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LTA4H

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https://www.readbyqxmd.com/read/29965770/qm-mm-molecular-dynamics-investigations-of-the-substrate-binding-of-leucotriene-a4-hydrolase-implication-for-the-catalytic-mechanism
#1
Xia Mu, Dingguo Xu
LTA4H is a monozinc bi-functional enzyme which exhibits both aminopeptidase and epoxide hydrolase activities. Its dual functions in anti- and pro-inflammatory role have attracted widely attention of the inhibitor design. In this work, we tried to construct Michaelis complexes of LTA4H with both native peptide substrate and LTA4 molecule using combined quantum mechanics and molecular mechanics molecular dynamics simulations. First of all, the zinc ion is coordinated by H295, H299 and E318. For its aminopeptidase activity, similar with conventional peptidases, the fourth ligand to zinc ion is suggested to be an active site water, which is further hydrogen boned with a downstream glutamic acid, E296...
July 2, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29682967/in-vivo-two-photon-fluorescence-imaging-of-the-activity-of-the-inflammatory-biomarker-lta-4-h-in-a-mouse-pneumonia-model
#2
Hui Wang, Ke Xue, Ping Li, Yuyun Yang, Zixu He, Wei Zhang, Wen Zhang, Bo Tang
Severe atmospheric haze caused by industrial pollution has severely affected human health and led to the increasing incidence of cardiopulmonary diseases, including pneumonia. Conventional methods for diagnosis of pneumonia are complicated and tedious, and current clinical imaging techniques might cause organ injuries to some extent. Therefore, an accurate, fast, and intact imaging method must be developed to diagnose pneumonia in the early stages. In this study, we propose a new two-photon fluorescence probe, named as ASPC, for detection of the activity of the inflammatory biomarker LTA4 H through specific recognition and cleavage of amides containing the unnatural amino acid l-AspBzl...
May 15, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29531307/mucosal-luminal-interface-proteomics-reveals-biomarkers-of-pediatric-inflammatory-bowel-disease-associated-colitis
#3
Shelley A Deeke, Amanda E Starr, Zhibin Ning, Sara Ahmadi, Xu Zhang, Janice Mayne, Cheng-Kang Chiang, Ruth Singleton, Eric I Benchimol, David R Mack, Alain Stintzi, Daniel Figeys
OBJECTIVE: Improved biomarkers are an unmet clinical need for suspected inflammatory bowel disease (IBD). Need is greatest for children, since current biomarkers suffers from low specificity, particularly in this population; thus, invasive testing methods, with the accompanying risk of complications, are necessary. Additionally, current biomarkers do not delineate disease extent assessment for ulcerative colitis (UC), a factor involved in therapeutic decisions. METHODS: Intestinal mucosal-luminal interface (MLI) aspirates from the ascending colon (AC) and descending colon (DC) were collected during diagnostic colonoscopy from treatment-naïve children...
May 2018: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/29413439/combined-pet-dce-mri-in-a-rabbit-model-of-atherosclerosis-integrated-quantification-of-plaque-inflammation-permeability-and-burden-during-treatment-with-a-leukotriene-a4-hydrolase-inhibitor
#4
Claudia Calcagno, Olivier Lairez, Julie Hawkins, Steven W Kerr, Melanie S Dugas, Thomas Simpson, Jelle Epskamp, Philip M Robson, Mootaz Eldib, Ilda Bander, Purushothaman K-Raman, Sarayu Ramachandran, Alison Pruzan, Audrey Kaufman, Venkatesh Mani, Alexander Ehlgen, Heiko G Niessen, John Broadwater, Zahi A Fayad
OBJECTIVES: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis. BACKGROUND: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18 F-fluorodeoxyglucose (18 F-FDG) PET, DCE-MRI, and morphological MRI...
February 2018: JACC. Cardiovascular Imaging
https://www.readbyqxmd.com/read/29376243/-discover-potential-inhibitors-of-5-lox-and-lta4h-from-rhei-radix-et-rhizoma-notopterygii-rhizoma-et-radix-and-genitana-macrophyllae-radix-based-on-molecular-simulation-methods
#5
Yu Gu, Xu Zhang, Yan-Kun Chen, Bo-Wen Zhao, Yan-Ling Zhang
5-lipoxygenase (5-LOX) and leukotriene A4 hydrolase (LTA4H), as the major targets of 5-LOX branch in the arachidonic acid (AA) metabolic pathway, play an important role in the treatment of inflammation. Rhei Radix et Rhizoma, Notopterygii Rhizoma et Radix and Genitana Macrophyllae Radix have clear anti-inflammation activities. In this paper, the targets of 5-LOX and LTA4H were used as the research carrier, and Hiphop module in DS4.0 (Discovery studio) was used to construct ingredients database for preliminary screening of three traditional Chinese medicines based on target inhibitor pharmacophore, so as to obtain 5-LOX and LTA4H potential active ingredients...
