Artursson E


Full name : Artursson Elisabet

First name : Elisabet

Mail : Swedish Defense Research Agency\; CBRN Defence and Security\; SE-901 82 Umea

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Country : Sweden

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Phone : +4690106715

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References (12)

Title : Supplemental treatment to atropine improves the efficacy to reverse nerve agent induced bronchoconstriction - Wigenstam_2022_Chem.Biol.Interact__110061
Author(s) : Wigenstam E , Artursson E , Bucht A , Thors L
Ref : Chemico-Biological Interactions , :110061 , 2022
Abstract : Exposure to highly toxic organophosphorus compounds causes inhibition of the enzyme acetylcholinesterase resulting in a cholinergic toxidrome and innervation of receptors in the neuromuscular junction may cause life-threatening respiratory effects. The involvement of several receptor systems was therefore examined for their impact on bronchoconstriction using an ex vivo rat precision-cut lung slice (PCLS) model. The ability to recover airways with therapeutics following nerve agent exposure was determined by quantitative analyses of muscle contraction. PCLS exposed to nicotine resulted in a dose-dependent bronchoconstriction. The neuromuscular nicotinic antagonist tubocurarine counteracted the nicotine-induced bronchoconstriction but not the ganglion blocker mecamylamine or the common muscarinic antagonist atropine. Correspondingly, atropine demonstrated a significant airway relaxation following ACh-exposure while tubocurarine did not. Atropine, the M3 muscarinic receptor antagonist 4-DAMP, tubocurarine, the beta(2)-adrenergic receptor agonist formoterol, the Na(+)-channel blocker tetrodotoxin and the K(ATP)-channel opener cromakalim all significantly decreased airway contractions induced by electric field stimulation. Following VX-exposure, treatment with atropine and the Ca(2+)-channel blocker magnesium sulfate resulted in significant airway relaxation. Formoterol, cromakalim and magnesium sulfate administered in combinations with atropine demonstrated an additive effect. In conclusion, the present study demonstrated improved airway function following nerve agent exposure by adjunct treatment to the standard therapy of atropine.
ESTHER : Wigenstam_2022_Chem.Biol.Interact__110061
PubMedSearch : Wigenstam_2022_Chem.Biol.Interact__110061
PubMedID: 35872047

Title : Broad-spectrum antidote discovery by untangling the reactivation mechanism of nerve agent inhibited acetylcholinesterase - Lindgren_2022_Chemistry_28_e202200678
Author(s) : Lindgren C , Forsgren N , Hoster N , Akfur C , Artursson E , Edvinsson L , Svensson R , Worek F , Ekstrom , Linusson A
Ref : Chemistry , 28 :e202200678 , 2022
Abstract : Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and prereactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.
ESTHER : Lindgren_2022_Chemistry_28_e202200678
PubMedSearch : Lindgren_2022_Chemistry_28_e202200678
PubMedID: 35420233
Gene_locus related to this paper: mouse-ACHE

Title : Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity - Artursson_2013_Biochem.Pharmacol_85_1389
Author(s) : Artursson E , Andersson PO , Akfur C , Linusson A , Borjegren S , Ekstrom F
Ref : Biochemical Pharmacology , 85 :1389 , 2013
Abstract : Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300muM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation.
ESTHER : Artursson_2013_Biochem.Pharmacol_85_1389
PubMedSearch : Artursson_2013_Biochem.Pharmacol_85_1389
PubMedID: 23376121
Gene_locus related to this paper: mouse-ACHE

Title : Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling - Berg_2011_PLoS.One_6_e26039
Author(s) : Berg L , Andersson CD , Artursson E , Hornberg A , Tunemalm AK , Linusson A , Ekstrom F
Ref : PLoS ONE , 6 :e26039 , 2011
Abstract : Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685*mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.
ESTHER : Berg_2011_PLoS.One_6_e26039
PubMedSearch : Berg_2011_PLoS.One_6_e26039
PubMedID: 22140425
Gene_locus related to this paper: mouse-ACHE

