Similar but Different: Thermodynamic and Structural Characterization of a Pair of Enantiomers Binding to Acetylcholinesterase

Berg, Lotta; Niemiec, Moritz S.; Qian, Weixing; Andersson, C. David; Wittung-Stafshede, Pernilla; Ekström, Fredrik; Linusson, Anna

doi:10.1002/anie.201205113

Cited by 19 publications

(32 citation statements)

References 33 publications

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“…Propoxur is used against insect pests for both agricultural and public health purposes [ 55 ], eserine and donepezil are used clinically in the treatment of neurological disorders [ 43 ], while ethopropazine has mainly been used as a biochemical tool to distinguish between cholinesterases and also for determining BuChE-specific tissues [ 50 , 56 ]. The non-covalent inhibitory activity of C7653, C5685R and C5685S has been studied against both h AChE and m AChE [ 41 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

“…The enzymes were further characterized using a set of non-covalent inhibitors of AChE. The interactions between donepezil, C7653, C5685R, C5685S and vertebrate AChE have been investigated using X-ray crystallography [ 41 , 42 , 57 ], but no crystal structure of AChE in complex with ethopropazine has yet been published. Donepezil and C7653 spans the entire active site gorge, with the benzylic moiety (donepezil) or the piperidine ring (C7653) forming a parallel key interaction with the indole ring of Trp 86 at the base of the active site gorge [ 41 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

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Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues

et al. 2015

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Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues

et al. 2015

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“…The crystals are isomorphous to those of mouse AChE reported earlier. [30b,45] The structure refinement was carried out by use of the programs Refmac [46] and Phenix. [47] The atomic model was manually fit into the electron density with the aid of the program Coot.…”

Section: Methodsmentioning

confidence: 99%

Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

et al. 2015

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Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

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“…Ihre Forschung dreht sich um Proteinbiophysik mit Schwerpunkt auf den Mechanismen von Kupfertransportproteinen und Kreuzreaktivität bei der Amyloidbildung. Wittung‐Stafshede ist Autorin einer Angewandte‐Chemie ‐Zuschrift über die thermodynamische und strukturelle Charakterisierung eines an Acetylcholinesterase bindenden Enantiomerenpaares und eines Beitrags über die Modulierung der physikalischen Eigenschaften von DNA durch Alpha‐Synuclein in Chemistry—A European Journal …”

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IUPAC 2019 Distinguished Women in Chemistry or Chemical Engineering

2019

Angewandte Chemie

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Similar but Different: Thermodynamic and Structural Characterization of a Pair of Enantiomers Binding to Acetylcholinesterase

Cited by 19 publications

References 33 publications

Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues

Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues

Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

IUPAC 2019 Distinguished Women in Chemistry or Chemical Engineering

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