December 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29202450/angiotensin-converting-enzyme-defines-matrikine-regulated-inflammation-and-fibrosis
#6
Philip J O'Reilly, Qiang Ding, Samia Akthar, Guoqiang Cai, Kristopher R Genschmer, Dhiren F Patel, Patricia L Jackson, Liliana Viera, Mojtaba Roda, Morgan L Locy, Ellen A Bernstein, Clare M Lloyd, Kenneth E Bernstein, Robert J Snelgrove, J Edwin Blalock
The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis...
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29180335/-pathogenic-role-of-leukotriene-b4-in-pulmonary-microvascular-endothelial-cell-hyper-permeability-induced-by-one-lung-ventilation-in-rabbits
#7
Li-Sha Li, Yong Yang, Xin-Ling Liu, Chuan-Rao Zhang, Qing-Yan Ye, Wen-Jun Hou, Yan-Hua Zhao, Gao-Peng Xiao, Xin-Nan Li, Yan-Hua Li, Rui Liu
OBJECTIVE: To elucidate the pathogenic role of leukotriene B4 (LTB4) in increased pulmonary microvascular endothelial cell permeability induced by one lung ventilation (OLV) in rabbits. METHODS: Forty-eight healthy Japanese white rabbits were randomly divided into control group (group C), saline pretreatment group (group S), bestatin (a leukotriene A4 hydrolase (LTA4H) inhibitor) plus saline pretreatment group (group B), OLV group (group O), saline pretreatment plus OLV group (group SO) and bestatin plus saline pretreatment with OLV group (group BO)...
November 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29067980/comparative-analysis-of-inflammatory-gene-expression-levels-in-metabolic-syndrome-coronary-artery-disease
#8
Jiny Nair, Vijay V Kakkar, Jayashree Shanker
BACKGROUND & OBJECTIVES: Metabolic syndrome (MetS) increases the likelihood of developing coronary artery disease (CAD), and inflammation is involved in the pathogenesis of both these conditions. The present work was conducted to examine the relative expression of 18 key inflammatory genes associated with MetS and incident CAD in a representative group of patients. METHODS: A total of 178 male patients, including 57 with CAD and 121 without CAD, were enrolled in the study...
June 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/29051536/feasibility-and-physiological-relevance-of-designing-highly-potent-aminopeptidase-sparing-leukotriene-a4-hydrolase-inhibitors
#9
Shin Numao, Franziska Hasler, Claire Laguerre, Honnappa Srinivas, Nathalie Wack, Petra Jäger, Andres Schmid, Arnaud Osmont, Patrik Röthlisberger, Jeremy Houguenade, Christian Bergsdorf, Janet Dawson, Nathalie Carte, Andreas Hofmann, Christian Markert, Liz Hardaker, Andreas Billich, Romain M Wolf, Carlos A Penno, Birgit Bollbuck, Wolfgang Miltz, Till A Röhn
Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs...
October 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042030/recent-advances-in-clinical-development-of-leukotriene-b4-pathway-drugs
#10
REVIEW
L Bhatt, K Roinestad, T Van, E B Springman
The LTB4 pathway is an attractive target for therapeutic drug development. Two broad classes of drugs have been pursued: antagonists of the primary LTB4 receptors (BLT1 and BLT2) and inhibitors of LTA4 Hydrolase (LTA4H), the rate limiting enzyme in the production of LTB4. An initial wave of effort culminated in the 1990s. Over the past 15 years, a second wave of more selective drug candidates, including at least 5 BLT antagonists and 6 LTA4H inhibitors, have reached Phase 2 clinical trials. Despite the extensive efforts to discover and develop LTB4 pathway targeting drugs, only one has reached the market to date...
October 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/29042025/biosynthesis-of-leukotriene-b-4
#11
REVIEW
Min Wan, Xiao Tang, Alena Stsiapanava, Jesper Z Haeggström
Leukotriene B4 (LTB4 ) is a lipid mediator derived from arachidonic acid (AA) by the sequential action of 5-lipoxygenase (5-LOX), 5-lipoxygenase-activating protein (FLAP) and LTA4 hydrolase (LTA4 H). It was initially recognized for its involvement in the recruitment of neutrophils and is one of the most potent chemotactic agents known to date. A large body of data has indicated that LTB4 plays a significant role in many chronic inflammatory diseases, such as arthritis, chronic obstructive pulmonary disease (COPD), cardiovascular disease, cancer and more recently, metabolic disorder...
October 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/28991413/ligand-based-modeling-for-the-prediction-of-pharmacophore-features-for-multi-targeted-inhibition-of-the-arachidonic-acid-cascade
#12
Nisha Saroj Devi, Rajasekar Shanmugam, Jayanta Ghorai, Meera Ramanan, Pazhamalai Anbarasan, Mukesh Doble
The single-target drugs against the arachidonic acid inflammatory pathway are associated with serious side effects, hence, as a first step towards multi-target drugs, we have studied the pharmacophoric features common to the inhibitors of 5-lipoxygenase-activating protein (FLAP), microsomal prostaglandin E-synthase 1 (mPGES-1) and leukotriene A4 hydrolase (LTA4H). FLAP and mPGES-1 shared subfamily-specific positions (SSPs) and four mPGES-1 inhibitors binding to them mapped onto the pharmacophore derived from FLAP inhibitors (Ph-FLAP)...