Title : Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad - Hornberg_2010_Biochem.Pharmacol_79_507
Author(s) : Hornberg A , Artursson E , Warme R , Pang YP , Ekstrom F
Ref : Biochemical Pharmacology , 79 :507 , 2010
Abstract : Organophosphorus insecticides and nerve agents inhibit the vital enzyme acetylcholinesterase by covalently bonding to the catalytic serine residue of the enzyme. Oxime-based reactivators, such as [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-o xoazanium dichloride (HI-6) and 1,7-heptylene-bis-N,N'-2-pyridiniumaldoxime dichloride (Ortho-7), restore the organophosphate-inhibited enzymatic activity by cleaving the phosphorous conjugate. In this article, we report the intermolecular interactions between Mus musculus acetylcholinesterase inhibited by the insecticide fenamiphos (fep-mAChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and kinetics. The crystal structures of the two oxime-bound fep-mAChE complexes show that both oximes interact with the peripheral anionic site involving different conformations of Trp286 and different peripheral-site residues (Tyr124 for HI-6 and Tyr72 for Ortho-7). Moreover, residues at catalytic site of the HI-6-bound fep-mAChE complex adopt conformations that are similar to those in the apo mAChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-mAChE complex. Interestingly, flipping of the His447 imidazole ring allows the formation of a hydrogen bonding network among the Glu334-His447-Ortho-7 triad, which presumably deprotonates the Ortho-7 oxime hydroxyl group, increases the nucleophilicity of the oxime group, and leads to cleavage of the phosphorous conjugate. These results offer insights into a detailed reactivation mechanism for the oximes and development of improved reactivators.
ESTHER : Hornberg_2010_Biochem.Pharmacol_79_507
PubMedSearch : Hornberg_2010_Biochem.Pharmacol_79_507
PubMedID: 19732756
Gene_locus related to this paper: mouse-ACHE

Title : Reactivation of tabun-hAChE investigated by structurally analogous oximes and mutagenesis - Artursson_2009_Toxicology_265_108
Author(s) : Artursson E , Akfur C , Hornberg A , Worek F , Ekstrom F
Ref : Toxicology , 265 :108 , 2009
Abstract : The nerve agent tabun inhibits the essential enzyme acetylcholinesterase (AChE) by a rapid phosphoramidation of the catalytic serine residue. Oximes, such as K027 and HLo-7, can reactivate tabun-inhibited human AChE (tabun-hAChE) whereas the activity of their close structural analogue HI-6 is notably low. To investigate HI-6, K027 and HLo-7, residues lining the active-site gorge of hAChE were substituted and the effects on kinetic parameters for reactivation were determined. None of the mutants (Asp74Asn, Asp74Glu, Tyr124Phe, Tyr337Ala, Tyr337Phe, Phe338Val and Tyr341Ala) were able to facilitate HI-6-mediated reactivation of tabun-hAChE. In contrast, Tyr124Phe and Tyr337Phe induce a 2-2.5-fold enhancement of the bimolecular rate constant for K027 and HLo-7. The largest effects on the dissociation constant (3.5-fold increase) and rate constant (20-fold decrease) were observed for Tyr341Ala and Asp74Asn, respectively. These findings demonstrate the importance of residues located distant from the conjugate during the reactivation of tabun-hAChE.
ESTHER : Artursson_2009_Toxicology_265_108
PubMedSearch : Artursson_2009_Toxicology_265_108
PubMedID: 19761810

Title : Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design - Ekstrom_2009_PLoS.One_4_e5957
Author(s) : Ekstrom F , Hornberg A , Artursson E , Hammarstrom LG , Schneider G , Pang YP
Ref : PLoS ONE , 4 :e5957 , 2009
Abstract : Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-o xoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.
ESTHER : Ekstrom_2009_PLoS.One_4_e5957
PubMedSearch : Ekstrom_2009_PLoS.One_4_e5957
PubMedID: 19536291
Gene_locus related to this paper: mouse-ACHE

