ArticleThe Biochemical journal2003
Acetylcholinesterase active centre and gorge conformations analysed by combinatorial mutations and enantiomeric phosphonates.
Article in The Biochemical journal, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 117 citations in OpenAlex.
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- Acetylcholine Detection Based on pH-Sensitive Liposomes.ACS omega · 2021Article
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- Moringa seed extract alleviates titanium oxide nanoparticles (TiO2-NPs)-induced cerebral oxidative damage, and increases cerebral mitochondrial viability.Environmental science and pollution research international · 2020Article
- Evaluation of high-affinity phenyltetrahydroisoquinoline aldoximes, linked through anti-triazoles, as reactivators of phosphylated cholinesterases.Toxicology letters · 2020Article
- Purification of recombinant human butyrylcholinesterase on Hupresin®.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · 2018Article
- Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure.The Journal of pharmacology and experimental therapeutics · 2018Article
- A new computational model for the prediction of toxicity of phosphonate derivatives using QSPR.Molecular diversity · 2018Article
- Supplementation of Maternal Diets with Docosahexaenoic Acid and Methylating Vitamins Impacts Growth and Development of Fetuses from Malnourished Gilts.Current developments in nutrition · 2018Article
- Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold.PloS one · 2018Article
- Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor.Chemico-biological interactions · 2017Article
- New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds.Molecules (Basel, Switzerland) · 2017Article
- Kamishoyosan and Shakuyakukanzoto promote recovery from paclitaxel-induced neurite retraction in PC12 cells.Journal of pharmaceutical health care and sciences · 2017Article
- HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants.Chemico-biological interactions · 2016Article
- Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?International journal of molecular sciences · 2016Article
- Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes.Chemical research in toxicology · 2015Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A series of eight double and triple mutants of mouse acetylcholinesterase (AChE; EC 3.1.1.7), with substitutions corresponding to residues found largely within the butyrylcholinesterase (BChE; EC 3.1.1.8) active-centre gorge, was analysed to compare steady-state kinetic constants for substrate turnover and inhibition parameters for enantiomeric methylphosphonate esters. The mutations combined substitutions in the acyl pocket (Phe(295)-->Leu and Phe(297)-->Ile) with the choline-binding site (Tyr(337)-->Ala and Phe(338)-->Ala) and with a side chain (Glu(202)--> Gln) N-terminal to the active-site serine, Ser(203). The mutations affected catalysis by increasing K (m) and decreasing k (cat), but these constants were typically affected by an order of magnitude or less, a relatively small change compared with the catalytic potential of AChE. To analyse the constraints on stereoselective phosphonylation, the mutant enzymes were reacted with a congeneric series of S (P)- and R (P)-methylphosphonates of known absolute stereochemistry. Where possible, the overall reaction rates were deconstructed into the primary constants for formation of the reversible complex and intrinsic phosphonylation. The multiple mutations greatly reduced the reaction rates of the more reactive S (P)-methylphosphonates, whereas the rates of reaction with the R (P)-methylphosphonates were markedly enhanced. With the phosphonates of larger steric bulk, the enhancement of rates for the R (P) enantiomers, coupled with the reduction of the S (P) enantiomers, was sufficient to invert markedly the enantiomeric preference. The sequence of mutations to enlarge the size of the AChE active-centre gorge, resembling in part the more spacious gorge of BChE, did not show an ordered conversion into BChE reactivity as anticipated for a rigid template. Rather, the individual aromatic residues may mutually interact to confer a distinctive stereospecificity pattern towards organophosphates.
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