We used mouse recombinant wild-type acetylcholinesterase (AChE; EC 3.1.1.7), butyrylcholinesterase (BChE; EC 3.1.1.8), and AChE mutants with mutations (Y337A, F295L, F297I, Y72N, Y124Q, and W286A) that resemble residues found at structurally equivalent positions in BChE, to find the basis for divergence between AChE and BChE in following reactions: reversible inhibition by two oximes, progressive inhibition by the organophosphorus compound DDVP, and oxime-assisted reactivation of the phosphorylated enzymes. The inhibition enzyme-oxime dissociation constants of AChE w.t. were 150 and 46 microM, of BChE 340 and 27 microM for 2-PAM and HI-6, respectively. Introduced mutations lowered oxime binding affinities for both oximes. DDVP progressively inhibited cholinesterases yielding symmetrical dimethylphosphorylated enzyme conjugates at rates between 104 and 105/min/M. A high extent of oxime-assisted reactivation of all conjugates was achieved, but rates by both oximes were up to 10 times slower for phosphorylated mutants than for AChE w.t.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbrc.2006.02.056 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of oximes in KIKO mouse plasma.
J Chromatogr B Analyt Technol Biomed Life Sci
December 2024
United States Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, USA. Electronic address:
Chemical warfare nerve agents (CWNAs) are potent and irreversible inhibitors of acetylcholinesterase (AChE). Oxime reactivators are an important part of the standard treatment for CWNA exposure as they can reactivate inhibited AChE. Evaluating the oxime candidates of interest in biological samples requires analytical detection methods and oxime reactivators as a class of compounds have historically been notoriously difficult to isolate, detect and analyze in an analytical laboratory, and there are currently no sensitive or robust analytical detection methods in the literature.
View Article and Find Full Text PDFHalogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes.
Bioorg Chem
December 2024
University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; University Hospital in Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address:
Mono-quaternary pyridinium oximes derived from K-oximes K027, K048 and K203 were designed, synthesized and evaluated for the reactivation of organophosphate-inhibited cholinesterases. The incorporation of the halogen atoms to the structure decreased the pK value of the oxime group resulting in an increased formation of oximate necessary for reactivation. The stability and pK values were found to be similar to analogous bis-quaternary compounds.
View Article and Find Full Text PDFas a model organism for screening acetylcholinesterase reactivators.
J Toxicol Environ Health A
December 2024
Interdisciplinary Center for Biotechnology Research, Federal University of Pampa, São Gabriel, Brazil.
Article Synopsis
- The insecticide chlorpyrifos (CP) inhibits acetylcholinesterase (AChE), leading to neurological issues and affecting organ functions across the body.
- This study assessed various oxime compounds as potential reactivators of AChE to combat CP’s harmful effects, using a new model organism to address ethical concerns in drug screening.
- Results showed that oximes, particularly pralidoxime and K048, effectively reactivated AChE, improved locomotor function, and reduced mortality in CP-exposed organisms, suggesting promising new therapeutic options for AChE-related disorders.
Pharmacology of Adenosine A Receptor Agonist in a Humanized Esterase Mouse Seizure Model Following Soman Intoxication.
Neurotox Res
September 2024
Neuroscience Department, Medical Toxicology Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, 21010-5400, USA.
Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A adenosine receptor (AAR) agonist N-bicyclo-(2.2.
View Article and Find Full Text PDFCholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases.
Biomolecules
May 2024
Division of Toxicology, Institute for Medical Research and Occupational Health, 10001 Zagreb, Croatia.
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!