Chatonnet A


Full name : Chatonnet Arnaud

First name : Arnaud

Mail : Dynamique Musculaire et Metabolisme INRA Place Viala Universite Montpellier

Zip Code : 34060

City : Montpellier

Country : France

Email :

Phone : (33)(0) 4 99 61 28 14

Fax : (33)(0) 4 67 54 56 94

Website : \/\/\/esther

Directory :

References (93)

Title : The ESTHER database on alpha\/beta hydrolase fold proteins - An overview of recent developments - Chatonnet_2023_Chem.Biol.Interact_14ChEPon_110671
Author(s) : Chatonnet A , Perochon M , Velluet E , Marchot P
Ref : Chemico-Biological Interactions , :110671 , 2023
Abstract : The ESTHER database, dedicated to ESTerases and alpha/beta-Hydrolase Enzymes and Relatives (, offers online access to a continuously updated, sequence-based classification of proteins harboring the alpha/beta hydrolase fold into families and subfamilies. In particular, the database proposes links to the sequences, structures, ligands and huge diversity of functions of these proteins, and to the related literature and other databases. Taking advantage of the promiscuity of enzymatic function, many engineered esterases, lipases, epoxide-hydrolases, haloalkane dehalogenases are used for biotechnological applications. Finding means for detoxifying those protein members that are targeted by insecticides, herbicides, antibiotics, or for reactivating human cholinesterases when inhibited by nerve gas, are still active areas of research. Using or improving the capacity of some enzymes to breakdown plastics with the aim to recycle valuable material and reduce waste is an emerging challenge. Most hydrolases in the superfamily are water-soluble and act on or are inhibited by small organic compounds, yet in a few subfamilies some members interact with other, unrelated proteins to modulate activity or trigger functional partnerships. Recent development in 3D structure prediction brought by AI-based programs now permits analysis of enzymatic mechanisms for a variety of hydrolases with no experimental 3D structure available. Finally, mutations in as many as 34 of the 120 human genes compiled in the database are now linked to genetic diseases, a feature fueling research on early detection, metabolic pathways, pharmacological treatment or enzyme replacement therapy. Here we review those developments in the database that took place over the latest decade and discuss potential new applications and recent and future expected research in the field.
ESTHER : Chatonnet_2023_Chem.Biol.Interact_14ChEPon_110671
PubMedSearch : Chatonnet_2023_Chem.Biol.Interact_14ChEPon_110671
PubMedID: 37582413

Title : Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model - Scheiner_2021_J.Med.Chem_64_9302
Author(s) : Scheiner M , Hoffmann M , He F , Poeta E , Chatonnet A , Monti B , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 64(13): :9302 , 2021
Abstract : A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE(-/-) mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
ESTHER : Scheiner_2021_J.Med.Chem_64_9302
PubMedSearch : Scheiner_2021_J.Med.Chem_64_9302
PubMedID: 34152756

Title : Comparative mapping of selected structural determinants on the extracellular domains of cholinesterase-like cell-adhesion molecules - Comoletti_2020_Neuropharmacol__108381
Author(s) : Comoletti D , Trobiani L , Chatonnet A , Bourne Y , Marchot P
Ref : Neuropharmacology , :108381 , 2020
Abstract : Cell adhesion generally involve formation of homophilic or heterophilic protein complexes between two cells to form transcellular junctions. Neural cell-adhesion members of the alpha/beta-hydrolase fold superfamily of proteins use their extracellular or soluble cholinesterase-like domain to bind cognate partners across cell membranes, as illustrated by the neuroligins. These cell-adhesion molecules currently comprise the synaptic organizers neuroligins found in all phyla, along with three proteins found only in invertebrates: the guidance molecule neurotactin, the glia-specific gliotactin, and the basement membrane protein glutactin. Although these proteins share a cholinesterase-like fold, they lack one or more residues composing the catalytic triad responsible for the enzymatic activity of the cholinesterases. Conversely, they are found in various subcellular localisations and display specific disulfide bonding and N-glycosylation patterns, along with individual surface determinants possibly associated with recognition and binding of protein partners. Formation of non-covalent dimers typical of the cholinesterases is documented for mammalian neuroligins, yet whether invertebrate neuroligins and their neurotactin, gliotactin and glutactin relatives also form dimers in physiological conditions is unknown. Here we provide a brief overview of the localization, function, evolution, and conserved versus individual structural determinants of these cholinesterase-like cell-adhesion proteins.
ESTHER : Comoletti_2020_Neuropharmacol__108381
PubMedSearch : Comoletti_2020_Neuropharmacol__108381
PubMedID: 33166544

Title : An evolutionary perspective on the first disulfide bond in members of the cholinesterase-carboxylesterase (COesterase) family: Possible outcomes for cholinesterase expression in prokaryotes - Chatonnet_2019_Chem.Biol.Interact_13ChEPon_308_179
Author(s) : Chatonnet A , Brazzolotto X , Hotelier T , Lenfant N , Marchot P , Bourne Y
Ref : Chemico-Biological Interactions , 308 :179 , 2019
Abstract : Within the alpha/beta hydrolase fold superfamily of proteins, the COesterase group (carboxylesterase type B, block C, cholinesterases ...) diverged from the other groups through simultaneous integration of an N-terminal, first disulfide bond and a significant increase in the protein mean size. This first disulfide bond ties a large Cys loop, which in the cholinesterases is named the omega loop and forms the upper part of the active center gorge, essential for the high catalytic activity of these enzymes. In some non-catalytic members of the family, the loop may be necessary for heterologous partner recognition. Reshuffling of this protein portion occurred at the time of emergence of the fungi/metazoan lineage. Homologous proteins with this first disulfide bond are absent in plants but they are found in a limited number of bacterial genomes. In prokaryotes, the genes coding for such homologous proteins may have been acquired by horizontal transfer. However, the cysteines of the first disulfide bond are often lost in bacteria. Natural expression in bacteria of CO-esterases comprising this disulfide bond may have required compensatory mutations or expression of new chaperones. This disulfide bond may also challenge expression of the eukaryote-specific cholinesterases in prokaryotic cells. Yet recently, catalytically active human cholinesterase variants with enhanced thermostability were successfully expressed in E. coli. The key was the use of a peptidic sequence optimized through the Protein Repair One Stop Shop process, an automated structure- and sequence-based algorithm for expression of properly folded, soluble and stable eukaryotic proteins. Surprisingly however, crystal structures of the optimized cholinesterase variants expressed in bacteria revealed co-existing formed and unformed states of the first disulfide bond. Whether the bond never formed, or whether it properly formed then broke during the production/analysis process, cannot be inferred from the structural data. Yet, these features suggest that the recently acquired first disulfide bond is difficult to maintain in E. coli-expressed cholinesterases. To explore the fate of the first disulfide bond throughout the cholinesterase relatives, we reanalyzed the crystal structures of representative COesterases members from natural prokaryotic or eukaryotic sources or produced as recombinant proteins in E. coli. We found that in most cases this bond is absent.
ESTHER : Chatonnet_2019_Chem.Biol.Interact_13ChEPon_308_179
PubMedSearch : Chatonnet_2019_Chem.Biol.Interact_13ChEPon_308_179
PubMedID: 31100280

Title : Structure-Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles - Dolles_2018_J.Med.Chem_61_1646
Author(s) : Dolles D , Hoffmann M , Gunesch S , Marinelli O , Moller J , Santoni G , Chatonnet A , Lohse MJ , Wittmann HJ , Strasser A , Nabissi M , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 61 :1646 , 2018
Abstract : The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted mu-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.
ESTHER : Dolles_2018_J.Med.Chem_61_1646
PubMedSearch : Dolles_2018_J.Med.Chem_61_1646
PubMedID: 29400965

Title : Natural genomic amplification of cholinesterase genes in animals - Chatonnet_2017_J.Neurochem_142 Suppl 2_73
Author(s) : Chatonnet A , Lenfant N , Marchot P , Selkirk ME
Ref : Journal of Neurochemistry , 142 Suppl 2 :73 , 2017
Abstract : Tight control of the concentration of acetylcholine at cholinergic synapses requires precise regulation of the number and state of the acetylcholine receptors, and of the synthesis and degradation of the neurotransmitter. In particular, the cholinesterase activity has to be controlled exquisitely. In the genome of the first experimental models used (man, mouse, zebrafish and drosophila), there are only one or two genes coding for cholinesterases, whereas there are more genes for their closest relatives the carboxylesterases. Natural amplification of cholinesterase genes was first found to occur in some cancer cells and in insect species subjected to evolutionary pressure by insecticides. Analysis of the complete genome sequences of numerous representatives of the various metazoan phyla show that moderate amplification of cholinesterase genes is not uncommon in molluscs, echinoderms, hemichordates, prochordates or lepidosauria. Amplification of acetylcholinesterase genes is also a feature of parasitic nematodes or ticks. In these parasites, over-production of cholinesterase-like proteins in secreted products and the saliva are presumed to have effector roles related to host infection. These amplification events raise questions about the role of the amplified gene products, and the adaptation processes necessary to preserve efficient cholinergic transmission. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
ESTHER : Chatonnet_2017_J.Neurochem_142 Suppl 2_73
PubMedSearch : Chatonnet_2017_J.Neurochem_142 Suppl 2_73
PubMedID: 28382676

Title : Learning performances and vulnerability to amyloid toxicity in the butyrylcholinesterase knockout mouse - Maurice_2016_Behav.Brain.Res_296_351
Author(s) : Maurice T , Strehaiano M , Simeon N , Bertrand C , Chatonnet A
Ref : Behavioural Brain Research , 296 :351 , 2016
Abstract : Butyrylcholinesterase (BChE) is an important enzyme for detoxication and metabolism of ester compounds. It also hydrolyzes the neurotransmitter acetylcholine (ACh) in pathological conditions and may play a role in Alzheimer's disease (AD). We here compared the learning ability and vulnerability to Abeta toxicity in male and female BChE knockout (KO) mice and their 129Sv wild-type (Wt) controls. Animals tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. Intracerebroventricular (ICV) injection of increasing doses of amyloid-beta[25-35] (Abeta25-35) peptide oligomers resulted, in Wt mice, in learning and memory deficits, oxidative stress and decrease in ACh hippocampal content. In BChE KO mice, the Abeta25-35-induced deficit in place learning was attenuated in males and blocked in females. No change in lipid peroxidation or ACh levels was observed after Abeta25-35 treatment in male or female BChE KO mice. These data showed that the genetic invalidation of BChE in mice augmented learning capacities and lowered the vulnerability to Abeta toxicity.
ESTHER : Maurice_2016_Behav.Brain.Res_296_351
PubMedSearch : Maurice_2016_Behav.Brain.Res_296_351
PubMedID: 26306824

Title : Relationships of human alpha\/beta hydrolase fold proteins and other organophosphate-interacting proteins - Lenfant_2016_Chem.Biol.Interact_259_343
Author(s) : Lenfant N , Bourne Y , Marchot P , Chatonnet A
Ref : Chemico-Biological Interactions , 259 :343 , 2016
Abstract : Organophosphates (OPs) are either found in nature or synthetized for use as pesticides, flame retardants, neurotoxic warfare agents or drugs (cholinergic enhancers in Alzheimer's disease and myasthenia gravis, or inhibitors of lipases in metabolic diseases). Because of the central role of acetylcholinesterase cholinergic neurotransmission in humans, one of the main purposes for using OPs is inactivation of the enzyme by phosphorylation of the nucleophilic serine residue in the active center. However, hundreds of serine hydrolases are expressed in the human proteome, and many of them are potential targets for OP adduction. In this review, we first situate the alpha/beta hydrolase fold proteins among the distinctively folded proteins known to interact with OPs, in particular the different lipases, peptidases, and enzymes hydrolyzing OPs. Second, we compile the human alpha/beta hydrolases and review those that have been experimentally shown to interact with OPs. Among the 120 human alpha/beta hydrolase fold proteins, 102 have a serine in the consensus GXSXG pentapeptide compatible with an active site, 6 have an aspartate or a cysteine as the active site nucleophile residue, and 12 evidently lack an active site. 76 of the 120 have been experimentally shown to bind an OP.
ESTHER : Lenfant_2016_Chem.Biol.Interact_259_343
PubMedSearch : Lenfant_2016_Chem.Biol.Interact_259_343
PubMedID: 27109753

Title : Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases - Torrent_2015_Acta.Neuropathol.Commun_3_18
Author(s) : Torrent J , Vilchez-Acosta A , Munoz-Torrero D , Trovaslet M , Nachon F , Chatonnet A , Grznarova K , Acquatella-Tran Van Ba I , Le Goffic R , Herzog L , Beringue V , Rezaei H
Ref : Acta Neuropathologica Commun , 3 :18 , 2015
Abstract : INTRODUCTION: The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases
RESULTS: Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity. Using several truncated PrP variants and specific tight-binding AChE inhibitors (AChEis), we then demonstrate that the PrP-AChE interaction requires two mutually exclusive sub-sites in PrP N-terminal domain and an aromatic-rich region at the entrance of AChE active center gorge. We show that AChEis that target this site impair PrP-AChE complex formation and also limit the accumulation of pathological prion protein (PrPSc) in prion-infected cell cultures. Furthermore, reduction of AChE levels in prion-infected heterozygous AChE knock-out mice leads to slightly but significantly prolonged incubation time. Finally, we found that AChE levels were altered in prion-infected cells and tissues, suggesting that AChE might be directly associated with abnormal PrP. CONCLUSION: Our results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.
ESTHER : Torrent_2015_Acta.Neuropathol.Commun_3_18
PubMedSearch : Torrent_2015_Acta.Neuropathol.Commun_3_18
PubMedID: 25853328

