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https://www.readbyqxmd.com/read/30547569/insights-into-the-mechanism-of-paraoxonase-1-comparing-the-reactivity-of-the-six-bladed-%C3%AE-propeller-hydrolases
#1
Timothy John Grunkemeyer, David Garcia Mata, Kiran Doddapaneni, Srividya Murali, Thomas J Magliery
The mammalian protein paraoxonase-1 (PON1) has been explored as a promising bioscavenger treatment for organophosphorus (OP) agent poisoning, but it is not active enough to protect against many agents. Engineering is limited because PON1's catalytic mechanism is poorly understood; moreover, its native activity and substrate are unknown. PON1 is a calcium-bound six-bladed β-propeller hydrolase that shares high structural homology, a conserved metal-coordinating active site, and substrate specificity overlap with other members of a superfamily that includes squid diisopropylfluorophosphatase (DFPase), bacterial drug responsive protein 35 (Drp35), and mammalian senescence marker protein 30 (SMP30)...
December 14, 2018: Biochemistry
https://www.readbyqxmd.com/read/30410011/k-variant-bche-and-pesticide-exposure-gene-environment-interactions-in-a-case-control-study-of-parkinson-s-disease-in-egypt
#2
Thomas W Rösler, Mohamed Salama, Ali S Shalash, Eman M Khedr, Abdelhalim El-Tantawy, Gharib Fawi, Amal El-Motayam, Ehab El-Seidy, Mohamed El-Sherif, Mohamed El-Gamal, Mohamed Moharram, Mohammad El-Kattan, Muhammad Abdel-Naby, Samia Ashour, Ulrich Müller, Astrid Dempfle, Gregor Kuhlenbäumer, Günter U Höglinger
Pesticide exposure is associated with increased risk of Parkinson's disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD...
November 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30385318/3d-structure-of-the-natural-tetrameric-form-of-human-butyrylcholinesterase-as-revealed-by-cryoem-saxs-and-md
#3
Konstantin M Boyko, Timur N Baymukhametov, Yury M Chesnokov, Michael Hons, Sofya V Lushchekina, Petr V Konarev, Alexey V Lipkin, Alexandre L Vasiliev, Patrick Masson, Vladimir O Popov, Michail V Kovalchuk
Human plasma butyrylcholinesterase (BChE) is an endogenous bioscavenger that hydrolyzes numerous medicamentous and poisonous esters and scavenges potent organophosphorus nerve agents. BChE is thus a marker for the diagnosis of OP poisoning. It is also considered a therapeutic target against Alzheimer's disease. Although the X-ray structure of a partially deglycosylated monomer of human BChE was solved 15 years ago, all attempts to determine the 3D structure of the natural full-length glycosylated tetrameric human BChE have been unsuccessful so far...
October 29, 2018: Biochimie
https://www.readbyqxmd.com/read/30359675/x-ray-structures-of-human-bile-salt-activated-lipase-conjugated-to-nerve-agents-surrogates
#4
Cédric Touvrey, Charlotte Courageux, Virginia Guillon, Raphael Terreux, Florian Nachon, Xavier Brazzolotto
The efficiency of human butyrylcholinesterase (BChE) as a stoichiometric bioscavenger of nerve agents is well established. However, wide use is currently limited by production and purification costs. Aiming at identifying an alternative human protein bioscavenger, we looked for an original scaffold candidate by virtual screening of the Protein Data Bank for functional similarity using the "Surfing the Molecules" software (sumo-pbil.ibcp.fr) and a search model based on the BChE active site topology...
October 22, 2018: Toxicology
https://www.readbyqxmd.com/read/30278860/identification-of-carboxylesterase-butyrylcholinesterase-acetylcholinesterase-paraoxonase-and-albumin-pseudoesterase-in-guinea-pig-plasma-through-nondenaturing-gel-electrophoresis
#5
Geoffroy Napon, Alicia J Dafferner, Ashima Saxena, Oksana Lockridge
Drugs to protect against nerve agent toxicity are tested in animals. The current preferred small animal model is guinea pigs because their plasma bioscavenging capacity resembles that of NHP. We stained nondenaturing polyacrylamide slab gels with a variety of substrates, inhibitors, and antibodies to identify the esterases in heparinized guinea pig plasma. An intense band of carboxylesterase activity migrated behind albumin. Minor carboxylesterase bands were revealed after background activity from paraoxonase was inhibited by using EDTA...
