1H-benzimidazole-7-carboxylic acid substituted by an ethoxy group at position 2 and a ({2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl}methyl) group at position 1. It is a angiotensin receptor antagonist used for the treatment of hypertension.

candesartan: a nonpeptide angiotensin II receptor antagonist
benzimidazolecarboxylic acid;
biphenylyltetrazole
angiotensin receptor antagonist;
antihypertensive agent;
environmental contaminant;
xenobiotic
clotrimazoleconazole antifungal drug;
imidazole antifungal drug;
imidazoles;
monochlorobenzenes
antiinfective agent;
environmental contaminant;
xenobiotic
avaproirbesartan : A biphenylyltetrazole that is an angiotensin II receptor antagonist used mainly for the treatment of hypertension.

Irbesartan: A spiro compound, biphenyl and tetrazole derivative that acts as an angiotensin II type 1 receptor antagonist. It is used in the management of HYPERTENSION, and in the treatment of kidney disease.
azaspiro compound;
biphenylyltetrazole
angiotensin receptor antagonist;
antihypertensive agent;
environmental contaminant;
xenobiotic
ly 171883LY 171883: structure in first source; leukotriene receptor antagonist

tomelukast : A member of the class of acetophenones that is 1-phenylethanone substituted at position 2 by a hydroxy group, a propyl group at position 3 and a 4-(1H-tetrazol-5-yl)butoxy group at position 4. A leukotriene antagonist, it exhibits anti-asthmatic activity.
acetophenones;
aromatic ether;
phenols;
tetrazoles
anti-asthmatic drug;
leukotriene antagonist
nifedipineNifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure.C-nitro compound;
dihydropyridine;
methyl ester
calcium channel blocker;
human metabolite;
tocolytic agent;
vasodilator agent
masoprocolnordihydroguaretic acid: antioxidant compound found in the creosote bush (Larrea tridentata)catechols;
lignan;
tetrol
antioxidant;
ferroptosis inhibitor;
geroprotector;
plant metabolite
ono 1078pranlukast: SRS-A antagonist; leukotriene D4 receptor antagonistchromones
pf 5901alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol: structure given in first source; platelet activating factor antagonistquinolines
ici 204,219zafirlukast: a leukotriene D4 receptor antagonistcarbamate ester;
indoles;
N-sulfonylcarboxamide
anti-asthmatic agent;
leukotriene antagonist
gentian violetcrystal violet : An organic chloride salt that is the monochloride salt of crystal violet cation. It has been used in creams for the topical treatment of bacterial and fungal infections, being effective against some Gram-positive bacteria (notably Staphylococcus species) and some pathogenic fungi (including Candida species) but use declined following reports of animal carcinogenicity. It has also been used for dying wood, silk, and paper, as well as a histological stain.

Gentian Violet: A dye that is a mixture of violet rosanilinis with antibacterial, antifungal, and anthelmintic properties.
organic chloride saltanthelminthic drug;
antibacterial agent;
antifungal agent;
antiseptic drug;
histological dye
bw-755c4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine: A dual inhibitor of both cyclooxygenase and lipoxygenase pathways. It exerts an anti-inflammatory effect by inhibiting the formation of prostaglandins and leukotrienes. The drug also enhances pulmonary hypoxic vasoconstriction and has a protective effect after myocardial ischemia.
ablukast
tepoxalintepoxalin : A hydroxamic acid obtained by formal condensation of the carboxy group of 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl]propanoic acid with the amino group of N-methylhydroxylamine. It is used in veterinary medicine for the control of pain and inflammation caused by musculoskeletal disorders such as hip dysplasia and arthritis in dogs.aromatic ether;
hydroxamic acid;
monochlorobenzenes;
pyrazoles
antipyretic;
apoptosis inhibitor;
EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor;
immunomodulator;
lipoxygenase inhibitor;
non-narcotic analgesic;
non-steroidal anti-inflammatory drug
zileuton1-benzothiophenes;
ureas
anti-asthmatic drug;
EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor;
ferroptosis inhibitor;
leukotriene antagonist;
non-steroidal anti-inflammatory drug
wy 48252Wy 48252: leukotriene D4 antagonist
pobilukastpobilukast: a leukotriene receptor antagonist; an antiasthmatic agent; structure in first source; RN refers to (R-(R*,S*)-isomer
valsartanvalsartan : A monocarboxylic acid amide consisting of L-valine in which the amino hydrogens have been replaced by a pentanoyl and a [2'-(1H-tetrazol-5-yl)biphenyl]-4-yl]methyl group. It exhibits antihypertensive activity.

