Structure–activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun

Carletti, E.; Aurbek, Nadine; Gillon, Émilie; Loiodice, Mélanie; Nicolet, Yvain; Fontecilla‐Camps, J.C.; Masson, Patrick; Thiermann, Horst; Nachon, Florian; Worek, Franz

doi:10.1042/bj20090091

Cited by 64 publications

(41 citation statements)

References 23 publications

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“…A tilted conjugated serine residue has previously been described for aged phosphoroamidates in butyrylcholinesterase. The tilt is due to a salt bridge between the negative charged dealkylated aging product and the histidine corresponding to His447 in AChE (His438 in butyrylcholinesterase) [34].…”

mentioning

confidence: 99%

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad

Hörnberg¹,

Artursson²,

Wärme³

et al. 2010

Biochemical Pharmacology

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-Ping Pang, Fredrik Ekström. Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-Oxime triad. Biochemical Pharmacology, Elsevier, 2009, 79 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 39A c c e p t e d M a n u s c r i p t 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.

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mentioning

confidence: 99%

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad

Hörnberg¹,

Artursson²,

Wärme³

et al. 2010

Biochemical Pharmacology

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“…The question is whether the large substituent of VR and CVX can fit in the acyl-binding pocket of BChE. Some clues were provided by structural data showing that a diethylamino group (TA1) or a N-propylamino group (TA6) do fit in that pocket (25). Here, the x-ray structures of VR-and CVX-BChE confirm that the long n-butyloxy of CVX or the bulky isobutyloxy of VR do fit as well.…”

Section: Discussionmentioning

confidence: 54%

“…This configuration is identical to that observed when TcAChE was inhibited by racemic VX, except that no conformational change of the catalytic histidine is observed. The absence of conformational change of His-438 shows one more time that this catalytic residue is not mobile in BChE (25). These combined results suggest that in the presence of both enantiomers at submillimolar concentration, BChE will react preferentially with VX R -(ϩ).…”

Section: Inhibition Rate Constants For Optically Pure Vx Enantiomers-mentioning

confidence: 57%

“…Compared with the ethoxy substituent in the VX adduct, the isobutyloxy group of the VR adduct induces a 0.7 Å shift of Leu-286, and the n-butyloxy group of CVX adduct induces a 0.4-Å shift of Val-288 and 0.8-Å shift of Leu-286. Rearrangement of the acyl loop conformation was already observed for soman (24) and phosphoramidyl adducts (25). In addition, strain in the acyl-binding pocket translates into a slightly different position of the phosphonyl head for VX and CVX.…”

Section: Inhibition Rate Constants For Optically Pure Vx Enantiomers-mentioning

confidence: 90%

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Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Wandhammer

Carletti²,

Schans

et al. 2011

Journal of Biological Chemistry

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Nerve agents are chiral organophosphate compounds (OPs) that exert their acute toxicity by phosphorylating the catalytic serine of acetylcholinesterase (AChE). The inhibited cholinesterases can be reactivated using oximes, but a spontaneous timedependent process called aging alters the adduct, leading to resistance toward oxime reactivation. Human butyrylcholinesterase (BChE) functions as a bioscavenger, protecting the cholinergic system against OPs. The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhibited in solution or in cristallo with racemic V-agents (VX, Russian VX, and Chinese VX) systematically show the formation of the P S adduct. In this configuration, no catalysis of aging seems possible as confirmed by the three-dimensional structures of the three conjugates incubated over a period exceeding a week. Crystals of BChE soaked in optically pure VX R -(؉) and VX S -(؊) solutions lead to the formation of the P S and P R adduct, respectively. These structural data support an in-line phosphonylation mechanism. Additionally, they show that BChE reacts with VX R -(؉) in the presence of racemic mixture of V-agents, at odds with earlier kinetic results showing a moderate higher inhibition rate for VX S -(؊). These combined results suggest that the simultaneous presence of both enantiomers alters the enzyme stereoselectivity. In summary, the three-dimensional data show that BChE reacts preferentially with P R enantiomer of V-agents and does not age, in complete contrast to AChE, which is selectively inhibited by the P S enantiomer and ages.

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“…The X-ray structure of human BChE in complex with a tabun molecule, a known inhibitor of the substrate binding site of the enzyme, was obtained from the Protein Data Bank, PDB ID: 2WID (15). The X-ray structure of aged human AChE, in which the catalytic SER200 is phosphoramidylated, in complex with snake venom fasciculin-II was obtained from the Protein Data Bank, PDB ID: 2X8B (16).…”

Section: In Silico Studiesmentioning

confidence: 99%

Protective role of caffeic acid phenethyl ester on serum cholinesterase inhibition by acute exposure to diazinon in rats

Oğuzhanoğlu¹,

Andaç²,

Tüfek³

et al. 2014

Turk J Med Sci

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Ethylene adsorption on a Ni 55 nanocluster was studied by means of the density functional theory (DFT)/B3LYP using the basis sets of 6-31G(d,p) and 86-411(41d)G in Gaussian 03. The Ni 55 nanocluster was found to have a distorted icosahedral geometry, in accordance with the experimental findings. The binding energy value for the Ni 55 nanocluster was calculated to be 3.51 eV/atom using equilibrium geometry calculations. The estimated bulk nickel binding energy was in reasonable agreement with the experimental value (4.85 versus 4.45 eV/atom). In addition, equilibrium geometry calculations were performed for ethylene adsorption on the Ni 55 nanocluster for 2 different coordination numbers of 6 and 8 with π -adsorption modes.The related adsorption energies were computed as -0.87 and -0.68 eV, respectively.

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Structure–activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun

Cited by 64 publications

References 23 publications

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad

Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Protective role of caffeic acid phenethyl ester on serum cholinesterase inhibition by acute exposure to diazinon in rats

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