October 1, 2018: Comparative Medicine
https://www.readbyqxmd.com/read/30123127/qm-mm-description-of-newly-selected-catalytic-bioscavengers-against-organophosphorus-compounds-revealed-reactivation-stimulus-mediated-by-histidine-residue-in-the-acyl-binding-loop
#6
Alexander Zlobin, Yuliana Mokrushina, Stanislav Terekhov, Arthur Zalevsky, Tatiana Bobik, Anastasiya Stepanova, Maria Aliseychik, Olga Kartseva, Sergey Panteleev, Andrey Golovin, Alexey Belogurov, Alexander Gabibov, Ivan Smirnov
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/30082075/corrigendum-to-catalytic-bioscavengers-as-countermeasures-against-organophosphate-nerve-agents-chem-biol-interact-292-2018-50-64
#7
Moshe Goldsmith, Yacov Ashani
No abstract text is available yet for this article.
September 25, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/30056174/catalytic-bioscavengers-against-organophosphorus-agents-mechanistic-issues-of-self-reactivating-cholinesterases
#8
Sofya Lushchekina, Patrick Masson
Catalytic bioscavengers are the second-generation bioscavengers. These biopharmaceuticals are intended to degrade toxic organophosphorus agents on the skin for decontamination or in the bloodstream for pre-treatment and post-exposure treatment of organophosphate poisoning. Because catalytic degradation has to be fast, their catalytic efficiency has to be as high as possible (kcat /Km >106 M-1  min-1 ). Certain evolved mammalian paraoxonases and bacterial phosphotriesterases already fulfill this requirement...
November 1, 2018: Toxicology
https://www.readbyqxmd.com/read/29990481/catalytic-bioscavengers-as-countermeasures-against-organophosphate-nerve-agents
#9
REVIEW
Moshe Goldsmith, Yacov Ashani
Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures against OPNA intoxications are aimed at mitigating their symptoms, but are unable to effectively prevent them. In addition, they may fail to prevent the onset of a cholinergic crisis in the brain and its secondary toxic manifestations. The need for improved medical countermeasures has led to the development of bioscavengers; proteins and enzymes that may prevent intoxication by binding and inactivating OPNAs before they can reach their target organs...
August 25, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29959732/organophosphorus-poisoning-in-animals-and-enzymatic-antidotes
#10
Laetitia Poirier, Pauline Jacquet, Laure Plener, Patrick Masson, David Daudé, Eric Chabrière
Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture...
June 29, 2018: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29768075/evaluating-mice-lacking-serum-carboxylesterase-as-a-behavioral-model-for-nerve-agent-intoxication
#11
Emily N Dunn, Teresa M Ferrara-Bowens, Mark E Chachich, Cary L Honnold, Cristin C Rothwell, Heidi M Hoard-Fruchey, Catherine A Lesyna, Erik A Johnson, Douglas M Cerasoli, John H McDonough, C Linn Cadieux
Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure...
October 2018: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/29664277/nerve-agents-what-they-are-how-they-work-how-to-counter-them
#12
Stefano Costanzi, John-Hanson Machado, Moriah Mitchell
Nerve agents are organophosphorus chemical warfare agents that exert their action through the irreversible inhibition of acetylcholinesterase, with a consequent overstimulation of cholinergic transmission followed by its shutdown. Beyond warfare, they have notoriously been employed in acts of terrorism as well as high profile assassinations. After a brief historical introduction on the development and deployment of nerve agents, this review provides a survey of their chemistry, the way they affect cholinergic transmission, the available treatment options, and the current directions for their improvement...
May 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29593539/optimization-of-cholinesterase-based-catalytic-bioscavengers-against-organophosphorus-agents
#13
Sofya V Lushchekina, Lawrence M Schopfer, Bella L Grigorenko, Alexander V Nemukhin, Sergei D Varfolomeev, Oksana Lockridge, Patrick Masson
Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29558934/high-yield-production-and-purification-of-two-recombinant-thermostable-phosphotriesterase-like-lactonases-from-sulfolobus-acidocaldarius-and-sulfolobus-solfataricus-useful-as-bioremediation-tools-and-bioscavengers
#14
Odile Francesca Restaino, Maria Giovanna Borzacchiello, Ilaria Scognamiglio, Luigi Fedele, Alberto Alfano, Elena Porzio, Giuseppe Manco, Mario De Rosa, Chiara Schiraldi
BACKGROUND: Thermostable phosphotriesterase-like lactonases (PLLs) are able to degrade organophosphates and could be potentially employed as bioremediation tools and bioscavengers. But nowadays their manufacturing in high yields is still an issue that limits their industrial applications. In this work we aimed to set up a high yield production and purification biotechnological process of two recombinant PLLs expressed in E. coli, the wild type SacPox from Sulfolobus acidocaldarius and a triple mutated SsoPox C258L/I261F/W263A, originally from Sulfolobus solfataricus...