Title : Molecular characterization of an acetylcholinesterase from the hemichordate Saccoglossus kowalevskii - Pezzementi_2015_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_181_50
Author(s) : Pezzementi L , Geiss C , King W , Lenfant N , Chatonnet A
Ref : Comparative Biochemistry & Physiology B Biochem Mol Biol , 181 :50 , 2015
Abstract : Our goal is to understand the evolution of the structure and function of cholinesterases (ChEs) in the deuterostome lineage and in particular to understand the role of paralogous enzymes such as the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) of the vertebrates. We have, in the past, characterized ChEs in two acraniate deuterostomes: amphioxus (a cephalochordate) and Ciona intestinalis (a urochordate). Here we present results on an AChE from a basal deuterostome, a model hemichordate, the acorn worm Saccoglossus kowalevskii. Of the eight genes coding for putative ChE-like proteins possessing Trp84, a characteristic of the choline-binding catalytic subsite of ChEs, we cloned a full length cDNA with a coding sequence typical of an acraniate AChE possessing a C-terminal exon coding for a typical T-peptide. We then used in vitro expression of the cDNA in COS-7 cells to characterize the AChE kinetically, pharmacologically, and biochemically. The cDNA codes for an AChE (AChE1), which is found in monomeric (G1), dimeric (G2), and tetrameric (G4) forms; and interacts with poly-L-proline, PRiMA, and ColQ, characteristic of an AChE possessing a T-peptide. The expression of the AChE is temperature dependent, with greater expression at 30 degrees C. We discuss the implications of these data for the evolution of the ChEs in the deuterostomes.
ESTHER : Pezzementi_2015_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_181_50
PubMedSearch : Pezzementi_2015_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_181_50
PubMedID: 25475711
Gene_locus related to this paper: sacko-ACHE1

Title : Creating a specialist protein resource network: a meeting report for the protein bioinformatics and community resources retreat - Babbitt_2015_Database.(Oxford)_2015_bav063
Author(s) : Babbitt PC , Bagos PG , Bairoch A , Bateman A , Chatonnet A , Chen MJ , Craik DJ , Finn RD , Gloriam D , Haft DH , Henrissat B , Holliday GL , Isberg V , Kaas Q , Landsman D , Lenfant N , Manning G , Nagano N , Srinivasan N , O'Donovan C , Pruitt KD , Sowdhamini R , Rawlings ND , Saier MH, Jr. , Sharman JL , Spedding M , Tsirigos KD , Vastermark A , Vriend G
Ref : Database (Oxford) , 2015 :bav063 , 2015
Abstract : During 11-12 August 2014, a Protein Bioinformatics and Community Resources Retreat was held at the Wellcome Trust Genome Campus in Hinxton, UK. This meeting brought together the principal investigators of several specialized protein resources (such as CAZy, TCDB and MEROPS) as well as those from protein databases from the large Bioinformatics centres (including UniProt and RefSeq). The retreat was divided into five sessions: (1) key challenges, (2) the databases represented, (3) best practices for maintenance and curation, (4) information flow to and from large data centers and (5) communication and funding. An important outcome of this meeting was the creation of a Specialist Protein Resource Network that we believe will improve coordination of the activities of its member resources. We invite further protein database resources to join the network and continue the dialogue.
ESTHER : Babbitt_2015_Database.(Oxford)_2015_bav063
PubMedSearch : Babbitt_2015_Database.(Oxford)_2015_bav063
PubMedID: 26284514

Title : Key challenges for the creation and maintenance of specialist protein resources - Holliday_2015_Proteins_83_1005
Author(s) : Holliday GL , Bairoch A , Bagos PG , Chatonnet A , Craik DJ , Finn RD , Henrissat B , Landsman D , Manning G , Nagano N , O'Donovan C , Pruitt KD , Rawlings ND , Saier MH, Jr. , Sowdhamini R , Spedding M , Srinivasan N , Vriend G , Babbitt PC , Bateman A
Ref : Proteins , 83 :1005 , 2015
Abstract : As the volume of data relating to proteins increases, researchers rely more and more on the analysis of published data, thus increasing the importance of good access to these data that vary from the supplemental material of individual articles, all the way to major reference databases with professional staff and long-term funding. Specialist protein resources fill an important middle ground, providing interactive web interfaces to their databases for a focused topic or family of proteins, using specialized approaches that are not feasible in the major reference databases. Many are labors of love, run by a single lab with little or no dedicated funding and there are many challenges to building and maintaining them. This perspective arose from a meeting of several specialist protein resources and major reference databases held at the Wellcome Trust Genome Campus (Cambridge, UK) on August 11 and 12, 2014. During this meeting some common key challenges involved in creating and maintaining such resources were discussed, along with various approaches to address them. In laying out these challenges, we aim to inform users about how these issues impact our resources and illustrate ways in which our working together could enhance their accuracy, currency, and overall value. Proteins 2015; 83:1005-1013. (c) 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.
ESTHER : Holliday_2015_Proteins_83_1005
PubMedSearch : Holliday_2015_Proteins_83_1005
PubMedID: 25820941

Title : Tracking the origin and divergence of cholinesterases and neuroligins: the evolution of synaptic proteins - Lenfant_2014_J.Mol.Neurosci_53_362
Author(s) : Lenfant N , Hotelier T , Bourne Y , Marchot P , Chatonnet A
Ref : Journal of Molecular Neuroscience , 53 :362 , 2014
Abstract : A cholinesterase activity can be found in all kingdoms of living organism, yet cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum. Among various proteins homologous to cholinesterases, one finds neuroligins. These proteins, with an altered catalytic triad and no known hydrolytic activity, display well-identified cell adhesion properties. The availability of complete genomes of a few metazoans provides opportunities to evaluate when these two protein families emerged during evolution. In bilaterian animals, acetylcholinesterase co-localizes with proteins of cholinergic synapses while neuroligins co-localize and may interact with proteins of excitatory glutamatergic or inhibitory GABAergic/glycinergic synapses. To compare evolution of the cholinesterases and neuroligins with other proteins involved in the architecture and functioning of synapses, we devised a method to search for orthologs of these partners in genomes of model organisms representing distinct stages of metazoan evolution. Our data point to a progressive recruitment of synaptic components during evolution. This finding may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of the cholinergic versus glutamatergic and GABAergic/glycinergic synapses.
ESTHER : Lenfant_2014_J.Mol.Neurosci_53_362
PubMedSearch : Lenfant_2014_J.Mol.Neurosci_53_362
PubMedID: 24390353

Title : Proteins with an alpha\/beta hydrolase fold: Relationships between subfamilies in an ever-growing superfamily - Lenfant_2013_Chem.Biol.Interact_203_266
Author(s) : Lenfant N , Hotelier T , Bourne Y , Marchot P , Chatonnet A
Ref : Chemico-Biological Interactions , 203 :266 , 2013
Abstract : Alpha/beta hydrolases function as hydrolases, lyases, transferases, hormone precursors or transporters, chaperones or routers of other proteins. The amount of structural and functional available data related to this protein superfamily expands exponentially, as does the number of proteins classified as alpha/beta hydrolases despite poor sequence similarity and lack of experimental data. However the superfamily can be rationally divided according to sequence or structural homologies, leading to subfamilies of proteins with potentially similar functions. Since the discovery of proteins homologous to cholinesterases but devoid of enzymatic activity (e.g., the neuroligins), divergent functions have been ascribed to members of other subfamilies (e.g., lipases, dipeptidylaminopeptidase IV, etc.). To study the potentially moonlighting properties of alpha/beta hydrolases, the ESTHER database (for ESTerase and alpha/beta Hydrolase Enzymes and Relatives; http:\/\/, which collects, organizes and disseminates structural and functional information related to alpha/beta hydrolases, has been updated with new tools and the web server interface has been upgraded. A new Overall Table along with a new Tree based on HMM models has been included to tentatively group subfamilies. These tools provide starting points for phylogenetic studies aimed at pinpointing the origin of duplications leading to paralogous genes (e.g., acetylcholinesterase versus butyrylcholinesterase, or neuroligin versus carboxylesterase). Another of our goals is to implement new tools to distinguish catalytically active enzymes from non-catalytic proteins in poorly studied or annotated subfamilies.
ESTHER : Lenfant_2013_Chem.Biol.Interact_203_266
PubMedSearch : Lenfant_2013_Chem.Biol.Interact_203_266
PubMedID: 23010363

Title : ESTHER, the database of the alpha\/beta-hydrolase fold superfamily of proteins: tools to explore diversity of functions - Lenfant_2013_Nucleic.Acids.Res_41_D423
Author(s) : Lenfant N , Hotelier T , Velluet E , Bourne Y , Marchot P , Chatonnet A
Ref : Nucleic Acids Research , 41 :D423 , 2013
Abstract : The ESTHER database, which is freely available via a web server (http:\/\/ and is widely used, is dedicated to proteins with an alpha/beta-hydrolase fold, and it currently contains >30 000 manually curated proteins. Herein, we report those substantial changes towards improvement that we have made to improve ESTHER during the past 8 years since our 2004 update. In particular, we generated 87 new families and increased the coverage of the UniProt Knowledgebase (UniProtKB). We also renewed the ESTHER website and added new visualization tools, such as the Overall Table and the Family Tree. We also address two topics of particular interest to the ESTHER users. First, we explain how the different enzyme classifications (bacterial lipases, peptidases, carboxylesterases) used by different communities of users are combined in ESTHER. Second, we discuss how variations of core architecture or in predicted active site residues result in a more precise clustering of families, and whether this strategy provides trustable hints to identify enzyme-like proteins with no catalytic activity.
ESTHER : Lenfant_2013_Nucleic.Acids.Res_41_D423
PubMedSearch : Lenfant_2013_Nucleic.Acids.Res_41_D423
PubMedID: 23193256

Title : A tetrameric acetylcholinesterase from the parasitic nematode Dictyocaulus viviparus associates with the vertebrate tail proteins PRiMA and ColQ - Pezzementi_2012_Mol.Biochem.Parasitol_181_40
Author(s) : Pezzementi L , Krejci E , Chatonnet A , Selkirk ME , Matthews JB
Ref : Molecular & Biochemical Parasitology , 181 :40 , 2012
Abstract : Dictyocaulus viviparus causes a serious lung disease of cattle. Similar to other parasitic nematodes, D. viviparus possesses several acetylcholinesterase (AChE) genes, one of which encodes a putative neuromuscular AChE, which contains a tryptophan (W) amphiphilic tetramerization (WAT) domain at its C-terminus. In the current study, we describe the biochemical characterization of a recombinant version of this WAT domain-containing AChE. To assess if the WAT domain is biologically functional, we investigated the association of the recombinant enzyme with the vertebrate tail proteins, proline-rich membrane anchor (PRiMA) and collagen Q (ColQ), as well as the synthetic polypeptide poly-l-proline. The results indicate that the recombinant enzyme hydrolyzes acetylthiocholine preferentially and exhibits inhibition by excess substrate, a characteristic of AChEs but not butyrylcholinesterases (BChEs). The enzyme is inhibited by the AChE inhibitor, BW284c51, but not by the BChE inhibitors, ethopropazine or iso-OMPA. The enzyme is able to assemble into monomeric (G(1)), dimeric (G(2)), and tetrameric (G(4)) globular forms and can also associate with PRiMA and ColQ, which contain proline-rich attachment domains (PRADs). This interaction is likely to be mediated via WAT-PRAD interactions, as the enzyme also assembles into tetramers with the synthetic polypeptide poly-l-proline. These interactions are typical of AChE(T) subunits. This is the first demonstration of an AChE(T) from a parasitic nematode that can assemble into heterologous forms with vertebrate proteins that anchor the enzyme in cholinergic synapses. We discuss the implications of our results for this particular host/parasite system and for the evolution of AChE.
ESTHER : Pezzementi_2012_Mol.Biochem.Parasitol_181_40
PubMedSearch : Pezzementi_2012_Mol.Biochem.Parasitol_181_40
PubMedID: 22027027

Title : Effect of locomotor training on muscle performance in the context of nerve-muscle communication dysfunction - Hadj-Said_2012_Muscle.Nerve_45_567
Author(s) : Hadj-Said W , Bangratz M , Vignaud A , Chatonnet A , Butler-Browne G , Nicole S , Agbulut O , Ferry A
Ref : Muscle & Nerve , 45 :567 , 2012
Abstract : INTRODUCTION: The effects of locomotor training (LT) on skeletal muscle after peripheral nerve injury and acetylcholinesterase deficiency are not well documented. METHODS: We determined the effects of LT on mouse soleus muscle performance after sciatic nerve transection with excision (full and permanent denervation), nerve transection (partial functional reinnervation), nerve crush (full denervation with full functional reinnervation), and acetylcholinesterase deficiency (alteration in neuromuscular junction functioning). RESULTS: We found no significant effect of LT on the recovery of soleus muscle weight, maximal force in response to muscle stimulation, and fatigue resistance after nerve transection with or without excision. However, LT significantly increased soleus muscle fatigue resistance after nerve crush and acetylcholinesterase deficiency. Moreover, hindlimb immobilization significantly aggravated the deficit in soleus muscle maximal force production and atrophy after nerve crush. CONCLUSIONS: LT is beneficial, and reduced muscle use is detrimental for intrinsic muscle performance in the context of disturbed nerve-muscle communication.
ESTHER : Hadj-Said_2012_Muscle.Nerve_45_567
PubMedSearch : Hadj-Said_2012_Muscle.Nerve_45_567
PubMedID: 22431091

Title : Enzymatic activity and protein interactions in alpha\/beta hydrolase fold proteins: moonlighting versus promiscuity - Marchot_2012_Protein.Pept.Lett_19_132
Author(s) : Marchot P , Chatonnet A
Ref : Protein Pept Lett , 19 :132 , 2012
Abstract : Genes coding for members of the alpha/beta hydrolase fold superfamily of proteins are present in all known genomes. Although there is no common and essential function performed by these proteins shared in all living organisms, this fold has been used for a number of diverse functions. The ancestry of both enzymatic and protein-protein interaction capability of this structural scaffold made it an important tinkering tool kit for protein function evolution. Recently, enzymes known since a long time have been found to have a second function in acting promiscuously on alternative substrates, or to be true moonlighting proteins acting also as transporters, receptors, chaperones... The reverse situation has been encountered for adhesion proteins shown to be enzymes. This review, while not exhaustive, surveys some of the best-known examples of multiple functions in alpha/beta hydrolase fold proteins.
ESTHER : Marchot_2012_Protein.Pept.Lett_19_132
PubMedSearch : Marchot_2012_Protein.Pept.Lett_19_132
PubMedID: 21933125

