Crystallographic snapshots of nonaged and aged conjugates of soman with acetylcholinesterase, and of a ternary complex of the aged conjugate with pralidoxime.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Acetylcholinesterase/*chemistry ; Acetylcholinesterase/*metabolism ; Cholinesterase Inhibitors/*chemistry ; Cholinesterase Inhibitors/*metabolism ; Pralidoxime Compounds/*chemistry ; Soman/*chemistry ; Soman/*metabolism; Animals ; Catalytic Domain ; Cholinesterase Inhibitors/pharmacology ; Crystallography, X-Ray ; Dealkylation ; Enzyme Activation/drug effects ; Humans ; Kinetics ; Models, Molecular ; Pralidoxime Compounds/pharmacology ; Soman/pharmacology ; Torpedo ; Water/chemistry ; Water/metabolism
    • 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.
    • Accession Number:
      0 (Cholinesterase Inhibitors)
      0 (Pralidoxime Compounds)
      059QF0KO0R (Water)
      96-64-0 (Soman)
      EC 3.1.1.7 (Acetylcholinesterase)
      P7MU9UTP52 (pralidoxime)
    • Publication Date:
      Date Created: 20090801 Date Completed: 20091231 Latest Revision: 20131121
    • Publication Date:
      20231215
    • Accession Number:
      10.1021/jm900433t
    • Accession Number:
      19642642