A step toward the reactivation of aged cholinesterases – Crystal structure of ligands binding to aged human butyrylcholinesterase

Wandhammer, M.; Koning, Martijn C. de; Grol, Marco van; Loiodice, Mélanie; Saurel, L.; Noort, Daan; Goeldner, Maurice; Nachon, Florian

doi:10.1016/j.cbi.2012.08.005

Cited by 42 publications

(36 citation statements)

References 25 publications

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“…In the catalytic site, 2‐PAM is bound by π‐stacking with the side‐chain of W86, and by hydrogen bonding of the oxime oxygen with the backbone oxygen of H447 (2.7 Å). The binding of 2‐PAM in T. californica AChE and human butyrylcholinesterase inhibited by aged soman is similar . In POX‐hAChE:2‐PAM, additional interactions include van der Waals contacts between 2‐PAM and the ethoxy group (4 Å) that faces the cationic site.…”

Section: Resultsmentioning

confidence: 97%

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

et al. 2016

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Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 97%

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

et al. 2016

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“…The study indicated that Cholinesterase (4B0O) regulated neurotransmission between cholinergic synapses and neuromuscular (Wandhammer et al, ). They were the targets of many toxicants, especially organophosphorus nerve agents (OPs).…”

Section: Resultsmentioning

confidence: 99%

“…These substances were toxic to the human nervous system by phosphorylating Cholinesterase. This process was closely associated with aging and decreased motor function (Masson et al, ; Wandhammer et al, ). Glycogen synthase kinase‐3 beta (5F94) can participate in the regulations of metabolism, proliferation, apoptosis and other physiological functions, and it has been proved to be related to the mechanism of memory and learning (Luo et al, ; Takashima, ).…”

Section: Resultsmentioning

confidence: 99%

A network pharmacology study on the triterpene saponins fromMedicago sativaL. for the treatment of Neurodegenerative diseases

Liu

Huang³

et al. 2019

J Food Biochem

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Neurodegenerative diseases (NDDs) are characterized by progressive and irreversible, is a kind of complex illnesses, and the long‐term therapy which is frequently associated with adverse side effects. Medicago sativa L., widely consumed as a vegetable, has the effects of improving memory and relieving central nervous system diseases. However, there are less studies on its specific mechanism for NDDs. In this investigation, we applied a method of network pharmacology, which combined molecular docking and network analysis to decipher the mechanisms of M. sativa in NDDs. The pharmacological system generated 55 triterpene saponins from M. sativa, and predicted 27 potential targets with 100 pathways in the treatment of NDDs. As a result, 13 compounds, 10 target proteins, and 6 signaling pathways were found to play important roles in the treatment of NDDs. In addition, in vitro experiments of isolates confirmed activities for NDDs, which were consistent with the results of network pharmacology prediction. Practical applications Medicago sativa L. has been widely consumed as a vegetable, which possesses many nutritional components. As a functional food stuff, M. sativa can improve human health, such as memory improving activities, relieving central nervous system diseases, immunomodulatory, antioxidant, anticancer, and anti‐inflammatory. In this article, the mechanism of triterpene saponins from M. sativa against NDDs was successfully predicted by network pharmacology method. The results will serve as a reference of M. sativa against NDDs.

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“…Similar to carbamates, OPs react with the active site of ChEs and other serine esterases due to the structural resemblance to their substrates (Nachon et al, 2011). The phosphorylated enzyme can be reactivated at a considerably slower rate than the carbamylated enzyme, and certain OPs can further undergo dealkyl ation following their interaction with the enzyme, which completely blocks its reactivation (known as aging; Taylor, 1996;Wandhammer et al, 2013) (Figure 52.2A).…”

Section: Molecular Mechanisms Of Cholinesterase Inhibitionmentioning

confidence: 95%

Cholinesterase Inhibitors

Waiskopf¹,

Soreq²

2015

Handbook of Toxicology of Chemical Warfare Agents

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A step toward the reactivation of aged cholinesterases – Crystal structure of ligands binding to aged human butyrylcholinesterase

Cited by 42 publications

References 25 publications

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

A network pharmacology study on the triterpene saponins fromMedicago sativaL. for the treatment of Neurodegenerative diseases

Cholinesterase Inhibitors

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