March 2018: Molecular Informatics
https://www.readbyqxmd.com/read/28839250/pharmacological-profile-and-efficiency-in-vivo-of-diflapolin-the-first-dual-inhibitor-of-5-lipoxygenase-activating-protein-and-soluble-epoxide-hydrolase
#13
Ulrike Garscha, Erik Romp, Simona Pace, Antonietta Rossi, Veronika Temml, Daniela Schuster, Stefanie König, Jana Gerstmeier, Stefanie Liening, Markus Werner, Heiner Atze, Sandra Wittmann, Christina Weinigel, Silke Rummler, Gerhard K Scriba, Lidia Sautebin, Oliver Werz
Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827365/capturing-lta-4-hydrolase-in-action-insights-to-the-chemistry-and-dynamics-of-chemotactic-ltb-4-synthesis
#14
Alena Stsiapanava, Bengt Samuelsson, Jesper Z Haeggström
Human leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4 H) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA4 into LTB4 , a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTA4 H complexed with LTA4 , providing the structural underpinnings of the enzyme's unique epoxide hydrolase (EH) activity, involving Zn2+ , Y383, E271, D375, and two catalytic waters...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28658259/neutrophil-derived-ltb4-induces-macrophage-aggregation-in-response-to-encapsulated-streptococcus-iniae-infection
#15
William J B Vincent, Elizabeth A Harvie, John-Demian Sauer, Anna Huttenlocher
Immune cells sense and react to a multitude of factors including both host and microbe-derived signals. Understanding how cells translate these cues into particular cellular behaviors is a complex yet critical area of study. We have previously shown that both neutrophils and macrophages are important for controlling the fish pathogen Streptococcus iniae. Here, we report both host and bacterial determinants leading to the formation of organized macrophage aggregates as part of the host inflammatory response in a subset of infected larvae...
2017: PloS One
https://www.readbyqxmd.com/read/28575166/lta4h-regulates-cell-cycle-and-skin-carcinogenesis
#16
Naomi Oi, Hiroyuki Yamamoto, Alyssa Langfald, Ruihua Bai, Mee-Hyun Lee, Ann M Bode, Zigang Dong
Leukotriene A4 hydrolase (LTA4H), a bifunctional zinc metallo-enzyme, is reportedly overexpressed in several human cancers. Our group has focused on LTA4H as a potential target for cancer prevention and/or therapy. In the present study, we report that LTA4H is a key regulator of cell cycle at the G0/G1 phase acting by negatively regulating p27 expression in skin cancer. We found that LTA4H is overexpressed in human skin cancer tissue. Knocking out LTA4H significantly reduced skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model...
July 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28419368/leukotriene-a4-hydrolase-genotype-and-hiv-infection-influence-intracerebral-inflammation-and-survival-from-tuberculous-meningitis
#17
RANDOMIZED CONTROLLED TRIAL
Nguyen T T Thuong, Dorothee Heemskerk, Trinh T B Tram, Le T P Thao, Lalita Ramakrishnan, Vu T N Ha, Nguyen D Bang, Tran T H Chau, Nguyen H Lan, Maxine Caws, Sarah J Dunstan, Nguyen V V Chau, Marcel Wolbers, Nguyen T H Mai, Guy E Thwaites
Background: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM...
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28419367/evaluating-the-impact-of-lta4h-genotype-and-immune-status-on-survival-from-tuberculous-meningitis
#18
Vinicius M Fava, Erwin Schurr
No abstract text is available yet for this article.
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28419315/clinical-parameters-routine-inflammatory-markers-and-lta4h-genotype-as-predictors-of-mortality-among-608-patients-with-tuberculous-meningitis-in-indonesia
#19
Arjan van Laarhoven, Sofiati Dian, Carolien Ruesen, Ela Hayati, Michelle S M A Damen, Jessi Annisa, Lidya Chaidir, Rovina Ruslami, Tri Hanggono Achmad, Mihai G Netea, Bachti Alisjahbana, Ahmad Rizal Ganiem, Reinout van Crevel
Background: Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear. Methods: We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM...
April 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28318626/the-leukotriene-b-4-leukotriene-b-4-receptor-axis-promotes-cisplatin-induced-acute-kidney-injury-by-modulating-neutrophil-recruitment
#20
Bo Deng, Yuli Lin, Shuai Ma, Yin Zheng, Xuguang Yang, Bingji Li, Wenyan Yu, Qingqing Xu, Tingyan Liu, Chuanming Hao, Rui He, Feng Ding
Cisplatin is an effective chemotherapeutic agent and widely used in treatment of various solid organ malignancies, including head and neck, ovarian, and testicular cancers. However, the induction of acute kidney injury (AKI) is one of its main side effects. Leukotriene B4 receptor 1 (BLT1) mediates the majority of physiological effects of leukotriene B4 (LTB4 ), a potent lipid chemoattractant generated at inflammation sites, but the role of the LTB4 -BLT1 axis in cisplatin-induced AKI remains unknown. Here we found upregulated LTB4 synthesis and BLT1 expression in the kidney after cisplatin administration...
July 2017: Kidney International
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