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Epoxide hydrolase

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https://www.readbyqxmd.com/read/27917951/catalytic-conversion-of-lipophilic-substrates-by-phase-constrained-enzymes-in-the-aqueous-or-in-the-membrane-phase
#1
Marcus Cebula, Ilke Simsek Turan, Birgitta Sjödin, Madhuranayaki Thulasingam, Joseph Brock, Volodymyr Chmyrov, Jerker Widengren, Hiroshi Abe, Bengt Mannervik, Jesper Z Haeggström, Agnes Rinaldo-Matthis, Engin U Akkaya, Ralf Morgenstern
Both soluble and membrane-bound enzymes can catalyze the conversion of lipophilic substrates. The precise substrate access path, with regard to phase, has however, until now relied on conjecture from enzyme structural data only (certainly giving credible and valuable hypotheses). Alternative methods have been missing. To obtain the first experimental evidence directly determining the access paths (of lipophilic substrates) to phase constrained enzymes we here describe the application of a BODIPY-derived substrate (PS1)...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#2
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
December 2, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27911800/an-%C3%AE-%C3%AE-hydrolase-fold-protein-in-the-biosynthesis-of-thiostrepton-exhibits-a-dual-activity-for-endopeptidyl-hydrolysis-and-epoxide-ring-opening-macrocyclization
#3
Qingfei Zheng, Shoufeng Wang, Panpan Duan, Rijing Liao, Dandan Chen, Wen Liu
Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27897114/ureas-applications-in-drug-design-and-development
#4
Ajit Dhananjay Jagtap, Nagendra Bharatrao Kondekar, Amit A Sadani, Ji-Wang Chern
The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small molecules displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead molecules have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivatives as modulators biological targets (viz...
November 29, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27884766/mechanisms-of-vascular-dysfunction-in-copd-and-effects-of-a-novel-soluble-epoxide-hydrolase-inhibitor-in-smokers
#5
Lucy Yang, Joseph Cheriyan, David D Gutterman, Ruth J Mayer, Zsuzsanna Ament, Jules L Griffin, Aili L Lazaar, David E Newby, Ruth Tal-Singer, Ian B Wilkinson
BACKGROUND: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD, and a novel sEH inhibitor GSK2256294 attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo. METHODS: Endogenous and stimulated endothelial release of EETs was assessed in 12 COPD patients, 11 overweight smokers, and 2 matched control groups, using forearm plethysmography with intra-arterial infusions of fluconazole, bradykinin, and the combination...
November 21, 2016: Chest
https://www.readbyqxmd.com/read/27878278/alteration-of-epoxyeicosatrienoic-acids-in-the-liver-and-kidney-of-cytochrome-p450-4f2-transgenic-mice
#6
Bijun Zhang, Guangrui Lai, Xiaoliang Liu, Yanyan Zhao
Arachidonic acid (AA) can be metabolized into 20-hydroxyeicosatetraenoic acid (20-HETE) by ω-hydroxylases, and epoxyeicosatrienoic acids (EETs) by epoxygenases. The effects of EETs in cardiovascular physiology are vasodilatory, anti-inflammatory and anti‑apoptotic, which are opposite to the function to 20‑HETE. However, EETs are not stable in vivo, and are rapidly degraded to the biologically less active metabolites, dihydroxyeicosatrienoic acids, via soluble epoxide hydrolase (sEH). Western blotting, reverse transcription‑quantitative polymerase chain reaction and liquid chromatography tandem mass spectrometry were performed in order to determine target RNA and protein expression levels...
November 23, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27830295/enhancing-productivity-for-cascade-biotransformation-of-styrene-to-s-vicinal-diol-with-biphasic-system-in-hollow-fiber-membrane-bioreactor
#7
Pengfei Gao, Shuke Wu, Prashant Praveen, Kai-Chee Loh, Zhi Li
Biotransformation is a green and useful tool for sustainable and selective chemical synthesis. However, it often suffers from the toxicity and inhibition from organic substrates or products. Here, we established a hollow fiber membrane bioreactor (HFMB)-based aqueous/organic biphasic system, for the first time, to enhance the productivity of a cascade biotransformation with strong substrate toxicity and inhibition. The enantioselective trans-dihydroxylation of styrene to (S)-1-phenyl-1,2-ethanediol, catalyzed by Escherichia coli (SSP1) coexpressing styrene monooxygenase and an epoxide hydrolase, was performed in HFMB with organic solvent in the shell side and aqueous cell suspension in the lumen side...