Title : Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates - Ekstrom_2006_Biochem.Pharmacol_72_597
Author(s) : Ekstrom F , Pang YP , Boman M , Artursson E , Akfur C , Borjegren S
Ref : Biochemical Pharmacology , 72 :597 , 2006
Abstract : Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited AChE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-pi interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE. Different ability to reactivate AChE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE.
ESTHER : Ekstrom_2006_Biochem.Pharmacol_72_597
PubMedSearch : Ekstrom_2006_Biochem.Pharmacol_72_597
PubMedID: 16876764
Gene_locus related to this paper: mouse-ACHE

Title : Retained activities of some membrane proteins in stable lipid bilayers on a solid support - Puu_1995_Biosens.Bioelectron_10_463
Author(s) : Puu G , Gustafson I , Artursson E , Ohlsson PA
Ref : Biosensors & Bioelectronics , 10 :463 , 1995
Abstract : Highly stable lipid bilayers, composed of biologically relevant lipids such as phosphatidylcholine, phosphatidylethanolamine and cholesterol, were formed on platinum surfaces. Bacteriorhodopsin isolated from purple membrane (PM) from Halobacterium halobium, cytochrome oxidase from bovine heart, acetylcholinesterase from bovine brain and the nicotinic acetylcholine receptor from Torpedo electric organ were also incorporated into these reconstituted membranes. The proteins retained their biological activities. Some of them were active several weeks after the reconstitution and after several cycles of assay, washing and storage.
ESTHER : Puu_1995_Biosens.Bioelectron_10_463
PubMedSearch : Puu_1995_Biosens.Bioelectron_10_463
PubMedID: 7786470

Title : Structurally Important Residues in the Region Ser91 to Asn98 of Torpedo Acetylcholinesterase -
Author(s) : Bucht G , Artursson E
Ref : In Multidisciplinary approaches to cholinesterase functions - Proceedings of Fourth International Meeting on Cholinesterases , (Shafferman, A. and Velan, B., Eds) Plenum Press, New York :185 , 1992

Title : Ketamine enantiomers and acetylcholinesterase - Puu_1991_Biochem.Pharmacol_41_2043
Author(s) : Puu G , Koch M , Artursson E
Ref : Biochemical Pharmacology , 41 :2043 , 1991
Abstract : (-)-ketamine was found to be more potent than (+)-ketamine in all the studied reactions with acetylcholinesterase. In most cases the difference was small but for two rate constants the (-)-form was unique in having effects. Thus, the stereoselectivity of ketamine in this system is the opposite of most other systems studied.
ESTHER : Puu_1991_Biochem.Pharmacol_41_2043
PubMedSearch : Puu_1991_Biochem.Pharmacol_41_2043
PubMedID: 2039553

Title : Reactivation of nerve agent inhibited human acetylcholinesterases by HI-6 and obidoxime - Puu_1986_Biochem.Pharmacol_35_1505
Author(s) : Puu G , Artursson E , Bucht G
Ref : Biochemical Pharmacology , 35 :1505 , 1986
Abstract : Acetylcholinesterase was purified from human caudate nucleus and skeletal muscle. The enzyme preparations were used to study aging and reactivation by HI-6 and obidoxime after inhibition by soman and its isomers. HI-6 was found to be the most potent reactivator. For both enzyme preparations a higher reactivatability and a higher rate of aging were observed after inhibition by C+-soman than after inhibition by C(-)-soman. Aging was retarded by propidium diiodide. Reactivation by the two oximes was also studied after inhibition by tabun, sarin and VX. Tissue homogenates were used for this part of the work. Our conclusion is that HI-6 is superior to obidoxime for human acetylcholinesterases inhibited by soman and sarin, while obidoxime is better towards tabun-inhibited enzyme.
ESTHER : Puu_1986_Biochem.Pharmacol_35_1505
PubMedSearch : Puu_1986_Biochem.Pharmacol_35_1505
PubMedID: 3518721