keyword
https://read.qxmd.com/read/38247466/repurposing-glutathione-transferases-directed-evolution-combined-with-chemical-modification-for-the-creation-of-a-semisynthetic-enzyme-with-high-hydroperoxidase-activity
#1
JOURNAL ARTICLE
Irene Axarli, Farid Ataya, Nikolaos E Labrou
Glutathione peroxidases (GPXs) are antioxidant selenoenzymes, which catalyze the reduction of hydroperoxides via glutathione (GSH), providing protection to cells against oxidative stress metabolites. The present study aims to create an efficient semisynthetic GPX based on the scaffold of tau class glutathione transferase (GSTU). A library of GSTs was constructed via DNA shuffling, using three homologue GSTUs from Glycine max as parent sequences. The DNA library of the shuffled genes was expressed in E. coli and the catalytic activity of the shuffled enzymes was screened using cumene hydroperoxide (CuOOH) as substrate...
December 25, 2023: Antioxidants (Basel, Switzerland)
https://read.qxmd.com/read/38042398/acute-poisoning-by-chlorpyrifos-differentially-impacts-survival-and-cardiorespiratory-function-in-normotensive-and-hypertensive-rats
#2
JOURNAL ARTICLE
Andrew Vieira Aitken, Vítor Sampaio Minassa, Thatiany Jardim Batista, Janne Ketly da Silva Oliveira, Karoline de Oliveira Sant'Anna, Igor Simões Assunção Felippe, Julian Francis Richmond Paton, Juliana Barbosa Coitinho Gonçalves, Nazaré Souza Bissoli, Karla Nívea Sampaio
Hypertension is the most important and well-known risk factor for cardiovascular disease (CVD). Recently, acute organophosphate (OP) poisoning has also been pointed as a CVD risk factor. Despite this evidence, no studies have contrasted the acute toxicosis and cardiovascular (CV) effects of OP poisoning under conditions of normotension and hypertension. In this work, adult male normotensive Wistar and Spontaneously Hypertensive rats (SHR) were intraperitoneally injected with saline or chlorpyrifos (CPF), an OP compound, monitored for acute toxicosis signs and 24-h survival...
November 30, 2023: Chemico-biological Interactions
https://read.qxmd.com/read/38035754/current-perspectives-on%C3%A2-the-management-of%C3%A2-patients-poisoned-with-novichok-a-scoping-review
#3
JOURNAL ARTICLE
Tess L Blom, Thijs T Wingelaar
INTRODUCTION: Nerve agents have emerged as a global threat since their discovery in the 1930s, posing severe risks due to their inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine in nerve synapses. Despite the enforcement of the Chemical Weapon Convention to control chemical weapons, including nerve agents, recent events, such as the Novichok attacks on Sergei Skripal and Alexei Navalny, have highlighted the persistent threat. Novichok, a distinct class of nerve agents, raises specific concerns regarding its management due to limited understanding...
November 30, 2023: Military Medicine
https://read.qxmd.com/read/37941439/engineering-of-a-phosphotriesterase-with-improved-stability-and-enhanced-activity-for-detoxification-of-the-pesticide-metabolite-malaoxon
#4
JOURNAL ARTICLE
Laura Job, Anja Köhler, Mauricio Testanera, Benjamin Escher, Franz Worek, Arne Skerra
Organophosphorus (OP) pesticides are still widely applied but pose a severe toxicological threat if misused, including suicidal attempts. For in vivo detoxification, the application of hydrolytic enzymes potentially offers a promising treatment. A well-studied example is the phosphotriesterase of the bacterium Brevundimonas diminuta (BdPTE). Whereas wild-type BdPTE can hydrolyse pesticides like paraoxon, chlorpyrifos-oxon and mevinphos with high catalytic efficiencies, kcat/KM > 2 × 107 M-1 min-1, degradation of malaoxon is unsatisfactory (kcat/KM ≈ 1 × 104 M-1 min-1)...