Title : Hydrolase versus other functions of members of the alpha\/beta-hydrolase fold superfamily of proteins -
Author(s) : Marchot P , Chatonnet A
Ref : Protein Pept Lett , 19 :130 , 2012
PubMedID: 21933117

Title : Evolution of Acetylcholinesterase and Butyrylcholinesterase in the Vertebrates: An Atypical Butyrylcholinesterase from the Medaka Oryzias latipes - Pezzementi_2011_PLoS.ONE_6_e17396
Author(s) : Pezzementi L , Nachon F , Chatonnet A
Ref : PLoS ONE , 6 :e17396 , 2011
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are thought to be the result of a gene duplication event early in vertebrate evolution. To learn more about the evolution of these enzymes, we expressed in vitro, characterized, and modeled a recombinant cholinesterase (ChE) from a teleost, the medaka Oryzias latipes. In addition to AChE, O. latipes has a ChE that is different from either vertebrate AChE or BChE, which we are classifying as an atypical BChE, and which may resemble a transitional form between the two. Of the fourteen aromatic amino acids in the catalytic gorge of vertebrate AChE, ten are conserved in the atypical BChE of O. latipes; by contrast, only eight are conserved in vertebrate BChE. Notably, the atypical BChE has one phenylalanine in its acyl pocket, while AChE has two and BChE none. These substitutions could account for the intermediate nature of this atypical BChE. Molecular modeling supports this proposal. The atypical BChE hydrolyzes acetylthiocholine (ATCh) and propionylthiocholine (PTCh) preferentially but butyrylthiocholine (BTCh) to a considerable extent, which is different from the substrate specificity of AChE or BChE. The enzyme shows substrate inhibition with the two smaller substrates but not with the larger substrate BTCh. In comparison, AChE exhibits substrate inhibition, while BChE does not, but may instead show substrate activation. The atypical BChE from O. latipes also shows a mixed pattern of inhibition. It is effectively inhibited by physostigmine, typical of all ChEs. However, although the atypical BChE is efficiently inhibited by the BChE-specific inhibitor ethopropazine, it is not by another BChE inhibitor, iso-OMPA, nor by the AChE-specific inhibitor BW284c51. The atypical BChE is found as a glycophosphatidylinositol-anchored (GPI-anchored) amphiphilic dimer (G2a), which is unusual for any BChE. We classify the enzyme as an atypical BChE and discuss its implications for the evolution of AChE and BChE and for ecotoxicology.
ESTHER : Pezzementi_2011_PLoS.ONE_6_e17396
PubMedSearch : Pezzementi_2011_PLoS.ONE_6_e17396
PubMedID: 21364766
Gene_locus related to this paper: oryla-BCHE

Title : Localization of butyrylcholinesterase at the neuromuscular junction of normal and acetylcholinesterase knockout mice - Blondet_2010_J.Histochem.Cytochem_58_1075
Author(s) : Blondet B , Carpentier G , Ferry A , Chatonnet A , Courty J
Ref : Journal of Histochemistry & Cytochemistry , 58 :1075 , 2010
Abstract : At the mouse neuromuscular junction (NMJ), there are two distinct cholinesterases (ChE): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Until now, it has been difficult to determine the precise localization of BChE at the NMJ. In this study, we use a modification of Koelle's method to stain AChE and BChE activity. This method does not interfere with fluorescent co-staining, which allows precise co-localization of ChE and other synaptic molecules at the NMJ. We demonstrate that AChE and BChE exhibit different localization patterns at the mouse NMJ. AChE activity is present both in the primary cleft and in the secondary folds, whereas BChE activity appears to be almost absent in the primary cleft and to be concentrated in subsynaptic folds. The same localization for BChE is observed in the AChE-knockout (KO) mouse NMJ. Collagenase treatment removed AChE from the primary cleft, but not from secondary folds in the wild-type mouse, whereas in the AChE-KO mouse, BChE remains in the secondary folds. After peripheral nerve injury and regeneration, BChE localization is not modified in either normal or KO mice. In conclusion, specific localization of BChE in the secondary folds of the NMJ suggests that this enzyme is not a strict surrogate of AChE and that the two enzymes have two different roles.
ESTHER : Blondet_2010_J.Histochem.Cytochem_58_1075
PubMedSearch : Blondet_2010_J.Histochem.Cytochem_58_1075
PubMedID: 20805581

Title : Insecticide resistance through mutations in cholinesterases or carboxylesterases: data mining in the ESTHER database - Hotelier_2010_J.Pestic.Sci_35_315
Author(s) : Hotelier T , Negre V , Marchot P , Chatonnet A
Ref : Journal of Pesticide Science , 35 :315 , 2010
Abstract : Resistance of arthropods to organophosphates and carbamates used as insecticides is mainly due to mutations in genes encoding carboxylesterase or acetylcholinesterase members of the alpha/beta-hydrolase fold superfamily of proteins. Mutations that have been described at the molecular level concern 24 species, 31 genes and 32 identical positions in the aligned aminoacid sequences. Seven of these positions are found in more than four species and can be considered as hot spots for mutations. Mutations in one single gene also result in cross resistance to pyrethroids. These figures along with all pieces of information related to these mutations can be recovered from the ESTHER database, dedicated to the alpha/beta-hydrolase fold superfamily (http:\/\/, through built-in or custom made queries. A sequence alignment of enzymes involved in resistance with highlighted mutated amino acid residues is provided. Selecting one amino acid residue leads to all information about mutations analyzed at this position. Links to the related literature are also available.
ESTHER : Hotelier_2010_J.Pestic.Sci_35_315
PubMedSearch : Hotelier_2010_J.Pestic.Sci_35_315

Title : Behavioral phenotyping of heterozygous acetylcholinesterase knockout (AChE+\/-) mice showed no memory enhancement but hyposensitivity to amnesic drugs - Espallergues_2010_Behav.Brain.Res_206_263
Author(s) : Espallergues J , Galvan L , Sabatier F , Rana-Poussine V , Maurice T , Chatonnet A
Ref : Behavioural Brain Research , 206 :263 , 2010
Abstract : Decrease in the expression or activity of acetylcholinesterase (AChE) enzymatic activity results in increased cholinergic tonus in the brain and periphery, with concomitant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, focusing on learning and memory functions. Male and female, AChE+/- and AChE+/+ littermate controls (129 sv strain) were tested at 5-9 weeks of age. AChE activity was significantly decreased in the hippocampus and cortex of AChE+/- mice, but butyrylcholinesterase activity was preserved. AChE+/- mice failed to show any difference in terms of locomotion, exploration and anxiety parameters in the open-field test. Animals were then tested for place learning in the water-maze. They were trained using a 'sustained acquisition' protocol (3 swim trials per day) or a 'mild acquisition' protocol (2 swim trials per day) to locate an invisible platform in fixed position (reference memory procedure). Then, during 3 days, they were trained to locate the platform in a variable position (working memory procedure). Learning profiles and probe test performances were similar for AChE+/- and AChE+/+ mice. Mice were then treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg) 20 min before each training session. Scopolamine impaired learning at both doses in AChE+/+ mice, but only at the highest dose in AChE+/- mice. Moreover, the intracerebroventricular injection of amyloid-beta25-35 peptide, 9 nmol, 7 days before water-maze acquisition, failed to induce learning deficits in AChE+/- mice, but impaired learning in AChE+/+ controls. The peptide failed to be toxic in forebrain structures of AChE+/- mice, since an increase in lipid peroxidation levels was measured in the hippocampus of AChE+/+ but not AChE+/- mice. We conclude that the increase in cholinergic tonus observed in AChE+/- mice did not result in increased memory functions but allowed a significant prevention of the deleterious effects of muscarinic blockade or amyloid toxicity.
ESTHER : Espallergues_2010_Behav.Brain.Res_206_263
PubMedSearch : Espallergues_2010_Behav.Brain.Res_206_263
PubMedID: 19766675

Title : Evolution of cholinesterases in the animal kingdom - Pezzementi_2010_Chem.Biol.Interact_187_27
Author(s) : Pezzementi L , Chatonnet A
Ref : Chemico-Biological Interactions , 187 :27 , 2010
Abstract : Cholinesterases emerged from a family of enzymes and proteins with adhesion properties. This family is absent in plants and expanded in multicellular animals. True cholinesterases appeared in triploblastic animals together with the cholinergic system. Lineage specific duplications resulted in two acetylcholinesterases in most hexapods and in up to four genes in nematodes. In vertebrates the duplication leading to acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is now considered to be an ancient event which occurred before the split of osteichthyes. The product of one or the other of the paralogues is responsible for the physiological hydrolysis of acetylcholine, depending on the species lineage and tissue considered. The BChE gene seems to have been lost in some fish lineages. The complete genome of amphioxus (Branchiostoma floridae: cephalochordate) contains a large number of duplicated genes or pseudogenes of cholinesterases. Sequence comparison and tree constructions raise the question of considering the atypical ChE studied in this organism as a representative of ancient BChE. Thus nematodes, arthropods, annelids, molluscs, and vertebrates typically possess two paralogous genes coding for cholinesterases. The origin of the duplication(s) is discussed. The mode of attachment through alternative C-terminal coding exons seems to have evolved independently from the catalytic part of the gene.
ESTHER : Pezzementi_2010_Chem.Biol.Interact_187_27
PubMedSearch : Pezzementi_2010_Chem.Biol.Interact_187_27
PubMedID: 20359467

Title : Effect of fluoxetine on neuromuscular function in acetylcholinesterase (AChE) knockout mice - Bertrand_2008_Chem.Biol.Interact_175_113
Author(s) : Bertrand C , Bonafos B , Tremblay M , Ferry A , Chatonnet A
Ref : Chemico-Biological Interactions , 175 :113 , 2008
Abstract : Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The causal mutations have been described in number of cases. The slow channel myasthenic syndrome (slow-channel-CMS) results in a marked prolongation of channel opening in stimulated receptors (nAChR) and the end plate acetylcholinesterase (AChE) deficiency congenital myasthenic syndrome (ColQ-CMS) results in an increased action of acetylcholine (ACh) at the synapse. Anticholinesterase medication is detrimental in these cases. The successful treatment of slow-channel-CMS patients with the antidepressant serotonin re-uptake inhibitor fluoxetine has been reported. At high concentration it has a non-depolarizing effect on nicotinic receptors. This led us to the idea that fluoxetine could protect AChR from a relative excess of ACh. We investigated the possible use of fluoxetine as treatment in the AChE KO mouse. Treatment at 6 mg/kg from 3 weeks to 2 months increased slightly the daily weight gain but not the final weight at 2 months in AChE-/- mice. Isometric force production of Tibialis anterior in response to electric nerve stimulation was measured in situ in AChE-/- and wild type mice treated or not by fluoxetine. The results show that the maximum twitch force in response to a single nerve stimulation, the maximal tetanic force (P0) in response to repetitive nerve stimulation and the tetanic fade are not changed in AChE-/- mice treated with fluoxetine versus control AChE-/- mice.
ESTHER : Bertrand_2008_Chem.Biol.Interact_175_113
PubMedSearch : Bertrand_2008_Chem.Biol.Interact_175_113
PubMedID: 18550043

Title : Acetylcholinesterase from the invertebrate Ciona intestinalis is capable of assembling into asymmetric forms when co-expressed with vertebrate collagenic tail peptide - Frederick_2008_FEBS.J_275_1309
Author(s) : Frederick A , Tsigelny I , Cohenour F , Spiker C , Krejci E , Chatonnet A , Bourgoin S , Richards G , Allen T , Whitlock MH , Pezzementi L
Ref : Febs J , 275 :1309 , 2008
Abstract : To learn more about the evolution of the cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase in the vertebrates, we investigated the AChE activity of a deuterostome invertebrate, the urochordate Ciona intestinalis, by expressing in vitro a synthetic recombinant cDNA for the enzyme in COS-7 cells. Evidence from kinetics, pharmacology, molecular biology, and molecular modeling confirms that the enzyme is AChE. Sequence analysis and molecular modeling also indicate that the cDNA codes for the AChE(T) subunit, which should be able to produce all three globular forms of AChE: monomers (G(1)), dimers (G(2)), and tetramers (G(4)), and assemble into asymmetric forms in association with the collagenic subunit collagen Q. Using velocity sedimentation on sucrose gradients, we found that all three of the globular forms are either expressed in cells or secreted into the medium. In cell extracts, amphiphilic monomers (G(1)(a)) and non-amphiphilic tetramers (G(4)(na)) are found. Amphiphilic dimers (G(2)(a)) and non-amphiphilic tetramers (G(4)(na)) are secreted into the medium. Co-expression of the catalytic subunit with Rattus norvegicus collagen Q produces the asymmetric A(12) form of the enzyme. Collagenase digestion of the A(12) AChE produces a lytic G(4) form. Notably, only globular forms are present in vivo. This is the first demonstration that an invertebrate AChE is capable of assembling into asymmetric forms. We also performed a phylogenetic analysis of the sequence. We discuss the relevance of our results with respect to the evolution of the ChEs in general, in deuterostome invertebrates, and in chordates including vertebrates.
ESTHER : Frederick_2008_FEBS.J_275_1309
PubMedSearch : Frederick_2008_FEBS.J_275_1309
PubMedID: 18279391
Gene_locus related to this paper: cioin-ACHE1 , cioin-ACHE2

