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Journal of Lipid Mediators and Cell... Oct 1995
Review
Topics: Amino Acid Sequence; Animals; Base Sequence; Bronchoconstriction; Cloning, Molecular; Glutathione; Glutathione Transferase; Humans; Leukotriene C4; Leukotrienes; Lung; Molecular Sequence Data; Substrate Specificity
PubMed: 8777577
DOI: 10.1016/0929-7855(95)00042-o -
Prostaglandins, Leukotrienes, and... 2003LTC(4) synthase conjugates LTA(4) with glutathione (GSH) to form LTC(4), the parent compound of the cysteinyl leukotrienes. LTC(4) synthase is a membrane protein that... (Review)
Review
LTC(4) synthase conjugates LTA(4) with glutathione (GSH) to form LTC(4), the parent compound of the cysteinyl leukotrienes. LTC(4) synthase is a membrane protein that functions as a non-covalent homodimer of two 18-kDa polypeptides. The enzymatic activity of LTC(4) synthase is augmented by Mg(2+) and inhibited by Co(2+) and the FLAP inhibitor MK-886. The K(m) and V(max) values of human LTC(4) synthase are 3.6 microM and 1.3 micromol/mg/min for LTA(4) and 1.6 mM and 2.7 micromol/mg/min for GSH, respectively. The deduced amino acid sequence and the predicted secondary structure of LTC(4) synthase share significant homology to FLAP, mGST-2, and mGST-3. Site-directed mutagenesis of LTC(4) synthase suggests that Arg-51 is involved in opening the epoxide ring of LTA(4) and Tyr-93 in GSH thiolate anion formation during catalytic conjugation. LTC(4) synthase is a TATA-less gene whose transcription involved both cell- and non-specific regulatory elements. LTC(4) synthase gene disrupted mice grow normally, and are attenuated for innate and adaptive immune inflammatory permeability responses.
Topics: Animals; Catalytic Domain; Cysteine; Glutathione; Glutathione Transferase; Humans; Inflammation; Leukotriene A4; Leukotriene C4; Leukotrienes; Lipoxygenase Inhibitors; Lung; Membrane Proteins; Mutagenesis, Site-Directed; Respiratory Tract Diseases; Transcription, Genetic
PubMed: 12895593
DOI: 10.1016/s0952-3278(03)00071-1 -
Journal of Lipid Mediators and Cell... Oct 1995The current challenge in research on leukotriene receptors is to clone these molecules. Traditional protein purification approaches have not been successful in providing... (Review)
Review
The current challenge in research on leukotriene receptors is to clone these molecules. Traditional protein purification approaches have not been successful in providing sequence information. Solubilization of cys-LT1 has been achieved but results in the dissociation of G-proteins and the loss of high affinity binding (Mong et al., 1986b; Mong and Sarau, 1990), while cys-LT2 activity cannot be monitored by other than functional assays and there have not been any purification attempts. Partial purification of B-LT has been reported but has not been continued to homogeneity (Sherman et al., 1992; Votta et al., 1990; Miki et al., 1990). Nor have attempts to clone these receptors through either homology screening or expression cloning been successful. The cloning of the prostanoid receptors, described in detail elsewhere in this volume, has shown that these receptors belong to a distinct family within the G-protein-coupled receptor superfamily. It is probable, therefore, that the leukotriene receptors will also belong to a separate group within this superfamily since phylogenic comparisons have shown that receptors displaying high affinity for structurally related ligands exist as discrete families. Recently, a human cDNA encoding an orphan FMLP-related receptor cloned from HL60 cells of myeloid lineage was identified as the receptor for another eicosanoid, lipoxin A (Fiore et al., 1994). FMLP has a similar profile of biological actions to LTB4. Moreover, LTD4 showed a high degree of cross-reactivity with this receptor with an affinity only 20-fold less that of lipoxin A, although LTB4 was inactive. It remains to be determined whether the leukotriene receptors will fall into this class of receptors. The cloning of the leukotriene receptors will allow identification of the different receptor types and subtypes and potentially splice variants. Evaluation of currently developed antagonists at these receptor types could also open the way for novel therapies for inflammatory conditions.
Topics: Affinity Labels; Animals; Humans; Leukotriene Antagonists; Leukotriene B4; Leukotrienes; Muscle Contraction; Receptors, Leukotriene; Receptors, Leukotriene B4; Signal Transduction
PubMed: 8777583
DOI: 10.1016/0929-7855(95)00027-n -
Pulmonary Pharmacology & Therapeutics 1998
Review
Topics: Animals; Asthma; Humans; Leukotrienes; Respiratory Tract Diseases
PubMed: 10210657
DOI: No ID Found -
Annual Review of Pharmacology and... Jan 2023Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also... (Review)
Review
Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.