November 6, 2023: Protein Engineering, Design & Selection: PEDS
https://read.qxmd.com/read/37860961/the-impact-of-molecular-variants-crystallization-conditions-and-the-space-group-on-ligand-protein-complexes-a-case-study-on-bacterial-phosphotriesterase
#5
JOURNAL ARTICLE
Orly Dym, Nidhi Aggarwal, Yacov Ashani, Haim Leader, Shira Albeck, Tamar Unger, Shelly Hamer-Rogotner, Israel Silman, Dan S Tawfik, Joel L Sussman
A bacterial phosphotriesterase was employed as an experimental paradigm to examine the effects of multiple factors, such as the molecular constructs, the ligands used during protein expression and purification, the crystallization conditions and the space group, on the visualization of molecular complexes of ligands with a target enzyme. In this case, the ligands used were organophosphates that are fragments of the nerve agents and insecticides on which the enzyme acts as a bioscavenger. 12 crystal structures of various phosphotriesterase constructs obtained by directed evolution were analyzed, with resolutions of up to 1...
November 1, 2023: Acta Crystallographica. Section D, Structural Biology
https://read.qxmd.com/read/37642747/strategies-for-enhanced-bioavailability-of-oxime-reactivators-in-the-central-nervous-system
#6
REVIEW
Eliska Prchalova, Zuzana Kohoutova, Karolina Knittelova, David Malinak, Kamil Musilek
Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood-brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters...
November 2023: Archives of Toxicology
https://read.qxmd.com/read/37249569/layered-design-of-a-highly-repeatable-electroactive-biofilm-for-a-standardized-biochemical-oxygen-demand-sensor
#7
JOURNAL ARTICLE
Huijuan Su, Xuejun Yan, Qian Zhao, Chengmei Liao, Lili Tian, Ziyuan Wang, Yuxuan Wan, Nan Li, Xin Wang
Microbial electrochemical sensors are promising to monitor bioavailable organics in real environments, but their application is restricted by the unpredictable performance of the electroactive biofilm (EAB), which is randomly acclimated from environmental microflora. With a long-term stable EAB as a template, we successfully designed EAB (DEAB) by the sequential growth of Geobacter anodireducens and automatched microbes, achieving a reproducible high current than those naturally acclimated from wastewater (NEAB)...
May 30, 2023: ACS Sensors
https://read.qxmd.com/read/35772844/characterization-of-molecular-and-kinetic-properties-of-two-acetylcholinesterases-from-the-colorado-potato-beetle-leptinotarsa-decemlineata
#8
JOURNAL ARTICLE
Kyungjae Andrew Yoon, Ju Hyeon Kim, Ralf Nauen, Andrei Alyokhin, John Marshall Clark, Si Hyeock Lee
The molecular and biochemical properties of two acetylcholinesterases (LdAChE1 and LdAChE2) from the Colorado potato beetle, Leptinotarsa decemlineata, were investigated in this study. Polyacrylamide gel electrophoresis in conjunction with western blotting with LdAChE1- or LdAChE2-specific antibodies suggested that LdAChE1 exists in a soluble form, whereas LdAChE2 exists in both soluble and amphiphilic forms with a glycophosphatidylinositol anchor. Both LdAChEs exist as homodimers with each monomer connected with a disulfide bond...
July 2022: Pesticide Biochemistry and Physiology
https://read.qxmd.com/read/35733041/a-three-dimensional-brain-on-a-chip-using-human-ipsc-derived-gabaergic-neurons-and-astrocytes
#9
JOURNAL ARTICLE
Lumei Liu, Youngmi Koo, Teal Russell, Yeoheung Yun
Brain-on-a-chip is a miniaturized engineering platform to mimic the structural and functional aspects of brain tissue. We describe a method to construct a three-dimensional (3D) brain-on-a-chip in this chapter. We firstly portray the method of a brain-on-a-chip model with cocultured mice neurons, microglia, and astrocytes to mimic brain tissue and membrane-free perfusion with endothelial cells, in which we successfully build the blood-brain barrier to screen neurotoxicity. Then we describe a method to construct a brain-on-a-chip with human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes to simulate human brain behavior...
2022: Methods in Molecular Biology
https://read.qxmd.com/read/35654125/design-and-production-strategies-for-developing-a-recombinant-butyrylcholinesterase-medical-countermeasure-for-organophosphorus-poisoning
#10
REVIEW
Joanne L Allard, Katherine A Shields, TrentP Munro, Linda H L Lua
Organophosphorus nerve agents represent a serious chemical threat due to their ease of production and scale of impact. The recent use of the nerve agent Novichok has re-emphasised the need for broad-spectrum medical countermeasures (MCMs) to these agents. However, current MCMs are limited. Plasma derived human butyrylcholinesterase (huBChE) is a promising novel bioscavenger MCM strategy, but is prohibitively expensive to isolate from human plasma at scale. Efforts to produce recombinant huBChE (rBChE) in various protein expression platforms have failed to achieve key critical attributes of huBChE such as circulatory half-life...