Title : Hyposensitivity to the amnesic effects of scopolamine or amyloid beta(25-35) peptide in heterozygous acetylcholinesterase knockout (AChE(+\/-)) mice - Espallergues_2008_Chem.Biol.Interact_175_131
Author(s) : Espallergues J , Galvan L , Lepourry L , Bonafos B , Maurice T , Chatonnet A
Ref : Chemico-Biological Interactions , 175 :131 , 2008
Abstract : We examined the sensitivity of AChE(+/-) mice to the amnesic effects of scopolamine and amyloid beta peptide. AChE(+/-) and AChE(+/+) littermates, tested at 5-9 weeks of age, failed to show any difference in locomotion, exploration and anxiety in the open-field test, or in-place learning in the water-maze. However, when treated with the muscarinic receptor antagonist scopolamine (0.5, 5mg/kg s.c.) 20 min before each water-maze training session, learning impairments were observed at both doses in AChE(+/+) mice, but only at the highest dose in AChE(+/-) mice. The central injection of Abeta(25-35) peptide (9 nmol) induced learning deficits only in AChE(+/+) but not in AChE(+/-) mice. Therefore, the hyper-activity of cholinergic systems in AChE(+/-) mice did not result in increased memory abilities, but prevented the deleterious effects of muscarinic blockade or amyloid toxicity.
ESTHER : Espallergues_2008_Chem.Biol.Interact_175_131
PubMedSearch : Espallergues_2008_Chem.Biol.Interact_175_131
PubMedID: 18533140

Title : Acetylcholinesterase activity in Clytia hemisphaerica (Cnidaria) - Denker_2008_Chem.Biol.Interact_175_125
Author(s) : Denker E , Chatonnet A , Rabet N
Ref : Chemico-Biological Interactions , 175 :125 , 2008
Abstract : Cholinesterase activity is known in representatives of all living organisms phyla but the origin of the cholinergic system as known in bilaterian animals is still undeciphered. In particular the implication of cholinesterases in the nervous system of non-bilaterian Metazoa is not well known. We thus chose to investigate this activity in the Clytia hemisphaerica (Cnidaria) medusa. In toto histochemical staining revealed an acetylcholinesterase activity in the tentacle bulbs but not in the nervous system. Sequences homologous to acetylcholinesterase were searched within Clytia ESTs and compared to other sequences found in public databases.
ESTHER : Denker_2008_Chem.Biol.Interact_175_125
PubMedSearch : Denker_2008_Chem.Biol.Interact_175_125
PubMedID: 18448086
Gene_locus related to this paper: 9cnid-b7zf10 , felca-CES1

Title : Genetic inactivation of acetylcholinesterase causes functional and structural impairment of mouse soleus muscles - Vignaud_2008_Cell.Tissue.Res_333_289
Author(s) : Vignaud A , Fougerousse F , Mouisel E , Guerchet N , Hourde C , Bacou F , Butler-Browne G , Chatonnet A , Ferry A
Ref : Cell Tissue Research , 333 :289 , 2008
Abstract : Acetylcholinesterase (AChE) plays an essential role in neuromuscular transmission. Not surprisingly, neuromuscular transmission during repetitive nerve stimulation is severely depressed in the AChE knockout mouse (KO). However, whether this deficit in AChE leads to skeletal muscle changes is not known. We have studied the in vitro contractile properties of the postural and locomotor soleus muscles of adult KO and normal (wildtype, WT) mice, and this was completed by histological and biochemical analyses. Our results show that muscle weight, cross-sectional area of muscle fibres and absolute maximal isometric force are all reduced in KO mice compared with WT mice. Of interest, the relative amount of slow myosin heavy chain (MHC-1) in muscle homogenates and the percentage of muscle fibres expressing MHC-1 are decreased in the KO mice. Surprisingly, AChE ablation does not modify twitch kinetics, absolute maximal power, fatigue resistance or citrate synthase activity, despite the reduced number of slow muscle fibres. Thus, a deficit in AChE leads to alterations in the structure and function of muscles but these changes are not simply related to the reduced body weight of KO mice. Our results also suggest that this murine model of congenital myasthenic syndrome with endplate AChE deficiency combines alterations in both neurotransmission and intrinsic muscle properties.
ESTHER : Vignaud_2008_Cell.Tissue.Res_333_289
PubMedSearch : Vignaud_2008_Cell.Tissue.Res_333_289
PubMedID: 18560895

Title : Genetic ablation of acetylcholinesterase alters muscle function in mice - Vignaud_2008_Chem.Biol.Interact_175_129
Author(s) : Vignaud A , Fougerousse F , Mouisel E , Bertrand C , Bonafos B , Molgo J , Ferry A , Chatonnet A
Ref : Chemico-Biological Interactions , 175 :129 , 2008
Abstract : Although acetylcholinesterase (AChE) knockout mice survive, they have abnormal neuromuscular function. We analysed further the effects of the mutation on hind limb muscle contractile properties. Tibialis anterior muscle from AChE KO mice is unable to maintain tension during a short period of repetitive nerve stimulation (tetanic fade) and has an increased twitch tension in response to a single nerve electric stimulation. In response to direct muscle stimulation, we found that maximal velocity of shortening of soleus muscle is increased and maximum tetanic force is decreased in AchE KO mice versus control animals. As the contractile properties of the soleus muscle were altered by AChE ablation, our results suggest cellular and molecular changes in AChE ablated muscle containing both fast and slow muscle fibres.
ESTHER : Vignaud_2008_Chem.Biol.Interact_175_129
PubMedSearch : Vignaud_2008_Chem.Biol.Interact_175_129
PubMedID: 18550042

Title : Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice - Girard_2007_Life.Sci_80_2380
Author(s) : Girard E , Bernard V , Minic J , Chatonnet A , Krejci E , Molgo J
Ref : Life Sciences , 80 :2380 , 2007
Abstract : At the neuromuscular junction (NMJ) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can hydrolyze acetylcholine (ACh). Released ACh quanta are known to diffuse rapidly across the narrow synaptic cleft and pairs of ACh molecules cooperate to open endplate channels. During their diffusion through the cleft, or after being released from muscle nicotinic ACh receptors (nAChRs), most ACh molecules are hydrolyzed by AChE highly concentrated at the NMJ. Advances in mouse genomics offered new approaches to assess the role of specific cholinesterases involved in synaptic transmission. AChE knockout mice (AChE-KO) provide a valuable tool for examining the complete abolition of AChE activity and the role of BChE. AChE-KO mice live to adulthood, and exhibit an increased sensitivity to BChE inhibitors, suggesting that BChE activity facilitated their survival and compensated for AChE function. Our results show that BChE is present at the endplate region of wild-type and AChE-KO mature muscles. The decay time constant of focally recorded miniature endplate currents was 1.04 +/- 0.06 ms in wild-type junctions and 5.4 ms +/- 0.3 ms in AChE-KO junctions, and remained unaffected by BChE-specific inhibitors, indicating that BChE is not limiting ACh duration on endplate nAChRs. Inhibition of BChE decreased evoked quantal ACh release in AChE-KO NMJs. This reduction in ACh release can explain the greatest sensitivity of AChE-KO mice to BChE inhibitors. BChE is known to be localized in perisynaptic Schwann cells, and our results strongly suggest that BChE's role at the NMJ is to protect nerve terminals from an excess of ACh.
ESTHER : Girard_2007_Life.Sci_80_2380
PubMedSearch : Girard_2007_Life.Sci_80_2380
PubMedID: 17467011

Title : Synaptic efficacy and remodeling at the neuromuscular junction of knockout mice deficient in acetylcholinesterase -
Author(s) : Girard E , Barbier J , Camp S , Taylor P , Chatonnet A , Krejci E , Molgo J
Ref : Journal de Physiologie (Paris) , 99 :254 , 2006

Title : Outcome of acetylcholinesterase deficiency for neuromuscular functioning - Mouisel_2006_Neurosci.Res_55_389
Author(s) : Mouisel E , Blondet B , Escourrou P , Chatonnet A , Molgo J , Ferry A
Ref : Neurosci Res , 55 :389 , 2006
Abstract : Acetylcholinesterase (AChE) plays an essential role in neuromuscular transmission, therefore it is surprising that AChE knockout (KO) mice could live to the adulthood. Neuromuscular functioning in KO and normal (wild type, WT) mice were studied, at different age (1.5-, 4- and 9-month-old). Hindlimb muscle force productions in response to nerve or muscle electric stimulation were recorded in situ and in vitro. Our results show that contrary to WT mice, 1.5-, 4- and 9-month-old KO mice exhibited a decreased in tetanic force during short periods (500 ms) of repetitive nerve stimulations (tetanic fade). Nevertheless submaximal muscle forces in response to single or repetitive nerve stimulation were increased (potentiation) in 1.5-, 4- and 9-month-old KO mice as compared to WT mice (p<0.05). Tetanic fade and potentiation were absent when muscles were directly stimulated, indicating neuromuscular transmission alterations in KO mice. Contrary to younger mice, muscle weight and maximal tetanic force in response to repetitive nerve stimulation were not reduced in 4- and 9-month-old KO mice as compared to WT mice (p>0.05). In conclusion AChE deficit leads to marked neuromuscular alterations in hind limb muscle functioning and a prominent symptom is the lack of resistance to fatigue.
ESTHER : Mouisel_2006_Neurosci.Res_55_389
PubMedSearch : Mouisel_2006_Neurosci.Res_55_389
PubMedID: 16766072

Title : New friendly tools for users of ESTHER, the database of the alpha\/beta-hydrolase fold superfamily of proteins - Renault_2005_Chem.Biol.Interact_157-158_339
Author(s) : Renault L , Negre V , Hotelier T , Cousin X , Marchot P , Chatonnet A
Ref : Chemico-Biological Interactions , 157-158 :339 , 2005
Abstract : The structural alpha/beta-hydrolase fold is characterized by a beta-sheet core of five to eight strands connected by alpha-helices to form a alpha/beta/alpha sandwich. The superfamily members, exemplified by the cholinesterases, diverged from a common ancestor into a number of hydrolytic enzymes displaying a wide range of substrate specificities, along with proteins with no recognized hydrolytic activity. In the enzymes, the catalytic triad residues are presented on loops of which one, the nucleophile elbow, is the most conserved feature of the fold. Of the other proteins, which all lack from one to all of the catalytic residues, some may simply be 'inactive' enzymes while others have been shown to be involved in heterologous surface recognition functions. The ESTHER (for esterases, alpha/beta-hydrolase enzymes and relatives) database ( gathers and annotates all the published pieces of information (gene and protein sequences; biochemical, pharmacological, and structural data) related to the superfamily, and connects them together to provide the bases for studying structure-function relationships within the superfamily. The most recent developments of the database are presented.
ESTHER : Renault_2005_Chem.Biol.Interact_157-158_339
PubMedSearch : Renault_2005_Chem.Biol.Interact_157-158_339
PubMedID: 16297901

Title : Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase - Boudinot_2005_Pharmacol.Biochem.Behav_80_53
Author(s) : Boudinot E , Taysse L , Daulon S , Chatonnet A , Champagnat J , Foutz AS
Ref : Pharmacol Biochem Behav , 80 :53 , 2005
Abstract : We investigated the contributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition to the respiratory dysfunction produced by organophosphates in mice which were adapted or not to low AChE activity. Effects of acute selective inhibition of AChE and BChE on ventilation measured by whole-body plethysmography were compared in mice with either normal AChE activity (wild-type), or mice adapted to a null AChE activity (homozygotes for AChE gene deletion) or adapted to an intermediate level of activity (heterozygotes). In wild-type mice acute reduction of AChE by Huperzine A (1 mg/kg) to the level found in asymptomatic heterozygotes, induced tremors but no respiratory depression, whereas the same dose of Huperzine in heterozygote animals further reduced AChE activity, increased tidal volume (V(T)) and decreased breathing frequency (f(R)). A lethal dose of Huperzine in wild-type mice augmented these respiratory effects, but was ineffective in homozygotes. BChE inhibition by bambuterol was ineffective in wild-type mice and heterozygotes, decreased V(T) in homozygotes adapted to null AChE activity but increased V(T) in wild-type mice acutely treated with Huperzine, also aggravating the cholinergic syndrome. We conclude that: (1) Huperzine does not perturb respiration at a dose inhibiting 40% of AChE, and at a lethal dose does not affect any other enzyme important for respiration; (2) Respiratory function is more sensitive to anticholinesterases in heterozygotes than in wild-type mice; (3) BChE may play distinct roles in respiratory function, because its inhibition has opposite effects on tidal volume depending on whether the mouse has adapted to null AChE or whether AChE has been lowered acutely; (4) BChE inhibition may contribute to the respiratory toxicity of organophosphates.
ESTHER : Boudinot_2005_Pharmacol.Biochem.Behav_80_53
PubMedSearch : Boudinot_2005_Pharmacol.Biochem.Behav_80_53
PubMedID: 15652380

Title : Synaptic remodeling at the skeletal neuromuscular junction of acetylcholinesterase knockout mice and its physiological relevance - Girard_2005_Chem.Biol.Interact_157-158_87
Author(s) : Girard E , Barbier J , Chatonnet A , Krejci E , Molgo J
Ref : Chemico-Biological Interactions , 157-158 :87 , 2005
Abstract : Acute inhibition of synaptic acetylcholinesterase (AChE) is fatal to normal animals, but AChE-knockout mice (AChE-/-) expressing normal levels of butyrylcholinesterase (BChE) could live to adulthood without AChE expression. The present study was undertaken to determine whether compensatory mechanisms occur in the mutant that allow an effective neuromuscular transmission in the chronic absence of AChE. For this we evaluated neuromuscular transmission and the distribution of nicotinic acetylcholine receptors (nAChRs) and motor nerve terminals on isolated nerve-muscle preparations from AChE-/- mice. AChE-/- hemidiaphragm muscles maintained at 32 degrees C can support muscle twitches, and tetanic contractions during intermittent nerve-stimulation over a wide range of physiological frequencies, even though they develop less force, than age-matched wild-type (AChE+/+) muscles. Tetanic fade in AChE-/- muscles was temperature-sensitive and more marked at 22 degrees C than at 32 degrees C. Inhibition of BChE by tetraisopropylpyrophosphoramide (Iso-OMPA) intensified tetanic fade in AChE-/- muscles, but had no effect on AChE+/+ muscles, suggesting that BChE plays a protective role in nerve terminals. Skeletal muscles from AChE-/- mice adapted to the lack of AChE enzymatic activity by triggering a synaptic remodeling that critically occurred between the second and third week of postnatal development, during synapse elimination. In AChE-/- muscles nAChRs distributed in a smaller and fragmented surface area, that mirrored the branching pattern of motor nerve terminals. These findings indicate that the neuromuscular system exhibits a remarkable plasticity and adaptive responses to the chronic absence of AChE activity that has important consequences for the functioning of the neuromuscular junction.
ESTHER : Girard_2005_Chem.Biol.Interact_157-158_87
PubMedSearch : Girard_2005_Chem.Biol.Interact_157-158_87
PubMedID: 16274683

