Functional Properties and Molecular Architecture of Leukotriene A4 Hydrolase, a Pivotal Catalyst of Chemotactic Leukotriene Formation

The leukotrienes are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nM concentrations. In addition, leukotriene B4modulates immune responses, participates in the host defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g., nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4is catalyzed by leukotriene A4hydrolase, a unique bifunctional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding of the function and molecular architecture of leukotriene A4hydrolase.

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Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19

10.21203/rs.3.rs-33171/v1 ◽

2020 ◽

Author(s):

Xiaopeng Tang ◽

Mingqian Fang ◽

Juan Zhang ◽

Zhiyi Liao ◽

Ruomei Cheng ◽

...

Keyword(s):

Epoxide Hydrolase ◽

Leukotriene B4 ◽

Spike Protein ◽

Aminopeptidase Activity ◽

Healthy Control ◽

Leukotriene A4 Hydrolase ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Leukotriene A4

Abstract Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that fibrinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent inflammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identified as a fibrinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the first endogenous inhibitor of LTA4H, a pro-inflammatory enzyme catalyzing final and rating limited step in biosynthesis of leukotriene-B4 that is an extremely inflammatory mediator and a target to design superior anti-inflammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and fibrinogen expression in vivo. Collectively, these findings identify the imbalance between inflammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior anti-inflammatory function because it specifically targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H’s aminopeptidase activity.

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Development of a Homogeneous Time-Resolved Fluorescence Leukotriene B4 Assay for Determining the Activity of Leukotriene A4 Hydrolase

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057107299873 ◽

2007 ◽

Vol 12 (4) ◽

pp. 536-545 ◽

Cited By ~ 10

Author(s):

Amy M. Liang ◽

Emmanuel Claret ◽

Josy Ouled-Diaf ◽

Alexandre Jean ◽

David Vogel ◽

...

Keyword(s):

Competitive Inhibition ◽

Inflammatory Diseases ◽

Leukotriene B4 ◽

Time Resolved Fluorescence ◽

Time Resolved ◽

Attractive Therapeutic Target ◽

Leukotriene A4 Hydrolase ◽

Buffer Composition ◽

Leukotriene A4 ◽

Rate Limiting

Leukotriene A4 (LTA4) hydrolase catalyzes a rate-limiting final biosynthetic step of leukotriene B4 (LTB4), a potent lipid chemotatic agent and proinflammatory mediator. LTB4 has been implicated in the pathogenesis of various acute and chronic inflammatory diseases, and thus LTA4 hydrolase is regarded as an attractive therapeutic target for anti-inflammation. To facilitate identification and optimization of LTA 4 hydrolase inhibitors, a specific and efficient assay to quantify LTB4 is essential. This article describes the development of a novel 384-well homogeneous time-resolved fluorescence assay for LTB4 (LTB4 HTRF® assay) and its application to establish an HTRF-based LTA4 hydrolase assay for lead optimization. This LTB4 HTRF assay is based on competitive inhibition and was established by optimizing the reagent concentration, buffer composition, incubation time, and assay miniaturization. The optimized assay is sensitive, selective, and robust, with a Z' factor of 0.89 and a subnanomolar detection limit for LTB 4. By coupling this LTB4 HTRF assay to the LTA4 hydrolase reaction, an HTRF-based LTA4 hydrolase assay was established and validated. Using a test set of 16 LTA4 hydrolase inhibitors, a good correlation was found between the IC50 values obtained using LTB4 HTRF with those determined using the LTB enzyme-linked immunoassay ( R = 0.84). The HTRF-based LTA4 hydrolase assay was shown to be an efficient and suitable4 assay for determining compound potency and library screening to guide the development of potent inhibitors of LTA4 hydrolase. ( Journal of Biomolecular Screening 2007:536-545)

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Genetic regulation of expression of leukotriene A4 hydrolase

ERJ Open Research ◽

10.1183/23120541.00058-2015 ◽

2016 ◽

Vol 2 (1) ◽

pp. 00058-2015 ◽

Cited By ~ 3

Author(s):

Tomasz Szul ◽

Peter Castaldi ◽

Michael H. Cho ◽

J. Edwin Blalock ◽

Amit Gaggar

Keyword(s):