May 30, 2022: Chemico-biological Interactions
https://read.qxmd.com/read/35453533/kinetic-processes-in-enzymatic-nanoreactors-for-in-vivo-detoxification
#11
JOURNAL ARTICLE
Zukhra Shajhutdinova, Tatiana Pashirova, Patrick Masson
Enzymatic nanoreactors are enzyme-encapsulated nanobodies that are capable of performing biosynthetic or catabolic reactions. For this paper, we focused on therapeutic enzyme nanoreactors for the neutralization of toxicants, paying special attention to the inactivation of organophosphorus compounds (OP). Therapeutic enzymes that are capable of detoxifying OPs are known as bioscavengers. The encapsulation of injectable bioscavengers by nanoparticles was first used to prevent fast clearance and the immune response to heterologous enzymes...
March 27, 2022: Biomedicines
https://read.qxmd.com/read/35440137/enzyme-nanoreactor-for-in-vivo-detoxification-of-organophosphates
#12
JOURNAL ARTICLE
Tatiana Pashirova, Zukhra Shaihutdinova, Milana Mansurova, Renata Kazakova, Dinara Shambazova, Andrei Bogdanov, Dmitry Tatarinov, David Daudé, Pauline Jacquet, Eric Chabrière, Patrick Masson
A nanoreactor containing an evolved mutant of Saccharolobus solfataricus phosphotriesterase (L72C/Y97F/Y99F/W263V/I280T) as a catalytic bioscavenger was made for detoxification of organophosphates. This nanoreactor intended for treatment of organophosphate poisoning was studied against paraoxon (POX). Nanoreactors were low polydispersity polymersomes containing a high concentration of enzyme (20 μM). The polyethylene glycol-polypropylene sulfide membrane allowed for penetration of POX and exit of hydrolysis products...
May 4, 2022: ACS Applied Materials & Interfaces
https://read.qxmd.com/read/34962578/post-vx-exposure-treatment-of-rats-with-engineered-phosphotriesterases
#13
JOURNAL ARTICLE
Lisa Stigler, Anja Köhler, Marianne Koller, Laura Job, Benjamin Escher, Heidrun Potschka, Horst Thiermann, Arne Skerra, Franz Worek, Timo Wille
The biologically stable and highly toxic organophosphorus nerve agent (OP) VX poses a major health threat. Standard medical therapy, consisting of reactivators and competitive muscarinic receptor antagonists, is insufficient. Recently, two engineered mutants of the Brevundimonas diminuta phosphotriesterase (PTE) with enhanced catalytic efficiency (kcat /KM  = 21 to 38 × 106  M-1  min-1 ) towards VX and a preferential hydrolysis of the more toxic P(-) enantiomer were described: PTE-C23(R152E)-PAS(100)-10-2-C3(I106A/C59V/C227V/E71K)-PAS(200) (PTE-2), a single-chain bispecific enzyme with a PAS linker and tag having enlarged substrate spectrum, and 10-2-C3(C59V/C227V)-PAS(200) (PTE-3), a stabilized homodimeric enzyme with a double PASylation tag (PAS-tag) to reduce plasma clearance...
December 28, 2021: Archives of Toxicology
https://read.qxmd.com/read/34274336/therapeutic-nanoreactors-for-detoxification-of-xenobiotics-concepts-challenges-and-biotechnological-trends-with-special-emphasis-to-organophosphate-bioscavenging
#14
REVIEW
Tatiana N Pashirova, Andrei Bogdanov, Patrick Masson
The introduction of enzyme nanoreactors in medicine is relatively new. However, this technology has already been experimentally successful in cancer treatments, struggle against toxicity of reactive oxygen species in inflammatory processes, detoxification of drugs and xenobiotics, and correction of metabolic and genetic defects by using encapsulated enzymes, acting in single or cascade reactions. Biomolecules, e.g. enzymes, antibodies, reactive proteins capable of inactivating toxicants in the body are called bioscavengers...
