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PDBsum entry 2wik
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References listed in PDB file
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Key reference
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Title
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Structure-Activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.
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Authors
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E.Carletti,
N.Aurbek,
E.Gillon,
M.Loiodice,
Y.Nicolet,
J.C.Fontecilla-Camps,
P.Masson,
H.Thiermann,
F.Nachon,
F.Worek.
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Ref.
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Biochem J, 2009,
421,
97.
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PubMed id
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Abstract
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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.
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