Topics: Humans; Leukotrienes; Inflammation; Asthma
PubMed: 36130059
DOI: 10.1146/annurev-pharmtox-051921-085014 -
Expert Opinion on Therapeutic Patents May 2017Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly... (Review)
Review
Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly involves 5-lipoxygenase (5-LO) and its 5-lipoxygenase-activating protein (FLAP), LTA hydrolase and LTC synthase that all may represent potential targets for LT biosynthesis inhibitors. Areas covered: We introduce the LT biosynthetic pathway and its cellular regulation, the diverse biological actions of LTs and their receptors, and we briefly describe the pharmacological strategies for suppression of LT formation as well as the classes of current LT biosynthesis inhibitors. The main focus is placed on the comprehensive discussion of recently reported inhibitors of 5-LO, FLAP, LTA hydrolase and LTC synthase, based on literature search (PubMed and Thomson Innovation Patents Searches), covering 2012-2016. Expert opinion: Although many new series of 5-LO inhibitors have been presented without patenting, essentially by academia, novel FLAP inhibitors (many patented) are most advanced in clinical development and are apparently the focus of pharmaceutical companies. Only few novel inhibitors of LTA hydrolase and LTC synthase were reported. Major issues in the development of LT synthesis inhibitors are related to loss of potency in biological relevant environment, poor pharmacokinetics, lack of oral efficacy, and side effects.
Topics: 5-Lipoxygenase-Activating Protein Inhibitors; Animals; Anti-Inflammatory Agents; Drug Design; Epoxide Hydrolases; Glutathione Transferase; Humans; Inflammation; Leukotrienes; Lipoxygenase Inhibitors; Patents as Topic
PubMed: 28005436
DOI: 10.1080/13543776.2017.1276568 -
Journal of Veterinary Pharmacology and... Oct 2008Leukotrienes are important mediators of inflammatory and allergic conditions in people and are suspected to play an important role in tumorigenesis and tumor growth of... (Review)
Review
Leukotrienes are important mediators of inflammatory and allergic conditions in people and are suspected to play an important role in tumorigenesis and tumor growth of several different tumor types. Based on this, researchers are making great progress in identifying novel pharmacologic targets for several human diseases. Leukotriene inhibition has resulted in therapeutic benefit in clinical trials involving people with osteoarthritis, allergic asthma, and atopic dermatitis. Despite this progress and the possibility that leukotriene inhibition may also play an important therapeutic role in veterinary patients, parallel advances have not yet been made in veterinary medicine. This article summarizes leukotriene function and synthesis. It also reviews the published literature regarding potential therapeutic applications of leukotriene inhibition in both human and veterinary medicine, focusing primarily on osteoarthritis, NSAID induced gastrointestinal mucosal damage, allergic asthma, atopic dermatitis, and cancer.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Humans; Leukotriene Antagonists; Leukotrienes; Neoplasms; Osteoarthritis; Pyrazoles; Receptors, Leukotriene
PubMed: 19000257
DOI: 10.1111/j.1365-2885.2008.00963.x -
Ernst Schering Research Foundation... 2000
Review
Topics: Amino Acid Sequence; Animals; Chemotaxis; Humans; Leukotriene B4; Leukotrienes; Molecular Sequence Data; Receptors, Leukotriene; Receptors, Leukotriene B4; Sequence Homology, Amino Acid; Signal Transduction
PubMed: 10943331
DOI: 10.1007/978-3-662-04047-8_7 -
Clinical and Experimental Allergy :... Dec 2010Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor... (Review)
Review
Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT(1) and CysLT(2) , have been identified. The activation of the CysLT(1) receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB(4) might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT(1) receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT(1) receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT(1) receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT(1) receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.
Topics: Anti-Asthmatic Agents; Asthma; Humans; Leukotriene Antagonists; Leukotrienes; Receptors, Leukotriene
PubMed: 21059119
DOI: 10.1111/j.1365-2222.2010.03630.x -
Nature Reviews. Drug Discovery Aug 2005Owing to their anti-inflammatory properties, leukotriene modifiers have been the primary therapeutics in asthma management for several years. Although blocking the... (Review)
Review
Owing to their anti-inflammatory properties, leukotriene modifiers have been the primary therapeutics in asthma management for several years. Although blocking the inflammatory component of human disease is a long-standing and established concept, the use of leukotriene modifiers in treating the inflammatory component of cardiovascular disease encompassing atherosclerosis, myocardial infarction, stroke and aortic aneurysm has, surprisingly, only been seriously contemplated in the past few years. As reviewed here, several exciting studies have recently contributed to this expanding area of interest, and so far one leukotriene modifier has entered Phase II clinical trials to assess its potential for reducing the risk of heart attacks.
Topics: Animals; Cardiovascular Diseases; Humans; Inflammation; Leukotriene Antagonists; Leukotrienes
PubMed: 16041318
DOI: 10.1038/nrd1796