Title : Cholinesterase activity in human pulmonary arteries and veins: correlation with mRNA levels - Kotelevets_2005_Life.Sci_76_2211
Author(s) : Kotelevets L , Walch L , Chastre E , Chatonnet A , Dulmet E , Brink C , Norel X
Ref : Life Sciences , 76 :2211 , 2005
Abstract : Isolated intact human pulmonary arteries and veins were used to determine the acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) activities in the absence or presence of two selective cholinesterase (ChE) inhibitors, iso-OMPA or BW284c51, respectively. These results were compared with the mRNA levels for each enzyme in human pulmonary vessels. Total ChE activities measured in presence of acetylthiocholine (ACTI, 1 mM) in intact vascular preparations were 45+/-04 and 114+/-07 mU/g tissue in human pulmonary arteries (n=14) and veins (n=14), respectively. These activities were completely abolished in presence of 10 microM neostigmine. In both types of vessels AChE and BChE activities were observed. These activities were at least 2-fold higher in human pulmonary veins when compared with arteries and were correlated with the accumulation of the corresponding transcripts (n=8). In each type of vessel, similar total ChE activities were detected in homogenized and intact preparations, while in human bronchial preparations this activity was 5-fold higher in homogenates than in intact preparations. Together these results provide evidence that the ChE activities in human pulmonary vessels may be extracellular and that the higher activity measured in veins as compared to arteries was associated with the differential accumulation of the corresponding transcripts.
ESTHER : Kotelevets_2005_Life.Sci_76_2211
PubMedSearch : Kotelevets_2005_Life.Sci_76_2211
PubMedID: 15733936

Title : Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models - Cousin_2005_Bioessays_27_189
Author(s) : Cousin X , Strahle U , Chatonnet A
Ref : Bioessays , 27 :189 , 2005
Abstract : Acetylcholinesterase (AChE) hydrolyses acetylcholine (ACh) ensuring the fast clearance of released neurotransmitter at cholinergic synapses. Many studies led to the hypothesis that AChE and the closely related enzyme butyrylcholinesterase (BChE) may play other, non-hydrolytic roles during development. In this review, we compare data from in vivo studies performed on invertebrate and vertebrate genetic models. The loss of function of ache in these systems is responsible for the appearance of several phenotypes. In all aspects so far studied, the phenotypes can be explained by an excess of the undegraded substrate, ACh, leading to misfunction and pathological alterations. Thus, the lack of AChE catalytic activity in the mutants appears to be solely responsible for the observed phenotypes. None of them appears to require the postulated adhesive or other non-hydrolytic functions of AChE.
ESTHER : Cousin_2005_Bioessays_27_189
PubMedSearch : Cousin_2005_Bioessays_27_189
PubMedID: 15666354

Title : Poster (72) Evolution of the Carboxylesterase_B family -
Author(s) : Chatonnet A , Cousin X , Hotelier T
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :358 , 2004

Title : Poster (73) Respiratory survival mechanisms in acetylcholinesterase knockout mice. -
Author(s) : Chatonnet F , Boudinot E , Chatonnet A , Champagnat J , Foutz AS
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :359 , 2004

Title : Synaptic transmission at AChE\/- and CoIQ-I-knockout mouse neuromuscular junctions -
Author(s) : Minic J , Barbier J , Chatonnet A , Krejci E , Molgo J
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :19 , 2004

Title : Evolution of the Carboxylcsterase_b (CO esterase) family: The closest relatives of choIinesterases among alpha\/beta hydrolase fold family. hypothesis of horizontal transfer from eucaryotes to bacteria -
Author(s) : Chatonnet A , Cousin X , Hotelier T
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :75 , 2004

Title : Poster (7) Synaptic transmission at AChE-\/- and ColQ knockout mouse neuromuscular junctions -
Author(s) : Minic J , Barbier J , Chatonnet A , Krejci E , Molgo J
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :324 , 2004

Title : Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice - Boudinot_2004_Respir.Physiol.Neurobiol_140_231
Author(s) : Boudinot E , Emery MJ , Mouisel E , Chatonnet A , Champagnat J , Escourrou P , Foutz AS
Ref : Respir Physiol Neurobiol , 140 :231 , 2004
Abstract : To investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control.
ESTHER : Boudinot_2004_Respir.Physiol.Neurobiol_140_231
PubMedSearch : Boudinot_2004_Respir.Physiol.Neurobiol_140_231
PubMedID: 15186785

Title : Breathing without acetylcholinesterase -
Author(s) : Chatonnet F , Boudinot E , Chatonnet A , Champagnat J , Foutz AS
Ref : Advances in Experimental Medicine & Biology , 551 :165 , 2004
PubMedID: 15602959

Title : ESTHER, the database of the alpha\/beta-hydrolase fold superfamily of proteins - Hotelier_2004_Nucleic.Acids.Res_32_D145
Author(s) : Hotelier T , Renault L , Cousin X , Negre V , Marchot P , Chatonnet A
Ref : Nucleic Acids Research , 32 :D145 , 2004
Abstract : The alpha/beta-hydrolase fold is characterized by a beta-sheet core of five to eight strands connected by alpha-helices to form a alpha/beta/alpha sandwich. In most of the family members the beta-strands are parallels, but some show an inversion in the order of the first strands, resulting in antiparallel orientation. The members of the superfamily diverged from a common ancestor into a number of hydrolytic enzymes with a wide range of substrate specificities, together with other proteins with no recognized catalytic activity. In the enzymes the catalytic triad residues are presented on loops, of which one, the nucleophile elbow, is the most conserved feature of the fold. Of the other proteins, which all lack from one to all of the catalytic residues, some may simply be 'inactive' enzymes while others are known to be involved in surface recognition functions. The ESTHER database (http:\/\/ gathers and annotates all the published information related to gene and protein sequences of this superfamily, as well as biochemical, pharmacological and structural data, and connects them so as to provide the bases for studying structure-function relationships within the family. The most recent developments of the database, which include a section on human diseases related to members of the family, are described.
ESTHER : Hotelier_2004_Nucleic.Acids.Res_32_D145
PubMedSearch : Hotelier_2004_Nucleic.Acids.Res_32_D145
PubMedID: 14681380

Title : Poster (12) Acetylcholinesterase is required for neuronal and muscular development in the zebra fish embryo -
Author(s) : Behra M , Cousin X , Etard C , Bertrand C , Vonesch JL , Biellmann D , Chatonnet A , Strahle U
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :327 , 2004
Gene_locus related to this paper: danre-ACHE

Title : A zebrafish mutant as a model for an acetylcholinesterase-deficient vertebrate. -
Author(s) : Behra M , Cousin X , Bertrand C , Vonesch JL , Chatonnet A , Strahle U
Ref : Cholinergic Mechanisms, CRC Press :467 , 2004
Gene_locus related to this paper: danre-ACHE

Title : Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia - Simpson_2003_Am.J.Hum.Genet_73_1147
Author(s) : Simpson MA , Cross H , Proukakis C , Pryde A , Hershberger R , Chatonnet A , Patton MA , Crosby AH
Ref : American Journal of Human Genetics , 73 :1147 , 2003
Abstract : Mast syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia that is present at high frequency among the Old Order Amish. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Patients have a thin corpus callosum and white-matter abnormalities, as seen on magnetic resonance imaging. Using an extensive Amish pedigree, we have mapped the Mast syndrome locus (SPG21) to a small interval of chromosome 15q22.31 that encompasses just three genes. Sequence analysis of the three transcripts revealed that all 14 affected cases were homozygous for a single base-pair insertion (601insA) in the acid-cluster protein of 33 kDa (ACP33) gene. This frameshift results in the premature termination (fs201-212X213) of the encoded product, which is designated "maspardin" (Mast syndrome, spastic paraplegia, autosomal recessive with dementia), and has been shown elsewhere to localize to intracellular endosomal/trans-Golgi transportation vesicles and may function in protein transport and sorting.
ESTHER : Simpson_2003_Am.J.Hum.Genet_73_1147
PubMedSearch : Simpson_2003_Am.J.Hum.Genet_73_1147
PubMedID: 14564668
Gene_locus related to this paper: human-SPG21

Title : Respiratory survival mechanisms in acetylcholinesterase knockout mouse - Chatonnet_2003_Eur.J.Neurosci_18_1419
Author(s) : Chatonnet F , Boudinot E , Chatonnet A , Taysse L , Daulon S , Champagnat J , Foutz AS
Ref : European Journal of Neuroscience , 18 :1419 , 2003
Abstract : Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. AChE-/- mice presented no AChE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 microg/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate AChE-/- mice without affecting littermate AChE+/+ and +/- animals. In vitro, bath-applied bambuterol (1-100 microm) and tetraisopropylpyrophosphoramide (10-100 microm) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 microm) and nicotine (0.5-10 microm) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE+/+ and +/- animals. These effects were greatly attenuated in AChE-/- animals. The results suggest that, in mice lacking AChE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.
ESTHER : Chatonnet_2003_Eur.J.Neurosci_18_1419
PubMedSearch : Chatonnet_2003_Eur.J.Neurosci_18_1419
PubMedID: 14511322

Title : Butyrylcholinesterase and acetylcholinesterase activity and quantal transmitter release at normal and acetylcholinesterase knockout mouse neuromuscular junctions - Minic_2003_Br.J.Pharmacol_138_177
Author(s) : Minic J , Chatonnet A , Krejci E , Molgo J
Ref : British Journal of Pharmacology , 138 :177 , 2003
Abstract : 1 The present study was performed to evaluate the presence and the physiological consequences of butyrylcholinesterase (BChE) inhibition on isolated phrenic-hemidiaphragm preparations from normal mice expressing acetylcholinesterase (AChE) and BChE, and from AChE-knockout mice (AChE(-/-)) expressing only BChE. 2 Histochemical and enzymatic assays revealed abundance of AChE and BChE in normal mature neuromuscular junctions (NMJs). 3 In normal NMJs, in which release was reduced by low Ca(2+)/high Mg(2+) medium BChE inhibition with tetraisopropylpyrophosphoramide (iso-OMPA) or bambuterol decreased ( approximately 50%) evoked quantal release, while inhibition of AChE with fasciculin-1, galanthamine (10, 20 micro M) or neostigmine (0.1-1 micro M) increased (50-80%) evoked quantal release. Inhibition of both AChE and BChE with galanthamine (80 micro M), neostigmine (3-10 micro M), O-ethylS-2-(diisopropylamino)ethyl-methylphosphono-thioate (MTP) or phospholine decreased evoked transmitter release (20-50%). 4 In AChE(-/-) NMJs, iso-OMPA pre-treatment decreased evoked release. 5 Muscarinic toxin-3 decreased evoked release in both AChE(-/-) and normal NMJs treated with low concentrations of neostigmine, galanthamine or fasciculin-1, but had no effect in normal NMJs pretreated with iso-OMPA, bambuterol, MTP and phospholine. 6 In normal and AChE(-/-) NMJs pretreatment with iso-OMPA failed to affect the time course of miniature endplate potentials and full-sized endplate potentials. 7 Overall, our results suggest that inhibition or absence of AChE increases evoked quantal release by involving muscarinic receptors (mAChRs), while BChE inhibition decreases release through direct or indirect mechanisms not involving mAChRs. BChE apparently is not implicated in limiting the duration of acetylcholine action on postsynaptic receptors, but is involved in a presynaptic modulatory step of the release process.
ESTHER : Minic_2003_Br.J.Pharmacol_138_177
PubMedSearch : Minic_2003_Br.J.Pharmacol_138_177
PubMedID: 12522088

Title : Acetylcholinesterase is required for neuronal and muscular development in the zebrafish embryo - Behra_2002_Nat.Neurosci_5_111
Author(s) : Behra M , Cousin X , Bertrand C , Vonesch JL , Biellmann D , Chatonnet A , Strahle U
Ref : Nat Neurosci , 5 :111 , 2002
Abstract : The neurotransmitter acetylcholine (ACh) has a crucial role in central and neuromuscular synapses of the cholinergic system. After release into the synaptic cleft, ACh is rapidly degraded by acetylcholinesterase (AChE). We have identified a mutation in the ache gene of the zebrafish, which abolishes ACh hydrolysis in homozygous animals completely. Embryos are initially motile but subsequently develop paralysis. Mutant embryos show defects in muscle fiber formation and innervation, and primary sensory neurons die prematurely. The neuromuscular phenotype in ache mutants is suppressed by a homozygous loss-of-function allele of the alpha-subunit of the nicotinic acetylcholine receptor (nAChR), indicating that the impairment of neuromuscular development is mediated by activation of nAChR in the mutant. Here we provide genetic evidence for non-classical functions of AChE in vertebrate development.
ESTHER : Behra_2002_Nat.Neurosci_5_111
PubMedSearch : Behra_2002_Nat.Neurosci_5_111
PubMedID: 11753420
Gene_locus related to this paper: danre-ACHE