Promoter Region ◽

Inflammatory Responses ◽

Luciferase Reporter ◽

Aminopeptidase Activity ◽

Chronic Obstructive ◽

Luciferase Reporter Gene ◽

Putative Promoter ◽

Leukotriene A4 Hydrolase ◽

Leukotriene A4 ◽

The Impact

In chronic inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD), the concurrent organ-specific and systemic inflammatory responses lead to airway remodelling and vascular dysfunction. Although a major common risk factor for COPD, cigarette smoke alone cannot explain the progression of this disease; there is increasing evidence that genetic predisposition also plays a role in COPD susceptibility and progression. A key enzyme in chronic lung inflammation is leukotriene A4 hydrolase (LTA4H). With its aminopeptidase activity, LTA4H degrades the neutrophil chemoattractant tripeptide PGP.In this study, we used the luciferase reporter gene analysis system and quantitative trait locus analysis to explore the impact of single-nucleotide polymorphisms (SNPs) in the putative promoter region ofLTA4Hon LTA4H expression.We show that not only is the putative promoter ofLTA4Hlarger than previously reported but also that SNPs in the expanded promoter region regulate expression of LTA4H both in cell-based systems and in peripheral blood samples from human subjects.These findings provide significant evidence for an active region upstream of the previously reportedLTA4Hpromoter, which may have implications related to ongoing inflammatory processes in chronic lung disease.

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Activation and inhibition of leukotriene A4 hydrolase aminopeptidase activity by diphenyl ether and derivatives

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.10.044 ◽

2008 ◽

Vol 18 (24) ◽

pp. 6549-6552 ◽

Cited By ~ 21

Author(s):

Xiaolu Jiang ◽

Lu Zhou ◽

Dengguo Wei ◽

Hu Meng ◽

Ying Liu ◽

...

Keyword(s):

Diphenyl Ether ◽

Aminopeptidase Activity ◽

Leukotriene A4 Hydrolase ◽

Leukotriene A4

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Regulation of the production (leukotriene A4 hydrolase) and the action (leukotriene B4 receptor sites) of leukotriene B4

Molecular Biology of the Arterial Wall ◽

10.1007/978-3-642-83118-8_40 ◽

1987 ◽

pp. 123-125

Author(s):

A. W. Ford-Hutchinson

Keyword(s):

Leukotriene B4 ◽

Receptor Sites ◽

Leukotriene A4 Hydrolase ◽

Leukotriene A4 ◽

Leukotriene B4 Receptor

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Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21010307 ◽

2020 ◽

Vol 21 (1) ◽

pp. 307 ◽

Cited By ~ 2

Author(s):

Sara Ottolenghi ◽

Aida Zulueta ◽

Anna Caretti

Keyword(s):

High Altitude ◽

Inflammatory Diseases ◽

Physiological Adaptation ◽

Adaptation To Hypoxia ◽

Chronic Obstructive ◽

Compensatory Response ◽

Obstructive Pulmonary Disease ◽

Pathological Conditions ◽

High Altitude Pulmonary Edema ◽

Sphingosine 1 Phosphate

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

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Neutrophil Elastase (NE) and NE Inhibitors: Canonical and Noncanonical Functions in Lung Chronic Inflammatory Diseases (Cystic Fibrosis and Chronic Obstructive Pulmonary Disease)

Journal of Aerosol Medicine ◽

10.1089/jam.2007.0653 ◽

2008 ◽

Vol 0 (0) ◽

pp. 080207080519480-20

Author(s):

Ali Roghanian ◽

Jean-Michel Sallenave

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Cystic Fibrosis ◽

Pulmonary Disease ◽

Neutrophil Elastase ◽

Inflammatory Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Chronic Inflammatory Diseases

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Protective Features of Autophagy in Pulmonary Infection and Inflammatory Diseases

Cells ◽

10.3390/cells8020123 ◽

2019 ◽

Vol 8 (2) ◽

pp. 123 ◽

Cited By ~ 12

Author(s):

Kui Wang ◽

Yi Chen ◽

Pengju Zhang ◽

Ping Lin ◽

Na Xie ◽

...

Keyword(s):

Pulmonary Infection ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Autophagy Pathway ◽

Pulmonary Arterial ◽

Cellular Components ◽

Cellular Stressors

Autophagy is a highly conserved catabolic process involving autolysosomal degradation of cellular components, including protein aggregates, damaged organelles (such as mitochondria, endoplasmic reticulum, and others), as well as various pathogens. Thus, the autophagy pathway represents a major adaptive response for the maintenance of cellular and tissue homeostasis in response to numerous cellular stressors. A growing body of evidence suggests that autophagy is closely associated with diverse human diseases. Specifically, acute lung injury (ALI) and inflammatory responses caused by bacterial infection or xenobiotic inhalation (e.g., chlorine and cigarette smoke) have been reported to involve a spectrum of alterations in autophagy phenotypes. The role of autophagy in pulmonary infection and inflammatory diseases could be protective or harmful dependent on the conditions. In this review, we describe recent advances regarding the protective features of autophagy in pulmonary diseases, with a focus on ALI, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), tuberculosis, pulmonary arterial hypertension (PAH) and cystic fibrosis.

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