ArticleThe Biochemical journal1996
Aging of phosphylated human acetylcholinesterase: catalytic processes mediated by aromatic and polar residues of the active centre.
Article in The Biochemical journal, 1996. 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, 170 citations in OpenAlex.
- Chemical, Physical, and Toxicological Properties of V-Agents.International journal of molecular sciences · 2023Review
- Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN).Advances in neurotoxicology · 2020Article
- Comparison of the reactivation rates of acetylcholinesterase modified by structurally different organophosphates using novel pyridinium oximes.Environmental toxicology and pharmacology · 2019Article
- Harnessing Nature's Diversity: Discovering organophosphate bioscavenger characteristics among low molecular weight proteins.Scientific reports · 2016Article
- Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.Chemical research in toxicology · 2016Review
- Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates.Annals of the New York Academy of Sciences · 2016Article
- Efforts toward treatments against aging of organophosphorus-inhibited acetylcholinesterase.Annals of the New York Academy of Sciences · 2016Review
- Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes.Chemical research in toxicology · 2015Article
- Mechanism behind Resistance against the Organophosphate Azamethiphos in Salmon Lice (Lepeophtheirus salmonis).PloS one · 2015Article
- A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.PloS one · 2015Article
- How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.The journal of physical chemistry. A · 2014Article
- Novel human butyrylcholinesterase variants: toward organophosphonate detoxication.Biochemistry · 2014Article
- Development of organophosphate hydrolase activity in a bacterial homolog of human cholinesterase.Frontiers in chemistry · 2014Article
- Structure and function of an insect α-carboxylesterase (αEsterase7) associated with insecticide resistance.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Identification of human butyrylcholinesterase organophosphate-resistant variants through a novel mammalian enzyme functional screen.The Journal of pharmacology and experimental therapeutics · 2012Article
- Aging mechanism of soman inhibited acetylcholinesterase.The journal of physical chemistry. B · 2012Article
- Probing the peripheral site of human butyrylcholinesterase.Biochemistry · 2012Article
- Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging.The Journal of biological chemistry · 2011Article
- Reaction of cresyl saligenin phosphate, the organophosphorus agent implicated in aerotoxic syndrome, with human cholinesterases: mechanistic studies employing kinetics, mass spectrometry, and X-ray structure analysis.Chemical research in toxicology · 2011Article
- Investigating the structural influence of surface mutations on acetylcholinesterase inhibition by organophosphorus compounds and oxime reactivation.Chemico-biological interactions · 2010Article
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6 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
We have examined the effects of 11 substitutions of active centre gorge residues of human acetylcholinesterase (HuAChE) on the rates of phosphonylation by 1,2,2-trimethylpropyl methyl-phosphonofluoridate (soman) and the aging of the resulting conjugates. The rates of phosphonylation were reduced to as little as one-seventieth, mainly in mutants of the hydrogen-bond network (Glu-202, Glu-450, Tyr-133). These recombinant enzymes as well as the F338A, W86A, W86F and D74N mutant HuAChEs varied in their resistance to aging (15-3300-fold relative to the wild type). The most dramatic resistance to aging was observed for the phosphonyl conjugate of the mutant W86A enzyme (1850-3300-fold relative to the wild type). It is proposed that Trp-86 contributes to the aging process by stabilizing the evolving carbonium ion on the 1,2,2-trimethylpropyl moiety, via charge-pi interaction. The rate-enhancing effect of Trp-86 provides a rationale for the unique facility of aging in soman-inhibited cholinesterases, compared with the corresponding conjugates in other serine hydrolases. Replacements of Glu-202 by aspartic acid, glutamine or alanine residues resulted in a similar (1/130-1/300) decrease of the rates of aging. A comparable decrease was also observed for the conjugate of the F338A mutant. These results, and the similar pH dependence of aging rates for the wild-type and E202Q and F338A mutant HuAChEs, indicate that Glu-202 is not involved in proton transfer to the phosphonyl moiety. On the basis of these findings and of molecular modelling we suggest that Glu-202 and Phe-338 contribute to the aging process by stabilizing the imidazolium of the catalytic triad His-447 via charge-charge and charge-pi interactions respectively, thereby facilitating an oxonium formation on the phosphonyl moiety.
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