Valsartan: A tetrazole derivative and ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKER that is used to treat HYPERTENSION.
biphenylyltetrazole;
monocarboxylic acid;
monocarboxylic acid amide
angiotensin receptor antagonist;
antihypertensive agent;
environmental contaminant;
xenobiotic
ubenimexubenimex: growth inhibitor
1-(10h-phenothiazin-2-yl)ethanone1-(10H-phenothiazin-2-yl)ethanone: structure in first sourcephenothiazines
fpl 55712FPL 55712: inhibitor of SRS-A and LTC4 and LTD4 receptorsaromatic ketone
sc 41930SC 41930: leukotriene B4 receptor antagonist; structure in first source
l 648051L 648051: antagonist of leukotriene D4 receptor; structure in first source
ly 255283LY 255283: structure given in UD; leukotriene B4 antagonistaromatic ketone
sr 2640SR 2640: leukotriene D4 and E4 antagonistquinolines
rg 12525RG 12525: leukotriene D4 antagonist; structure in first source
rg 14893RG 14893: structure in first source; leukotriene B4 receptor antagonist
pyrrolidino-benzylphenoxyethanamine
ly 293111LY 293111: a leukotriene B4 receptor antagonist; structure given in first sourcearomatic ether
7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2h-1-benzopyran-2-propanoic acid7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid: structure in first source; inhibits leukotriene B4 receptors
amastatinamastatin : A tetrapeptide comprising (2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl, L-valyl, L-valyl and L-aspartic acid units joined in sequence

amastatin: structure; inhibits aminopeptidase
tetrapeptideEC 3.4.11.* (aminopeptidase) inhibitor;
protease inhibitor
e 3040E 3040: a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase; structure given in first sourcebenzothiazoles;
organic hydroxy compound;
pyridines;
secondary amino compound
anti-inflammatory drug;
EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor;
uricosuric drug
cocainecocaine : A tropane alkaloid obtained from leaves of the South American shrub Erythroxylon coca.

Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake.
benzoate ester;
methyl ester;
tertiary amino compound;
tropane alkaloid
adrenergic uptake inhibitor;
central nervous system stimulant;
dopamine uptake inhibitor;
environmental contaminant;
local anaesthetic;
mouse metabolite;
plant metabolite;
serotonin uptake inhibitor;
sodium channel blocker;
sympathomimetic agent;
vasoconstrictor agent;
xenobiotic
diethylstilbestroldiethylstilbestrol : An olefinic compound that is trans-hex-3-ene in which the hydrogens at positions 3 and 4 have been replaced by p-hydroxyphenyl groups.

Diethylstilbestrol: A synthetic nonsteroidal estrogen used in the treatment of menopausal and postmenopausal disorders. It was also used formerly as a growth promoter in animals. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), diethylstilbestrol has been listed as a known carcinogen. (Merck, 11th ed)
olefinic compound;
polyphenol
antifungal agent;
antineoplastic agent;
autophagy inducer;
calcium channel blocker;
carcinogenic agent;
EC 1.1.1.146 (11beta-hydroxysteroid dehydrogenase) inhibitor;
EC 3.6.3.10 (H(+)/K(+)-exchanging ATPase) inhibitor;
endocrine disruptor;
xenoestrogen
spiro[1,3-dihydroperimidine-2,1'-cycloheptane]naphthalenes
5-(2-furanyl)-N-[1-[(2-methylphenyl)methyl]-3-pyrazolyl]-7-(trifluoromethyl)-3-pyrazolo[1,5-a]pyrimidinecarboxamidepyrazolopyrimidine
1-methyl-N-[4-(4-morpholinyl)phenyl]-2-quinoliniminemorpholines
gl-4
leukotriene b4leukotriene B4 : A leukotriene composed of (6Z,8E,10E,14Z)-icosatetraenoic acid having (5S)- and (12R)-hydroxy substituents. It is a lipid mediator of inflammation that is generated from arachidonic acid via the 5-lipoxygenase pathway.

Leukotriene B4: The major metabolite in neutrophil polymorphonuclear leukocytes. It stimulates polymorphonuclear cell function (degranulation, formation of oxygen-centered free radicals, arachidonic acid release, and metabolism). (From Dictionary of Prostaglandins and Related Compounds, 1990)
dihydroxy monocarboxylic acid;
hydroxy polyunsaturated fatty acid;
leukotriene;
long-chain fatty acid
human metabolite;
mouse metabolite;
plant metabolite;
vasoconstrictor agent
leukotriene c4leukotriene C4 : A leukotriene that is (5S,7E,9E,11Z,14Z)-5-hydroxyicosa-7,9,11,14-tetraenoic acid in which a glutathionyl group is attached at position 6 via a sulfide linkage.

