Abstract |
Organophosphate compounds (OP) are potent inhibitors of acetylcholinesterases ( AChEs) and can cause lethal poisoning in humans. Inhibition of AChEs by the OP soman involves phosphonylation of the catalytic serine, and subsequent dealkylation produces a form known as the "aged" enzyme. The nonaged form can be reactivated to a certain extent by nucleophiles, such as pralidoxime (2-PAM), whereas aged forms of OP-inhibited AChEs are totally resistant to reactivation. Here, we solved the X-ray crystal structures of AChE from Torpedo californica (TcAChE) conjugated with soman before and after aging. The absolute configuration of the soman stereoisomer adduct in the nonaged conjugate is P(S)C(R). A structural reorientation of the catalytic His440 side chain was observed during the aging process. Furthermore, the crystal structure of the ternary complex of the aged conjugate with 2-PAM revealed that the orientation of the oxime function does not permit nucleophilic attack on the phosphorus atom, thus providing a plausible explanation for its failure to reactivate the aged soman/AChE conjugate. Together, these three crystal structures provide an experimental basis for the design of new reactivators.
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Authors | Benoît Sanson, Florian Nachon, Jacques-Philippe Colletier, Marie-Thérèse Froment, Lilly Toker, Harry M Greenblatt, Joel L Sussman, Yaacov Ashani, Patrick Masson, Israel Silman, Martin Weik |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 23
Pg. 7593-603
(Dec 10 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19642642
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cholinesterase Inhibitors
- Pralidoxime Compounds
- Water
- Soman
- Acetylcholinesterase
- pralidoxime
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Topics |
- Acetylcholinesterase
(chemistry, metabolism)
- Animals
- Catalytic Domain
- Cholinesterase Inhibitors
(chemistry, metabolism, pharmacology)
- Crystallography, X-Ray
- Dealkylation
- Enzyme Activation
(drug effects)
- Humans
- Kinetics
- Models, Molecular
- Pralidoxime Compounds
(chemistry, pharmacology)
- Soman
(chemistry, metabolism, pharmacology)
- Torpedo
- Water
(chemistry, metabolism)
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