Title : Links between kinetic data and sequences in the alpha\/beta-hydrolases fold database - Chatonnet_2001_Brief.Bioinform_2_30
Author(s) : Chatonnet A , Cousin X , Robinson A
Ref : Brief Bioinform , 2 :30 , 2001
Abstract : While the number of sequenced genes is increasing dramatically, the number of different protein structural families is expected to be more limited. Changes in enzymatic activity or protein interactions can dramatically modify the role of homologous proteins in different organisms or mutants. However, experimental data associated with sequences or mutations stored in databases are often limited to a short description of the enzymatic pathway, molecular interaction or phenotype associated with the changes in amino acid sequence. In the alpha/beta-hydrolases fold database ESTHER, we are experimenting with links between experimental kinetic data and sequences, mutations and protein structures. This effort will lead to the integration of pharmacological data with genome-wide databases.
ESTHER : Chatonnet_2001_Brief.Bioinform_2_30
PubMedSearch : Chatonnet_2001_Brief.Bioinform_2_30
PubMedID: 11465060

Title : Zebrafish acetylcholinesterase is encoded by a single gene localized on linkage group 7. Gene structure and polymorphism\; molecular forms and expression pattern during development - Bertrand_2001_J.Biol.Chem_276_464
Author(s) : Bertrand C , Chatonnet A , Takke C , Yan YL , Postlethwait J , Toutant JP , Cousin X
Ref : Journal of Biological Chemistry , 276 :464 , 2001
Abstract : We cloned and sequenced the acetylcholinesterase gene and cDNA of zebrafish, Danio rerio. We found a single gene (ache) located on linkage group LG7. The relative organization of ache, eng2, and shh genes is conserved between zebrafish and mammals and defines a synteny. Restriction fragment length polymorphism analysis was allowed to identify several allelic variations. We also identified two transposable elements in non-coding regions of the gene. Compared with other vertebrate acetylcholinesterase genes, ache gene contains no alternative splicing at 5' or 3' ends where only a T exon is present. The translated sequence is 60-80% identical to acetylcholinesterases of the vertebrates and exhibits an extra loop specific to teleosts. Analysis of molecular forms showed a transition, at the time of hatching, from the globular G4 form to asymmetric A12 form that becomes prominent in adults. In situ hybridization and enzymatic activity detection on whole embryos confirmed early expression of the acetylcholinesterase gene in nervous and muscular tissues. We found no butyrylcholinesterase gene or activity in Danio. These findings make zebrafish a promising model to study function of acetylcholinesterase during development and regulation of molecular forms assembly in vivo.
ESTHER : Bertrand_2001_J.Biol.Chem_276_464
PubMedSearch : Bertrand_2001_J.Biol.Chem_276_464
PubMedID: 11016933
Gene_locus related to this paper: danre-ACHE , danre-Q6P004

Title : Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase - Xie_2000_J.Pharmacol.Exp.Ther_293_896
Author(s) : Xie W , Stribley JA , Chatonnet A , Wilder PJ , Rizzino A , McComb RD , Taylor P , Hinrichs SH , Lockridge O
Ref : Journal of Pharmacology & Experimental Therapeutics , 293 :896 , 2000
Abstract : Acetylcholinesterase (AChE; EC is the primary terminator of nerve impulse transmission at cholinergic synapses and is believed to play an important role in neural development. Targeted deletion of four exons of the ACHE gene reduced AChE activity by half in heterozygous mutant mice and totally eliminated AChE activity in nullizygous animals. Butyrylcholinesterase (EC activity was normal in AChE -/- mice. Although nullizygous mice were born alive and lived up to 21 days, physical development was delayed. The neuromuscular junction of 12-day-old nullizygous animals appeared normal in structure. Nullizygous mice were highly sensitive to the toxic effects of the organophosphate diisopropylfluorophosphate and to the butyrylcholinesterase-specific inhibitor bambuterol. These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE and that the inhibition of targets other than AChE by organophosphorus agents results in death.
ESTHER : Xie_2000_J.Pharmacol.Exp.Ther_293_896
PubMedSearch : Xie_2000_J.Pharmacol.Exp.Ther_293_896
PubMedID: 10869390
Gene_locus related to this paper: mouse-ACHE

Title : Kinetic parameters of cholinesterase interactions with organophosphates: retrieval and comparison tools available through ESTHER database: ESTerases, alpha\/beta Hydrolase Enzymes and Relatives - Chatonnet_1999_Chem.Biol.Interact_119-120_567
Author(s) : Chatonnet A , Hotelier T , Cousin X
Ref : Chemico-Biological Interactions , 119-120 :567 , 1999
Abstract : Cholinesterases are targets for organophosphorus compounds which are used as insecticides, chemical warfare agents and drugs for the treatment of disease such as glaucoma, or parasitic infections. The widespread use of these chemicals explains the growing of this area of research and the ever increasing number of sequences, structures, or biochemical data available. Future advances will depend upon effective management of existing information as well as upon creation of new knowledge. The ESTHER database goal is to facilitate retrieval and comparison of data about structure and function of proteins presenting the alpha/beta hydrolase fold. Protein engineering and in vitro production of enzymes allow direct comparison of biochemical parameters. Kinetic parameters of enzymatic reactions are now included in the database. These parameters can be searched and compared with a table construction tool. ESTHER can be reached through internet ( The full database or the specialised X-window Client-server system can be downloaded from our ftp server ( Forms can be used to send updates or corrections directly from the web.
ESTHER : Chatonnet_1999_Chem.Biol.Interact_119-120_567
PubMedSearch : Chatonnet_1999_Chem.Biol.Interact_119-120_567
PubMedID: 10421496

Title : Knockout of one acetylcholinesterase allele in the mouse - Xie_1999_Chem.Biol.Interact_119-120_289
Author(s) : Xie W , Wilder PJ , Stribley J , Chatonnet A , Rizzino A , Taylor P , Hinrichs SH , Lockridge O
Ref : Chemico-Biological Interactions , 119-120 :289 , 1999
Abstract : One allele of the AChE gene (ACHE) was knocked out in embryonic stem (ES) cells by homologous recombination. The targeting vector contained 2 kb of a TK gene cassette for negative selection, 884 bp of ACHE including exon 1, 1.6 kb of a Neo(r) gene cassette for positive selection, 5.2 kb of the ACHE Bam HI fragment including exon 6, and 3 kb of Bluescript. The use of this vector deleted exons 2-5, which removed 93% of the ACHE coding sequence including the signal peptide, the active site serine, and the histidine and glutamic acid of the catalytic triad. The gene targeting vector was transfected into ES cells by electroporation. Colonies resistant to G418 and gancyclovir were screened for homologous recombination by Southern blotting. Out of 200 colonies, four were found to have undergone homologous recombination. These four ACHE (+/-) ES cell lines were expanded to provide cells for microinjection into C57Bl/6 mouse blastocysts. The injected blastocysts were implanted into pseudopregnant CD/l white mice. More than 200 injected blastocysts were transferred into 20 mice. More than 65 mice were born, of which 11 were chimeras. Chimeras were identified by their black and agouti coat color. Littermates were all black. Thus far, seven male chimeras have been bred with more than 130 C57Bl/6 females to generate 26 agouti mice out of 199 living offspring. This demonstrated that the ACHE (+/-) ES cells contributed to the germline. Offspring with agouti coat color have a 50% chance of carrying the knockout allele. The 26 agouti offspring were screened for an ACHE (+/-) genotype by tail biopsy PCR. Ten out of 26 agouti mice are heterozygous ACHE knockout mice, and they are healthy and alive at 29 days of age. We expect a phenotype to appear in nullizygous animals.
ESTHER : Xie_1999_Chem.Biol.Interact_119-120_289
PubMedSearch : Xie_1999_Chem.Biol.Interact_119-120_289
PubMedID: 10421464

Title : Acetylcholinesterase Expression During Development of Danio Rerio -
Author(s) : Bertrand C , Cousin X , Toutant JP , Chatonnet A
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :141 , 1998

Title : Comparison of the effects of mutations and inhibition or activation by cholinergic compounds on kinetic parameters of Acetylcholinesterase: The ESTHER database and server -
Author(s) : Chatonnet A , Hotelier T , Cousin X
Ref : Journal de Physiologie (Paris) , 92 :419 , 1998

Title : ESTHER 1998, aChEdb Short Tutorial -
Author(s) : Chatonnet A , Hotelier T , Cousin X
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :463 , 1998

Title : aCHEdb: the database system for ESTHER, the alpha\/beta fold family of proteins and the Cholinesterase gene server - Cousin_1998_Nucleic.Acids.Res_26_226
Author(s) : Cousin X , Hotelier T , Giles K , Toutant JP , Chatonnet A
Ref : Nucleic Acids Research , 26 :226 , 1998
Abstract : Acetylcholinesterase belongs to a family of proteins, the alpha/beta hydrolase fold family, whose constituents evolutionarily diverged from a common ancestor and share a similar structure of a central beta sheet surrounded by alpha helices. These proteins fulfil a wide range of physiological functions (hydrolases, adhesion molecules, hormone precursors) [Krejci,E., Duval,N., Chatonnet,A., Vincens,P. and Massouli,J. (1991) Proc. Natl. Acad. Sci. USA , 88, 6647-6651]. ESTHER (for esterases, alpha/beta hydrolase enzymes and relatives) is a database aimed at collecting in one information system, sequence data together with biological annotations and experimental biochemical results related to the structure-function analysis of the enzymes of the family. The major upgrade of the database comes from the use of a new database management system: aCHEdb which uses the ACeDB program designed by Richard Durbin and Jean Thierry-Mieg. It can be found at http:\/\/
ESTHER : Cousin_1998_Nucleic.Acids.Res_26_226
PubMedSearch : Cousin_1998_Nucleic.Acids.Res_26_226
PubMedID: 9399841

Title : Butyrylcholinesterase antisense transfection increases apoptosis in differentiating retinal reaggregates of the chick embryo - Robitzki_1998_J.Neurochem_71_1413
Author(s) : Robitzki AA , Mack A , Hoppe U , Chatonnet A , Layer PG
Ref : Journal of Neurochemistry , 71 :1413 , 1998
Abstract : To investigate the roles of the enzymes butyryl- and acetylcholinesterase (BChE and AChE) in retinal proliferation and differentiation, we use reaggregated spheres from retinal cells of the 6-day-old chick embryo, forming cellular and fibrous areas homologous to all layers of a normal retina. Recently, we could suppress BChE expression by transfecting these so-called retinospheroids during their proliferation period with a pSVK3 expression vector containing a 5' fragment of the rabbit BChE gene in antisense orientation. Along with morphological changes, proliferation was significantly decreased. Here, we have studied the effect of antisense BChE suppression during the differentiation period of retinospheroids. As BChE is suppressed, the differentiation of AChE-positive cells is increased, whereas the immunoreactivities for red and green cone-specific opsins are strongly reduced. Concomitantly, the rate of apoptosis as determined by propidium iodide uptake, by increased CPP 32-like caspase expression, and by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and DNA fragmentation assays is roughly doubled, predominantly at the expense of degenerating photoreceptor precursors. This is further strong evidence that the proliferation marker BChE regulates an intricate balance between cell proliferation, cell differentiation, and programmed cell death in this in vitro retinal system.
ESTHER : Robitzki_1998_J.Neurochem_71_1413
PubMedSearch : Robitzki_1998_J.Neurochem_71_1413
PubMedID: 9751172

Title : ACHE Knockout Mouse\; Cat AChE and Cat BChE Sequences\; Tetramers of BChE -
Author(s) : Lockridge O , Xie W , Chatonnet A , Taylor P , Bartels CF
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :41 , 1998

Title : The alpha\/beta hydrolase fold family of proteins database and the cholinesterase gene server ESTHER - Cousin_1997_Nucleic.Acids.Res_25_143
Author(s) : Cousin X , Hotelier T , Giles K , Lievin P , Toutant JP , Chatonnet A
Ref : Nucleic Acids Research , 25 :143 , 1997
Abstract : ESTHER (for esterases, alpha/betahydrolase enzyme and relatives) is a database of sequences phylogenetically related to cholinesterases. These sequences define a homogeneous group of enzymes (carboxylesterases, lipases and hormone-sensitive lipases) sharing a similar structure of a central beta-sheet surrounded by alpha-helices. Among these proteins a wide range of functions can be found (hydrolases, adhesion molecules, hormone precursors). The purpose of ESTHER is to help comparison of structures and functions of members of the family. Since the last release, new features have been added to the server. A BLAST comparison tool allows sequence homology searches within the database sequences. New sections are available: kinetics and inhibitors of cholinesterases, fasciculin-acetylcholinesterase interaction and a gene structure review. The mutation analysis compilation has been improved with three-dimensional images. A mailing list has been created.
ESTHER : Cousin_1997_Nucleic.Acids.Res_25_143
PubMedSearch : Cousin_1997_Nucleic.Acids.Res_25_143
PubMedID: 9016525

Title : Transfection of reaggregating embryonic chicken retinal cells with an antisense 5'-DNA butyrylcholinesterase expression vector inhibits proliferation and alters morphogenesis - Robitzki_1997_J.Neurochem_69_823
Author(s) : Robitzki AA , Mack A , Chatonnet A , Layer PG
Ref : Journal of Neurochemistry , 69 :823 , 1997
Abstract : The function of the enzyme butyrylcholinesterase (BChE) in the developing and mature brain is still unclear. We have inserted 577 bp of the 5' upstream region plus 106 bp of the exon 1 of the rabbit BChE gene in reverse orientation under control of an SV40 early promoter derivative in an expression vector. This vector was introduced by calcium phosphate-mediated transfection into embryonic chicken retina cells during the first days of reaggregation culture. Depending on the retinal origin, the transfected cell population forms histotypic retina-like spheres, so-called rosetted or stratified retinospheroids. We show that antisense 5'-BChE gene expression decreased the steady-state mRNA level of BChE and the translation of the BChE protein, inhibited proliferation, and accelerated histogenesis in both cellular systems. The pronounced effects of antisense 5'-BChE transfection of spheroids document a key role of BChE during the early reaggregation process of retinal cells, most likely by regulating their growth and differentiation.
ESTHER : Robitzki_1997_J.Neurochem_69_823
PubMedSearch : Robitzki_1997_J.Neurochem_69_823
PubMedID: 9231744