September 1, 2021: Chemico-biological Interactions
https://read.qxmd.com/read/34160649/catalytic-activity-and-stereoselectivity-of-engineered-phosphotriesterases-towards-structurally-different-nerve-agents-in-vitro
#15
COMPARATIVE STUDY
Anja Köhler, Benjamin Escher, Laura Job, Marianne Koller, Horst Thiermann, Arne Skerra, Franz Worek
Highly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay...
August 2021: Archives of Toxicology
https://read.qxmd.com/read/33961835/conjugates-of-human-serum-butyrylcholinesterase-and-nerve-agents-are-behaviorally-safe-in-rhesus-macaques
#16
JOURNAL ARTICLE
Ashima Saxena, Todd M Myers, Maurice L Sipos
Exogenously administered human serum butyrylcholinesterase (Hu BChE) affords protection by binding to organophosphorus (OP) nerve agents and pesticides in circulation. The resulting Hu BChE-OP conjugate undergoes 'aging' and the conjugate circulates until cleared from the body. Thus, we evaluated the effects of Hu BChE-OP conjugates on the general health and operant behavior of macaques. Rhesus macaques trained to perform a six-item serial probe recognition (SPR) task were administered 30 mg/kg of Hu BChE-soman conjugate (n=4) or Hu BChE-VX conjugate (n=4) by intramuscular injection...
May 4, 2021: Chemico-biological Interactions
https://read.qxmd.com/read/33529769/organophosphate-detoxification-by-membrane-engineered-red-blood-cells
#17
JOURNAL ARTICLE
Paige N Smith, Leran Mao, Kaustubh Sinha, Alan J Russell
Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing shift away from small molecule drugs towards biotherapeutics heightens the need to further improve the pharmacokinetics of these biological drugs. Three pervasive obstacles that limit the therapeutic capacity of biotherapeutics are proteolytic degradation, circulating half-life, and the development of anti-drug antibodies. These challenges can culminate in limited efficiency and consequently warrant the need for higher drug doses and more frequent administration...
April 1, 2021: Acta Biomaterialia
https://read.qxmd.com/read/33513869/a-thermophilic-bacterial-esterase-for-scavenging-nerve-agents-a-kinetic-biophysical-and-structural-study
#18
JOURNAL ARTICLE
Janek Bzdrenga, Elodie Trenet, Fabien Chantegreil, Kevin Bernal, Florian Nachon, Xavier Brazzolotto
Organophosphorous nerve agents (OPNA) pose an actual and major threat for both military and civilians alike, as an upsurge in their use has been observed in the recent years. Currently available treatments mitigate the effect of the nerve agents, and could be vastly improved by means of scavengers of the nerve agents. Consequently, efforts have been made over the years into investigating enzymes, also known as bioscavengers, which have the potential either to trap or hydrolyze these toxic compounds. We investigated the previously described esterase 2 from Thermogutta terrifontis (TtEst2) as a potential bioscavenger of nerve agents...
January 27, 2021: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/33410774/counteracting-poisoning-with-chemical-warfare-nerve-agents
#19
REVIEW
Nikolina Maček Hrvat, Zrinka Kovarik
Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim's survival and recovery...
December 31, 2020: Arhiv za Higijenu Rada i Toksikologiju
https://read.qxmd.com/read/33217476/reprogramming-the-rapid-clearance-of-thrombolytics-by-nanoparticle-encapsulation-and-anchoring-to-circulating-red-blood-cells
#20
JOURNAL ARTICLE
Mohit Pratap Singh, Nicholas H Flynn, Sri Nandhini Sethuraman, Saeed Manouchehri, Jerry Ritchey, Jing Liu, Joshua D Ramsey, Carey Pope, Ashish Ranjan
Rapid clearance of thrombolytics from blood following intravenous injection is a major clinical challenge in cardiovascular medicine. To overcome this barrier, nanoparticle (NP) based drug delivery systems have been reported. Although superior than conventional therapy, a large proportion of the injected NP is still cleared by the reticuloendothelial system. Previously, we and others showed that ex vivo attachment of bioscavengers, thrombolytics, and nanoparticles (NPs) to glycophorin A receptors on red blood cells (RBCs) improved the blood half-life...
November 17, 2020: Journal of Controlled Release
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