Leukotriene C4: The conjugation product of LEUKOTRIENE A4 and glutathione. It is the major arachidonic acid metabolite in macrophages and human mast cells as well as in antigen-sensitized lung tissue. It stimulates mucus secretion in the lung, and produces contractions of nonvascular and some VASCULAR SMOOTH MUSCLE. (From Dictionary of Prostaglandins and Related Compounds, 1990)
leukotrienebronchoconstrictor agent;
human metabolite;
mouse metabolite
leukotriene d4leukotriene D4 : A leukotriene that is (7E,9E,11Z,14Z)-icosa-7,9,11,14-tetraenoic acid substituted by a hydroxy group at position 5 (5S) and a L-cysteinylglycinyl group at position 6 (6R).

Leukotriene D4: One of the biologically active principles of SRS-A. It is generated from LEUKOTRIENE C4 after partial hydrolysis of the peptide chain, i.e., cleavage of the gamma-glutamyl portion. Its biological actions include stimulation of vascular and nonvascular smooth muscle, and increases in vascular permeability. (From Dictionary of Prostaglandins and Related Compounds, 1990)
dipeptide;
leukotriene;
organic sulfide
bronchoconstrictor agent;
human metabolite;
mouse metabolite
leukotriene e4leukotriene E4 : A leukotriene that is (7E,9E,11Z,14Z)-icosa-7,9,11,14-tetraenoic acid substituted by a hydroxy group at position 5 (5S) and an L-cystein-S-yl group at position 6 (6R).

Leukotriene E4: A biologically active principle of SRS-A that is formed from LEUKOTRIENE D4 via a peptidase reaction that removes the glycine residue. The biological actions of LTE4 are similar to LTC4 and LTD4. (From Dictionary of Prostaglandins and Related Compounds, 1990)
amino dicarboxylic acid;
L-cysteine thioether;
leukotriene;
non-proteinogenic L-alpha-amino acid;
secondary alcohol
montelukastmontelukast: a leukotriene D4 receptor antagonistaliphatic sulfide;
monocarboxylic acid;
quinolines
anti-arrhythmia drug;
anti-asthmatic drug;
leukotriene antagonist
l 735821L 735821: inhibits KCNQ2 channelsN-acyl-amino acid
bay u9773BAY u9773: a leukotriene C4 antagonist

BAYu9773 : A dicarboxylic acid that is that is (7E,9E,11Z,14Z)-icosa-7,9,11,14-tetraenoic acid substituted by a hydroxy group at position 4S and a (4-carboxyphenyl)sulfanediyl group at 5R. It is a dual cysteinyl leukotriene receptor antagonist that acts at the CysLT1 and CysLT2 receptors (IC50 = 0.44 and 0.30 muM, respectively).
benzoic acids;
dicarboxylic acid;
organic sulfide;
polyunsaturated fatty acid;
secondary alcohol
leukotriene antagonist
l 365260L 365260: a CCK-B antagonist; structure given in first source; potent & selective CCK-B & gastrin receptor ligand; L 365260 and L 365346 are (R)- and (S)-stereoisomers, respectivelybenzodiazepine
sulindac sulfidesulindac sulfide : An aryl sulfide that is a metabolite of sulindac. A non-steroidal anti-inflammatory drug, which also has anticancer activity.

sulindac sulfide: sulfated analog of indomethacin & inhibitor of prostaglandin synthesis in vitro; RN given refers to cpd without isomeric designation; structure given in first source
aryl sulfide;
monocarboxylic acid;
organofluorine compound
antineoplastic agent;
apoptosis inducer;
non-steroidal anti-inflammatory drug
sb 201993(E)-3-((((6-(2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)benzoic acid: structure given in first source; a competitive LTB(4) receptor antagonist
ono 4057ONO-LB 457: LTB4 receptor antagonist; structure given in first source
ticolubantTicolubant: a leukotriene B4 antagonist
ly 223982LY 223982: RN & structure in first source; leukotriene B4 antagonist
gw 1929GW 1929: activates peroxisome proliferator-activated receptor-gamma; structure in first sourcebenzophenones
cp 195543CP 195543: a potent & selective leukotriene B4 antagonist; structure in first source
cp 105696CP 105696: a leukotriene B4 receptor antagonist; structure in first source
l 365260
leucettamine bleucettamine B: a protein kinase inhibitor isolated from the marine sponge Leucetta microraphis; structure in first source
ubenimexpeptide
mk 0571
montelukast sodiumorganic sodium salt
pf-044189481-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid: structure in first source
3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)propoxy)benzoic acidorganonitrogen compound;
organooxygen compound