Title : Regulation of cholinesterase gene expression affects neuronal differentiation as revealed by transfection studies on reaggregating embryonic chicken retinal cells - Robitzki_1997_Eur.J.Neurosci_9_2394
Author(s) : Robitzki AA , Mack A , Hoppe U , Chatonnet A , Layer PG
Ref : European Journal of Neuroscience , 9 :2394 , 1997
Abstract : In the embryonic chicken neuroepithelium, butyrylcholinesterase (BChE) as a proliferation marker and then acetylcholinesterase (AChE) as a differentiation marker are expressed in a mutually exclusive manner. These and other data indicate a coregulation of cholinesterase expression, and also possible roles of cholinesterases during neurogenesis. Here, both aspects are investigated by two independent transfection protocols of dissociated retina cells of the 6-day-old chick embryo in reaggregation culture, both protocols leading to efficient overexpression of AChE protein. The effect of the overexpressed AChE protein on the re-establishment of retina-like three-dimensional networks (so-called retinospheroids) was studied. In a first approach, we transfected retinospheroids with a pSVK3 expression vector into which a cDNA construct encoding the entire rabbit AChE gene had been inserted in sense orientation. As detected at the mRNA level, rabbit AChE was heterologously overexpressed in chicken retinospheroids. Remarkably, this was accompanied by a strong increase in endogenous chicken AChE protein, while the total AChE activity was only slightly increased. This increase was due to chicken enzyme, as shown by species-specific inhibition studies using fasciculin. Clearly, total AChE activity is regulated post-translationally. As an alternative method of AChE overexpression, transfection of spheroids was performed with an antisense-5'-BChE vector, which not only resulted in the down-regulation of BChE expression, but also strongly increased chicken AChE transcripts, protein and enzyme activity. Histologically, a higher concentration of AChE protein (as a consequence of either AChE overexpression or BChE suppression) was associated with an advanced degree of tissue differentiation, as detected by immunostaining for the cytoskeletal protein vimentin.
ESTHER : Robitzki_1997_Eur.J.Neurosci_9_2394
PubMedSearch : Robitzki_1997_Eur.J.Neurosci_9_2394
PubMedID: 9464933

Title : A cholinesterase genes server (ESTHER): a database of cholinesterase-related sequences for multiple alignments, phylogenetic relationships,mutations and structural data retrieval. - Cousin_1996_Nucleic.Acids.Res_24_132
Author(s) : Cousin X , Hotelier T , Lievin P , Toutant JP , Chatonnet A
Ref : Nucleic Acids Research , 24 :132 , 1996
Abstract : We have built a database of sequences phylogenetically related to cholinesterases (ESTHER) for esterases, alpha/beta hydrolase enzymes and relatives). These sequences define a homogeneous group of enzymes (carboxylesterases, lipases and hormone-sensitive lipases) with some related proteins devoid of enzymatic activity. The purpose of ESTHER is to help comparison and alignment of any new sequence appearing in the field, to favour mutation analysis of structure-function relationships and to allow structural data recovery. ESTHER is a World Wide Web server with the URL
ESTHER : Cousin_1996_Nucleic.Acids.Res_24_132
PubMedSearch : Cousin_1996_Nucleic.Acids.Res_24_132
PubMedID: 8594562

Title : Properties of Class a Acetylcholinesterase, the Enzyme Encoded by ACE-1 in Caenorhabditis elegans -
Author(s) : Arpagaus M , Schirru N , Culetto E , Talesa V , Cousin X , Chatonnet A , Fedon Y , Berge JB , Fournier D , Toutant JP
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :7 , 1995

Title : Butyrylcholinesterase Transcription Start Site and Promoter -
Author(s) : Jbilo O , Toutant JP , Chatonnet A , Lockridge O
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :23 , 1995

Title : A Database of Sequences Related to AcetylcholinesteraselLipase\/alpha:beta Hydrolase Superfamily with Public Access on Internet -
Author(s) : Cousin X , Hotelier T , Mazzoni C , Arpagaus M , Toutant JP , Chatonnet A
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :489 , 1995

Title : Acetylcholinesterase and Butyrylcholinesterase Expression in Adult Rabbit Tissues and during Development -
Author(s) : Jbilo O , L'Hermite Y , Talesa V , Toutant JP , Chatonnet A
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :49 , 1995

Title : cDNA sequence, gene structure, and in vitro expression of ace-1, the gene encoding acetylcholinesterase of class A in the nematode Caenorhabditis elegans - Arpagaus_1994_J.Biol.Chem_269_9957
Author(s) : Arpagaus M , Fedon Y , Cousin X , Chatonnet A , Berge JB , Fournier D , Toutant JP
Ref : Journal of Biological Chemistry , 269 :9957 , 1994
Abstract : Three genes, ace-1, ace-2, and ace-3, encode three acetylcholinesterase classes (A, B, and C) in the nematode Caenorhabditis elegans. A fragment of genomic DNA was amplified by a polymerase chain reaction (PCR) using degenerate oligonucleotides based on sequences conserved in the cholinesterase family. This fragment mapped to chromosome X at a position that perfectly matched the location of ace-1 previously determined by genetic methods. Comparison of genomic and cDNA sequences showed that the open reading frame was interrupted by eight introns. The product of ace-1 (ACE-1, 620 amino acids) presented 42% identity with Torpedo and human acetylcholinesterases, 41% with human butyrylcholinesterase, and 35% with Drosophila acetylcholinesterase. The overall structure of cholinesterases was conserved in ACE-1 as indicated by the conserved sequence positions of Ser-216, His-468, and Glu-346 (S200, H440, E327 in Torpedo (AChE) as components of the catalytic triad, of the six cysteines which form three intrachain disulfide bonds, and of Trp-99(84), a critical side chain in the choline binding site. Spodoptera Sf9 cells were infected by a recombinant baculovirus containing ace-1 cDNA. The secreted enzyme was active and existed as hydrophilic 5 and 11.5 S molecular forms. It hydrolyzed both acetylthiocholine and butyrylthiocholine and was inhibited by acetylthiocholine above 10 mM.
ESTHER : Arpagaus_1994_J.Biol.Chem_269_9957
PubMedSearch : Arpagaus_1994_J.Biol.Chem_269_9957
PubMedID: 8144590
Gene_locus related to this paper: caeel-ACHE1

Title : Promoter and transcription start site of human and rabbit butyrylcholinesterase genes - Jbilo_1994_J.Biol.Chem_269_20829
Author(s) : Jbilo O , Toutant JP , Vatsis KP , Chatonnet A , Lockridge O
Ref : Journal of Biological Chemistry , 269 :20829 , 1994
Abstract : Two kilobase segments of the 5'-untranslated regions of the human and rabbit butyrylcholinesterase (BCHE) genes were characterized. The sequences shared extensive identity except for a 333-base pair (bp) Alu repeat present only in human BCHE. One single transcription start site was found in both genes with the techniques of primer extension, amplification of the 5'-end of mRNA, and RNase protection. Cap sites in human and rabbit BCHE genes were found in strictly homologous positions. In human BCHE, the transcription start site was found 157 bp upstream of Met-28, the translation start site. Potential regulatory elements in both promoters included one AP1 site and multiple sites for topoisomerase, Oct-1 and PEA-3. Transient expression of BCHE-reporter gene constructs showed that a 194-bp fragment of the 5'-flanking region of human BCHE and a 570-bp fragment of rabbit BCHE were sufficient for promoting chloramphenicol acetyltransferase activity in HeLa cells. No consensus TATA and CAAT boxes were found. However, the sequence around the transcription start site exhibited homology with initiator elements found in other TATA-less promoters in developmentally regulated genes.
ESTHER : Jbilo_1994_J.Biol.Chem_269_20829
PubMedSearch : Jbilo_1994_J.Biol.Chem_269_20829
PubMedID: 8063698

Title : Acetylcholinesterase and butyrylcholinesterase expression in adult rabbit tissues and during development - Jbilo_1994_Eur.J.Biochem_225_115
Author(s) : Jbilo O , L'Hermite Y , Talesa V , Toutant JP , Chatonnet A
Ref : European Journal of Biochemistry , 225 :115 , 1994
Abstract : A large cDNA fragment covering the complete sequence of the mature catalytic subunit of rabbit acetylcholinesterase (AChE) has been cloned and sequenced. This sequence was compared to that of rabbit butyrylcholinesterase [BChE; Jbilo, O. & Chatonnet, A. (1990) Nucleic Acids Res. 18, 3990]. Amino acid sequences of AChE and BChE have 51% identity. They both possessed a choline-binding site W84, a catalytic triad S200-H440-E327 and six cysteine residues (positions 67-94, 254-265, 402-521) in conserved sequence positions to those that form three intrachain disulfide bonds in all cholinesterases (by convention, numbering of amino acids is that used for Torpedo AChE). Rabbit AChE had a larger number of aromatic residues lining the active-site gorge than rabbit BChE (14 compared to 8, respectively) and a smaller number of potential N-glycosylation sites (3 compared to 8, respectively). Both catalytic subunits have a hydrophilic C-terminus (catalytic subunits of type T). Expression of acetylcholinesterase and butyrylcholinesterase genes (ACHE and BCHE) was studied in rabbit tissues and during development by a correlation of Northern-blot analysis and enzymic activities. This correlation was rendered difficult by the presence of an eserine-resistant esterase active on butyrylthiocholine in serum, liver and lung. When the contribution of this carboxylesterase was taken into account, brain was found as the richest source of BChE followed by lung and heart. Rabbit liver had a very low content of BChE that correlated with the low BChE activity in plasma. During development, BCHE transcripts were detected as early as day 10 post coitum, whereas ACHE transcripts appeared only on day 12.
ESTHER : Jbilo_1994_Eur.J.Biochem_225_115
PubMedSearch : Jbilo_1994_Eur.J.Biochem_225_115
PubMedID: 7925428
Gene_locus related to this paper: rabit-ACHE , rabit-BCHE

Title : Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA - Jbilo_1994_Toxicon_32_1445
Author(s) : Jbilo O , Bartels CF , Chatonnet A , Toutant JP , Lockridge O
Ref : Toxicon , 32 :1445 , 1994
Abstract : Cholinesterase inhibitors occur naturally in the calabar bean (eserine), green potatoes (solanine), insect-resistant crab apples, the coca plant (cocaine) and snake venom (fasciculin). There are also synthetic cholinesterase inhibitors, for example man-made insecticides. These inhibitors inactivate acetylcholinesterase and butyrylcholinesterase as well as other targets. From a study of the tissue distribution of acetylcholinesterase and butyrylcholinesterase mRNA by Northern blot analysis, we have found the highest levels of butyrylcholinesterase mRNA in the liver and lungs, tissues known as the principal detoxication sites of the human body. These results indicate that butyrylcholinesterase may be a first line of defense against poisons that are eaten or inhaled.
ESTHER : Jbilo_1994_Toxicon_32_1445
PubMedSearch : Jbilo_1994_Toxicon_32_1445
PubMedID: 7886701

Title : Expression of acetylcholinesterase gene during in vitro differentiation of rabbit muscle satellite cells - Barjot_1993_Neuromuscul.Disord_3_443
Author(s) : Barjot C , Jbilo O , Chatonnet A , Bacou F
Ref : Neuromuscular Disorders , 3 :443 , 1993
Abstract : We investigated the myogenic properties and the expression of acetylcholinesterase (AChE) in culture of satellite cells (SCs) isolated from slow and fast rabbit muscles. Slow SCs form myotubes more rapidly (day 9 vs day 11) than fast SCs, and differentiate further into striated and contractile fibers. AChE activity and mRNA expression are higher in SCs cultured from slow than from fast muscles, as also observed in the muscles themselves. However, the two types of SC cultures do not show obvious difference in their patterns of AChE molecular forms. Taken together, these preliminary data support the view that there might be more than one SC population in skeletal muscles.
ESTHER : Barjot_1993_Neuromuscul.Disord_3_443
PubMedSearch : Barjot_1993_Neuromuscul.Disord_3_443
PubMedID: 8186690

Title : Localization of acetylcholinesterase activity and mRNA in the rabbit embryo between 10 and 15 days - Vigneron_1993_Neuromuscul.Disord_3_447
Author(s) : Vigneron P , Jbilo O , Chatonnet A
Ref : Neuromuscular Disorders , 3 :447 , 1993
Abstract : Histoenzymatic methods and in situ hybridization were used to follow AChE expression in rabbit embryos from 10 to 15 days. Transcripts of AChE are detected at the same developmental stages in all structures where enzymatic activity is found, except in neuronal extension and the ventral part of mesonephros. AChE and BChE expression were compared. BChE transcripts are detected before BChE activity can be revealed in blood cells and mesonephros.
ESTHER : Vigneron_1993_Neuromuscul.Disord_3_447
PubMedSearch : Vigneron_1993_Neuromuscul.Disord_3_447
PubMedID: 8186691

Title : Poster: Phylogeny of cholinesterases inferred by maximum parsimony method or distance matrix methods (Fitch-Margoliash and Neighbor Joining Methods) -
Author(s) : Cousin X , Toutant JP , Jbilo O , Chatonnet A , Arpagaus M
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :195 , 1991

Title : Poster: Use of the polymerase chain reaction for homology probing of butyrylchoIinesterase (BCHE) in several animal species -
Author(s) : Arpagaus M , Vaughan TA , La Du BN , Lockridge O , Masson P , Chatonnet A , Newton M , Taylor P
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :194 , 1991