November 9, 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27821754/the-biosynthetic-pathway-of-the-nonsugar-high-intensity-sweetener-mogroside-v-from-siraitia-grosvenorii
#8
Maxim Itkin, Rachel Davidovich-Rikanati, Shahar Cohen, Vitaly Portnoy, Adi Doron-Faigenboim, Elad Oren, Shiri Freilich, Galil Tzuri, Nadine Baranes, Shmuel Shen, Marina Petreikov, Rotem Sertchook, Shifra Ben-Dor, Hugo Gottlieb, Alvaro Hernandez, David R Nelson, Harry S Paris, Yaakov Tadmor, Yosef Burger, Efraim Lewinsohn, Nurit Katzir, Arthur Schaffer
The consumption of sweeteners, natural as well as synthetic sugars, is implicated in an array of modern-day health problems. Therefore, natural nonsugar sweeteners are of increasing interest. We identify here the biosynthetic pathway of the sweet triterpenoid glycoside mogroside V, which has a sweetening strength of 250 times that of sucrose and is derived from mature fruit of luo-han-guo (Siraitia grosvenorii, monk fruit). A whole-genome sequencing of Siraitia, leading to a preliminary draft of the genome, was combined with an extensive transcriptomic analysis of developing fruit...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27815261/soluble-epoxide-hydrolase-deficiency-or-inhibition-enhances-murine-hypoxic-pulmonary-vasoconstriction-after-lipopolysaccharide-challenge
#9
Martin Wepler, Arkadi Beloiartsev, Mary D Buswell, Dipak Panigrahy, Rajeev Malhotra, Emmanuel S Buys, Peter Radermacher, Fumito Ichinose, Donald B Bloch, Warren M Zapol
RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) is the response of the pulmonary vasculature to low levels of alveolar oxygen. HPV improves systemic arterial oxygenation by matching pulmonary perfusion to ventilation during alveolar hypoxia, and is impaired in lung diseases such as the acute respiratory distress syndrome (ARDS) and in experimental models of endotoxemia. Epoxyeicosatrienoic acids (EETs) are pulmonary vasoconstrictors, which are metabolized to less vasoactive dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH)...
November 4, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27800556/aspartyl-oxidation-catalysts-that-dial-in-functional-group-selectivity-along-with-regio-and-stereoselectivity
#10
Joshua S Alford, Nadia C Abascal, Christopher R Shugrue, Sean M Colvin, David K Romney, Scott J Miller
A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions...
October 26, 2016: ACS Central Science
https://www.readbyqxmd.com/read/27795395/exported-epoxide-hydrolases-modulate-erythrocyte-vasoactive-lipids-during-plasmodium-falciparum-infection
#11
Natalie J Spillman, Varun K Dalmia, Daniel E Goldberg
: Erythrocytes are reservoirs of important epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs). EETs function as vasodilators and anti-inflammatory modulators in the bloodstream. Bioactive EETs are hydrolyzed to less active diols (dihydroxyeicosatrienoic acids) by epoxide hydrolases (EHs). The malaria parasite Plasmodium falciparum infects host red blood cells (RBCs) and exports hundreds of proteins into the RBC compartment. In this study, we show that two parasite epoxide hydrolases, P falciparum epoxide hydrolases 1 (PfEH1) and 2 (PfEH2), both with noncanonical serine nucleophiles, are exported to the periphery of infected RBCs...
October 18, 2016: MBio
https://www.readbyqxmd.com/read/27782740/vasodilatory-responses-of-renal-interlobular-arteries-to-epoxyeicosatrienoic-acids-analog-are-not-enhanced-in-ren-2-transgenic-hypertensive-rats-evidence-against-a-role-of-direct-vascular-effects-of-epoxyeicosatrienoic-acids-in-progression-of-experimental-heart
#12
A Sporková, Z Husková, P Škaroupková, N R Reddy, J R Falck, J Sadowski, L Červenka
Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the role of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls...
October 26, 2016: Physiological Research
https://www.readbyqxmd.com/read/27753791/soluble-epoxide-hydrolase-inhibitor-attenuates-lipopolysaccharide-induced-acute-lung-injury-and-improves-survival-in-mice
#13
Yong Zhou, Tian Liu, Jia-Xi Duan, Ping Li, Guo-Ying Sun, Yong-Ping Liu, Jun Zhang, Liang Dong, Kin Sing Stephen Lee, Bruce D Hammcok, Jian-Xin Jiang, Cha-Xiang Guan
Acute lung injury (ALI) is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production leading to lung edema. The mortality rate of patients suffering from ALI remains high. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of polyunsaturated fatty acid (PUFA) with anti-hypertensive, profibrinolytic and anti-inflammatory functions. EETs are rapidly hydrated by soluble epoxide hydrolase (sEH) to their less potent diols...