March 20, 2018: BMC Biotechnology
https://www.readbyqxmd.com/read/29411865/purification-characterization-and-n-glycosylation-of-recombinant-butyrylcholinesterase-from-transgenic-rice-cell-suspension-cultures
#15
Jasmine M Corbin, Muchena J Kailemia, C Linn Cadieux, Salem Alkanaimsh, Kalimuthu Karuppanan, Raymond L Rodriguez, Carlito B Lebrilla, Douglas M Cerasoli, Karen A McDonald, Somen Nandi
Recombinant butyrylcholinesterase produced in a metabolically regulated transgenic rice cell culture (rrBChE) was purified to produce a highly pure (95%), active form of enzyme. The developed downstream process uses common manufacturing friendly operations including tangential flow filtration, anion-exchange chromatography, and affinity chromatography to obtain a process recovery of 42% active rrBChE. The purified rrBChE was then characterized to confirm its comparability to the native human form of the molecule (hBChE)...
May 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29393817/relationship-between-paraoxonase-1-and-butyrylcholinesterase-activities-and-nutritional-status-in-mexican-children
#16
Rocío Ramírez-Jiménez, María Fernanda Martínez-Salazar, Damianys Almenares-López, Leticia Yáñez-Estrada, Antonio Monroy-Noyola
BACKGROUND: The enzymes butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) are the primary bioscavenging enzymes in serum and exhibit antioxidant and anti-inflammatory activities. PON1 has been associated with diseases caused by high oxidative stress, whereas BuChE appears to be involved in the pathophysiology of the metabolic syndrome and related disorders. It has been suggested that children from rural communities in Mexico may have a predisposition to develop obesity or type 2 diabetes during adolescence or adulthood...
March 2018: Metabolic Syndrome and related Disorders
https://www.readbyqxmd.com/read/29190644/structural-analysis-of-human-glycoprotein-butyrylcholinesterase-using-atomistic-molecular-dynamics-the-importance-of-glycosylation-site-asn241
#17
Austen Bernardi, Karl N Kirschner, Roland Faller
Human butyrylcholinesterase (BChE) is a glycoprotein capable of bioscavenging toxic compounds such as organophosphorus (OP) nerve agents. For commercial production of BChE, it is practical to synthesize BChE in non-human expression systems, such as plants or animals. However, the glycosylation profile in these systems is significantly different from the human glycosylation profile, which could result in changes in BChE's structure and function. From our investigation, we found that the glycan attached to ASN241 is both structurally and functionally important due to its close proximity to the BChE tetramerization domain and the active site gorge...
2017: PloS One
https://www.readbyqxmd.com/read/29183815/bioscavenger-is-effective-as-a-delayed-therapeutic-intervention-following-percutaneous-vx-poisoning-in-the-guinea-pig
#18
T M Mann, M E Price, C L Whitmore, R L Perrott, T R Laws, R R McColm, E R Emery, J E H Tattersall, A C Green, H Rice
The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD50 )...
September 1, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29077024/bacterial-expression-of-human-butyrylcholinesterase-as-a-tool-for-nerve-agent-bioscavengers-development
#19
Xavier Brazzolotto, Alexandre Igert, Virginia Guillon, Gianluca Santoni, Florian Nachon
Human butyrylcholinesterase is a performant stoichiometric bioscavenger of organophosphorous nerve agents. It is either isolated from outdated plasma or functionally expressed in eukaryotic systems. Here, we report the production of active human butyrylcholinesterase in a prokaryotic system after optimization of the primary sequence through the Protein Repair One Stop Shop process, a structure- and sequence-based algorithm for soluble bacterial expression of difficult eukaryotic proteins. The mutant enzyme was purified to homogeneity...
October 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28874829/plant-expressed-cocaine-hydrolase-variants-of-butyrylcholinesterase-exhibit-altered-allosteric-effects-of-cholinesterase-activity-and-increased-inhibitor-sensitivity
#20
Katherine E Larrimore, I Can Kazan, Latha Kannan, R Player Kendle, Tameem Jamal, Matthew Barcus, Ashini Bolia, Stephen Brimijoin, Chang-Guo Zhan, S Banu Ozkan, Tsafrir S Mor
Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme's ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in plants and their enzymatic properties were investigated...
September 5, 2017: Scientific Reports
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