Title : Poster: Structure of rabbit butyrylchoIinesterase gene: description of a repetitive short interspersed element (SINE) specific of rabbit genome -
Author(s) : Jbilo O , Lorca T , Barakat A , Chatonnet A
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :188 , 1991

Title : Poster: Search for alternative splicing of butyrylcholinesterase transcripts -
Author(s) : Jbilo O , Chatonnet A , Arpagaus M , Lockridge O
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :187 , 1991

Title : Cholinesterase-like domains in enzymes and structural proteins: functional and evolutionary relationships and identification of a catalytically essential aspartic acid - Krejci_1991_Proc.Natl.Acad.Sci.U.S.A_88_6647
Author(s) : Krejci E , Duval N , Chatonnet A , Vincens P , Massoulie J
Ref : Proceedings of the National Academy of Sciences of the United States of America , 88 :6647 , 1991
Abstract : Primary sequences of cholinesterases and related proteins have been systematically compared. The cholinesterase-like domain of these proteins, about 500 amino acids, may fulfill a catalytic and a structural function. We identified an aspartic acid residue that is conserved among esterases and lipases (Asp-397 in Torpedo acetylcholinesterase) but that had not been considered to be involved in the catalytic mechanism. Site-directed mutagenesis demonstrated that this residue is necessary for activity. Analysis of evolutionary relationships shows that the noncatalytic members of the family do not constitute a separate subgroup, suggesting that loss of catalytic activity occurred independently on several occasions, probably from bifunctional molecules. Cholinesterases may thus be involved in cell-cell interactions in addition to the hydrolysis of acetylcholine. This would explain their specific expression in well-defined territories during embryogenesis before the formation of cholinergic synapses and their presence in noncholinergic tissues.
ESTHER : Krejci_1991_Proc.Natl.Acad.Sci.U.S.A_88_6647
PubMedSearch : Krejci_1991_Proc.Natl.Acad.Sci.U.S.A_88_6647
PubMedID: 1862088

Title : Rabbit Butyrylcholinesterase Gene: An Evolutionary Perspective -
Author(s) : Chatonnet A , Jbilo O
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :157 , 1991

Title : Structure of rabbit butyrylcholinesterase gene deduced from genomic clones and from cDNA with introns - Chatonnet_1991_Cell.Mol.Neurobiol_11_119
Author(s) : Chatonnet A , Lorca T , Barakat A , Aron E , Jbilo O
Ref : Cellular Molecular Neurobiology , 11 :119 , 1991
Abstract : 1. Three clones were isolated from a rabbit genomic library. They covered the entire coding sequence of the rabbit BChE gene. The positions of splice sites between exons 2, 3, and 4 are identical to those found in the human gene (Arpagaus et al., 1990). Exon 2 covers 83% of the coding sequence. This contrasts with the small size of exon 3 (167 bp) and large size of introns 2 and 3 (greater than 20 kb each). The active-site serine at position 198 is found in a highly conserved region. Aspartic acids in positions 91 and 170 are conserved in human and rabbit, and one of them could be involved in the calytic triad. Aspartic acid 70, present in the anionic site of human BChE, is also conserved in rabbit BChE. The coding sequences of human and rabbit BChE are 89% identical over 744 bp around the active-site serine. 2. In addition to the genomic clones, one cDNA clone (BNY1) was isolated. This cDNA was unusual in that it contained intronic sequences. The insert of 1 kb contained 167 coding bases homologous to the nucleotide sequence 1434 to 1600 of human cDNA and corresponded to exon 3 of the BChE gene. On each side of this coding region, consensus sequences of intron-exon boundaries were found. 3. The presence of large-size transcripts in Northern blots and the existence of a cDNA copy of unprocessed mRNA found in the BNY1 clone suggest a slow processing of transcripts. A genomic sequence unspliced in a cDNA of Torpedo AChE could give a transmembrane domain (Sikorav et al., 1988); the corresponding sequence in rabbit BChE gene, also found in a cDNA, had no homology with Torpedo AChE but could be translated in a hydrophobic C-terminal domain if maintained in mature mRNA.
ESTHER : Chatonnet_1991_Cell.Mol.Neurobiol_11_119
PubMedSearch : Chatonnet_1991_Cell.Mol.Neurobiol_11_119
PubMedID: 2013056

Title : Use of the polymerase chain reaction for homology probing of butyrylcholinesterase from several vertebrates - Arpagaus_1991_J.Biol.Chem_266_6966
Author(s) : Arpagaus M , Chatonnet A , Masson P , Newton M , Vaughan TA , Bartels CF , Nogueira CP , La Du BN , Lockridge O
Ref : Journal of Biological Chemistry , 266 :6966 , 1991
Abstract : Genomic blots from man, monkey, cow, sheep, pig, rabbit, dog, rat, mouse, guinea pig, and chicken DNA were hybridized with probes derived from the four exons of the human butyrylcholinesterase gene (BCHE) (Arpagaus, M., Kott, M., Vatsis, K. P., Bartels, C. F., La Du, B. N., and Lockridge, O. (1990) Biochemistry 29, 124-131). Results showed that the BCHE gene was present in a single copy in the genome of all these vertebrates. The polymerase chain reaction was used to amplify genomic DNA from these animals with oligonucleotides derived from the human BCHE coding sequence. The amplified segment contained 423 bp of BCHE sequence including the active site serine of the enzyme (amino acid 198) and a component of the anionic site, aspartate 70. Amplification was successful for monkey, pig, cow, dog, sheep, and rabbit DNA, but unsuccessful for rat, guinea pig, mouse, and chicken DNA. Amplified segments were cloned in M13 and sequenced. The mouse sequence was obtained by sequencing a genomic clone. The highest identity of the human amino acid sequence was found with monkey (100%) and the lowest with mouse (91.5%). The sequence around the active site serine 198, Phe-Gly-Glu-Ser-Ala-Gly-Ala, was conserved in all eight animals as was the anionic site component, aspartate 70. A phylogenetic tree of mammalian butyrylcholinesterases was constructed using the partial BCHE sequences.
ESTHER : Arpagaus_1991_J.Biol.Chem_266_6966
PubMedSearch : Arpagaus_1991_J.Biol.Chem_266_6966
PubMedID: 2016308
Gene_locus related to this paper: bovin-BCHE , canfa-BCHE , macmu-BCHE , pig-BCHE , sheep-BCHE

Title : Evidence for a single butyrylcholinesterase gene in individuals carrying the C5 plasma cholinesterase variant (CHE2) - Masson_1990_FEBS.Lett_262_115
Author(s) : Masson P , Chatonnet A , Lockridge O
Ref : FEBS Letters , 262 :115 , 1990
Abstract : DNA of 3 unrelated individuals carrying the human plasma butyrylcholinesterase C5 variant (CHE2) was isolated from white blood cells. Southern blot patterns of DNA restriction fragments probed with each of the 4 butyrylcholinesterase exons provided evidence that the production of C5 is not directed by a second butyrylcholinesterase gene. This finding supports the suggestion that the C5 variant is a hybrid enzyme resulting from the association of butyrylcholinesterase subunits with a non-cholinesterase protein.
ESTHER : Masson_1990_FEBS.Lett_262_115
PubMedSearch : Masson_1990_FEBS.Lett_262_115
PubMedID: 2318303

Title : Complete sequence of rabbit butyrylcholinesterase -
Author(s) : Jbilo O , Chatonnet A
Ref : Nucleic Acids Research , 18 :3990 , 1990
PubMedID: 2374720
Gene_locus related to this paper: rabit-BCHE

Title : Comparison of butyrylcholinesterase and acetylcholinesterase. -
Author(s) : Chatonnet A , Lockridge O
Ref : Biochemical Journal , 260 :625 , 1989
PubMedID: 2669736

Title : Brain cDNA clone for human cholinesterase - McTiernan_1987_Proc.Natl.Acad.Sci.U.S.A_84_6682
Author(s) : McTiernan C , Adkins S , Chatonnet A , Vaughan TA , Bartels CF , Kott M , Rosenberry TL , La Du BN , Lockridge O
Ref : Proceedings of the National Academy of Sciences of the United States of America , 84 :6682 , 1987
Abstract : A cDNA library from human basal ganglia was screened with oligonucleotide probes corresponding to portions of the amino acid sequence of human serum cholinesterase (EC Five overlapping clones, representing 2.4 kilobases, were isolated. The sequenced cDNA contained 207 base pairs of coding sequence 5' to the amino terminus of the mature protein in which there were four ATG translation start sites in the same reading frame as the protein. Only the ATG coding for Met-(-28) lay within a favorable consensus sequence for functional initiators. There were 1722 base pairs of coding sequence corresponding to the protein found circulating in human serum. The amino acid sequence deduced from the cDNA exactly matched the 574 amino acid sequence of human serum cholinesterase, as previously determined by Edman degradation. Therefore, our clones represented cholinesterase (EC rather than acetylcholinesterase (EC It was concluded that the amino acid sequences of cholinesterase from two different tissues, human brain and human serum, were identical. Hybridization of genomic DNA blots suggested that a single gene, or very few genes, coded for cholinesterase.
ESTHER : McTiernan_1987_Proc.Natl.Acad.Sci.U.S.A_84_6682
PubMedSearch : McTiernan_1987_Proc.Natl.Acad.Sci.U.S.A_84_6682
PubMedID: 3477799
Gene_locus related to this paper: human-BCHE

Title : Is the peptidase activity of highly purified human plasma cholinesterase due to a specific cholinesterase isoenzyme or a contaminating dipeptidylaminopeptidase? - Chatonnet_1986_Biochimie_68_657
Author(s) : Chatonnet A , Masson P
Ref : Biochimie , 68 :657 , 1986
Abstract : The peptidase site of human plasma cholinesterase (butyrylcholinesterase) is distinct from its esteratic site. We found that the number of peptidase sites on an enzyme highly purified from pooled plasma is less than 0.1, as compared with 4 esteratic sites, per tetramer. However, the subunits which carry the peptidase sites are electrophoretically indistinguishable from esteratic subunits. The atypical-silent enzyme (Ea1Es1) had a much higher absolute peptidase activity when substance P was used as the substrate, and we found that the number of peptidase and esteratic sites of this enzyme was roughly the same. This suggests that the mutated esteratic site of the silent possesses a peptidase activity. The esteratic site of the usual allozyme (Eu1Eu1) has no peptidase activity towards substance P. However, a small proportion of peptidase subunits are present in all preparations of enzymes purified from the plasmas of homozygote individuals. The peptidase activity of butyrylcholinesterase might therefore correspond to a specific isoenzyme produced by an epigenetic mechanism or produced by a gene distinct from genes E1 and E2 encoding for cholinesterase subunits. However, the possibility that highly purified cholinesterase contains traces of a dipeptidylaminopeptidase cannot be completely ruled out.
ESTHER : Chatonnet_1986_Biochimie_68_657
PubMedSearch : Chatonnet_1986_Biochimie_68_657
PubMedID: 2425854

Title : Study of the peptidasic site of cholinesterase: preliminary results - Chatonnet_1985_FEBS.Lett_182_493
Author(s) : Chatonnet A , Masson P
Ref : FEBS Letters , 182 :493 , 1985
Abstract : The peptidasic site of highly purified human plasma cholinesterase was investigated using active-site-directed inhibitors. Peptidase activity was assayed taking substance P as substrate. Inhibition by organophosphates indicated that the peptidasic site contained an active serine. The presence of essential histidine residues associated with serine was revealed by histidine modifications. Carboxyl group reagents showed that the active centre contained carboxyl groups in a non-polar environment. The removal of sialic acids did not alter peptidase activity. The peptidasic site of cholinesterase shared many properties with serine proteases sites and esteratic sites of cholinesterases. In addition, with the peptidasic site, as well as the esteratic site, there was always the possibility of 'aging' when inhibited by DFP or soman.
ESTHER : Chatonnet_1985_FEBS.Lett_182_493
PubMedSearch : Chatonnet_1985_FEBS.Lett_182_493
PubMedID: 2579854

Title : [The peptidase site of butyrylcholinesterase is distinct from the esterase site]. [French] - Chatonnet_1984_C.R.Acad.Sci.III_299_529
Author(s) : Chatonnet A , Masson P
Ref : Comptes Rendus de l Academie des Sciences , 299 :529 , 1984
Abstract : Highly purified human plasma butyrylcholinesterase was inhibited by reversible inhibitors of esterase activity and modified by active-site-directed irreversible inhibitors of esterases and proteases. Peptidase and esterase activities of inhibited enzyme were simultaneously essayed from rates of hydrolysis of substance P (first cleavage) and butyrylthiocholine respectively. Inhibition parameters values and rates of inactivation of the two activities provide evidence that the peptidasic site is distinct from the esteratic site.
ESTHER : Chatonnet_1984_C.R.Acad.Sci.III_299_529
PubMedSearch : Chatonnet_1984_C.R.Acad.Sci.III_299_529
PubMedID: 6208983

Title : Acetylcholinesterase molecular forms in the fast or slow muscles of the chicken and the pigeon - Chatonnet_1983_FEBS.Lett_161_122
Author(s) : Chatonnet A , Bacou F
Ref : FEBS Letters , 161 :122 , 1983
Abstract : Molecular forms of acetylcholinesterase (AChE) were examined in various skeletal muscles of the chicken and the pigeon. In chicken pectoralis m., AChE was found to be restricted to endplate containing segments, and no asymmetric form could be detected in aneural samples. In the chicken muscles studied, a relation has been established between globular (G1,G2,G4) forms or asymmetric (A8,A12) forms, and muscle fibre types. Asymmetric forms are preponderant in fast-twitch muscles, whereas in slow tonic muscles 80% of the AChE activity is due to globular forms. However, comparison with pigeon muscles shows that AChE chicken muscle patterns may not be generalized.
ESTHER : Chatonnet_1983_FEBS.Lett_161_122
PubMedSearch : Chatonnet_1983_FEBS.Lett_161_122
PubMedID: 6884521