October 6, 2016: Shock
https://www.readbyqxmd.com/read/27732914/an-%C3%AF-3-enriched-diet-alone-does-not-attenuate-ccl4-induced-hepatic-fibrosis
#14
Todd R Harris, Sean Kodani, Jun Yang, Denise M Imai, Bruce D Hammock
Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study, we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid and eicosapentaenoic acid ethyl esters)...
December 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27732913/targeting-arachidonic-acid-pathway-to-prevent-programmed-hypertension-in-maternal-fructose-fed-male-adult-rat-offspring
#15
You-Lin Tain, Wei-Chia Lee, Kay L H Wu, Steve Leu, Julie Y H Chan
Hypertension can be programmed in response to nutritional insults in early life. Maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming and arachidonic acid metabolism pathway. We examined whether early treatment with a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-Deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) can prevent HF-induced programmed hypertension. Pregnant Sprague Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) during the whole period of pregnancy and lactation...
September 7, 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27709014/role-of-farnesoid-x-receptor-in-establishment-of-ontogeny-of-phase-i-drug-metabolizing-enzyme-genes-in-mouse-liver
#16
Lai Peng, Stephanie Piekos, Grace L Guo, Xiao-Bo Zhong
The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation. Farnesoid X receptor (FXR) is critical for bile acid and lipid homeostasis in liver. However, the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear. Hence, we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and Fxr-null mice at 6 different ages from prenatal to adult were used...
September 2016: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/27702689/screening-of-soluble-epoxide-hydrolase-inhibitory-ingredients-from-traditional-chinese-medicines-for-anti-inflammatory-use
#17
Jun-Yan Liu, Christophe Morisseau, Huazhang Huang, Bruce D Hammock
ETHNOPHARMACOLOGICAL RELEVANCE: Inhibition of soluble epoxide hydrolase (sEH) has been extensively reported to be anti-inflammatory in multiple animal models. Some anti-inflammatory traditional Chinese medicines (TCMs) and a few natural compounds were also found to be inhibitory to sEH in vitro. AIM OF THE STUDY: To determine whether the active intergradient (AI) against sEH of anti-inflammatory TCMs in vitro is anti-inflammatory in vivo and the sEH inhibitory action of the AI contributes to its anti-inflammatory effect in vivo...
October 1, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27696333/soluble-epoxide-hydrolase-inhibitor-suppresses-the-expression-of-triggering-receptor-expressed-on-myeloid-cells-1-by-inhibiting-nf-kb-activation-in-murine-macrophage
#18
Liang Dong, Yong Zhou, Zhao-Qiong Zhu, Tian Liu, Jia-Xi Duan, Jun Zhang, Ping Li, Bruce D Hammcok, Cha-Xiang Guan
Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. TREM-1 amplifies the inflammatory response. Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 enzyme, have anti-inflammatory properties. However, the effects of EETs on TREM-1 expression under inflammatory stimulation remain unclear. Therefore, inhibition of soluble epoxide hydrolase (sEH) with a highly selective inhibitor [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, TPPU] was used to stabilize EETs...
October 1, 2016: Inflammation
https://www.readbyqxmd.com/read/27681558/vasopressin-lowers-renal-epoxyeicosatrienoic-acid-levels-by-activating-soluble-epoxide-hydrolase
#19
Christin Boldt, Tom Röschel, Nina Himmerkus, Allein Plain, Markus Bleich, Robert Labes, Maximilian Blum, Hans Krause, Ahmed Magheli, Torsten Giesecke, Kerim Mutig, Michael Rothe, Steven M Weldon, Duska Dragun, Wolf-Hagen Schunck, Sebastian Bachmann, Alexander Paliege
Activation of the thick ascending limb (TAL) Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) by the antidiuretic hormone arginine vasopressin (AVP) is an essential mechanism of renal urine concentration and contributes to extracellular fluid and electrolyte homeostasis. AVP effects in the kidney are modulated by locally and/or by systemically produced epoxyeicosatrienoic acid derivates (EET). The relation between AVP and EET metabolism has not been determined. Here, we show that chronic treatment of AVP-deficient Brattleboro rats with the AVP V2 receptor analog desmopressin (dDAVP; 5 ng/h, 3 days) significantly lowered renal EET levels (-56 ± 3% for 5,6-EET, -50 ± 3...
December 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27634339/epoxy-fatty-acids-mediate-analgesia-in-murine-diabetic-neuropathy
#20
K Wagner, K S S Lee, J Yang, B D Hammock
BACKGROUND: Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs...
September 15, 2016: European Journal of Pain: EJP
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