Reaction participants Show >> << Hide
- Name help_outline an acylcholine Identifier CHEBI:35287 Charge 1 Formula C6H13NO2R SMILEShelp_outline C[N+](C)(C)CCOC([*])=O 2D coordinates Mol file for the small molecule Search links Involved in 7 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (Beilstein: 3587155; CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,048 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline a carboxylate Identifier CHEBI:29067 Charge -1 Formula CO2R SMILEShelp_outline [O-]C([*])=O 2D coordinates Mol file for the small molecule Search links Involved in 5,652 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline choline Identifier CHEBI:15354 (Beilstein: 1736748; CAS: 62-49-7) help_outline Charge 1 Formula C5H14NO InChIKeyhelp_outline OEYIOHPDSNJKLS-UHFFFAOYSA-N SMILEShelp_outline C[N+](C)(C)CCO 2D coordinates Mol file for the small molecule Search links Involved in 56 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,176 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:21964 | RHEA:21965 | RHEA:21966 | RHEA:21967 | |
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Publications
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The structure of G117H mutant of butyrylcholinesterase: nerve agents scavenger.
Amitay M., Shurki A.
Organophosphate ester (OP) compounds are known for their ubiquitous use as insecticides. At the same time, these chemicals are highly toxic and can be used as nerve agents. G117H mutant of human Butyrylcholinesterase (BChE) was found to be capable of hydrolyzing certain OPs and protect against the ... >> More
Organophosphate ester (OP) compounds are known for their ubiquitous use as insecticides. At the same time, these chemicals are highly toxic and can be used as nerve agents. G117H mutant of human Butyrylcholinesterase (BChE) was found to be capable of hydrolyzing certain OPs and protect against their toxicity. However, for therapeutic use, the rate of hydrolysis is too low. Its catalytic power can be improved by rational design, but the structure of the G117H mutant is first required. In this work, we determined, computationally, the three dimensional structure of the G117H BChE mutant. The structure was then validated by simulating acetylation of acetylthiocholine (ATC). Several plausible conformers of G117H BChE were examined but only the (62,-75) conformer fully reproduced catalytic effect. The (62,-75) conformer is, therefore, suggested as the structure adopted by the G117H BChE mutant. This conformer is shown to explain the loss of esterase activity observed for the G122H Acetylcholinesterase mutant together with its recovery when additional mutations are placed turning the enzyme also into an OP hydrolase. Furthermore, similarity of the structure to the structure of RNase A, which is known to hydrolyze the O--P bond in RNA, grants it further credibility and suggests a mechanism for the OP hydrolysis. << Less
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Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.
Carletti E., Aurbek N., Gillon E., Loiodice M., Nicolet Y., Fontecilla-Camps J.C., Masson P., Thiermann H., Nachon F., Worek F.
hBChE [human BChE (butyrylcholinesterase)] naturally scavenges OPs (organophosphates). This bioscavenger is currently in Clinical Phase I for pretreatment of OP intoxication. Phosphylated ChEs (cholinesterases) can undergo a spontaneous time-dependent process called 'aging' during which the conjug ... >> More
hBChE [human BChE (butyrylcholinesterase)] naturally scavenges OPs (organophosphates). This bioscavenger is currently in Clinical Phase I for pretreatment of OP intoxication. Phosphylated ChEs (cholinesterases) can undergo a spontaneous time-dependent process called 'aging' during which the conjugate is dealkylated, leading to creation of an enzyme that cannot be reactivated. hBChE inhibited by phosphoramidates such as tabun displays a peculiar resistance to oxime-mediated reactivation. We investigated the basis of oxime resistance of phosphoramidyl-BChE conjugates by determining the kinetics of inhibition, reactivation (obidoxime {1,1'-(oxybis-methylene) bis[4-(hydroxyimino) methyl] pyridinium dichloride}, TMB-4 [1,3-trimethylene-bis(4-hydroxyiminomethylpyridinium) dibromide], HLö 7 {1-[[[4-(aminocarbonyl) pyridinio]methoxy]methyl]-2,4-bis-[(hydroxyimino)methyl] pyridinium dimethanesulfonate)}, HI-6 {1-[[[4-(aminocarbonyl) pyridinio] methoxy] methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride monohydrate} and aging, and the crystal structures of hBChE inhibited by different N-monoalkyl and N,N-dialkyl tabun analogues. The refined structures of aged hBChE conjugates show that aging proceeds through O-dealkylation of the P(R) enantiomer of N,N-diethyl and N-propyl analogues, with subsequent formation of a salt bridge preventing reactivation, similarly to a previous observation made on tabun-ChE conjugates. Interestingly, the N-methyl analogue projects its amino group towards the choline-binding pocket, so that aging proceeds through deamination. This orientation results from a preference of hBChE's acyl-binding pocket for larger than 2-atoms linear substituents. The correlation between the inhibitory potency and the N-monoalkyl chain length is related to increasingly optimized interactions with the acyl-binding pocket as shown by the X-ray structures. These kinetics and X-ray data lead to a structure-activity relationship that highlights steric and electronic effects of the amino substituent of phosphoramidate. This study provides the structural basis to design new oximes capable of reactivating phosphoramidyl-hBChE conjugates after intoxication, notably when hBChE is used as pretreatment, or to design BChE-based catalytic bioscavengers. << Less