Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 203, Issue 1, Pages 19-23Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2012.08.005
Keywords
Butyrylcholinesterase; Acetylcholinesterase; X-ray structure; Nerve agents; Aging; Reactivators
Funding
- Defense Threat Reduction Agency [HDTRA-08-C-0024]
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Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with somanaged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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