Mechanism of inhibition of cholinesterases by huperzine A.
Huperzine A, an alkaloid isolated from Huperzia serrata was found to reversibly inhibit acetylcholinesterases (EC 3.1.1.7) and butyrylcholinesterases (EC 3.1.1.8) with on- and off-rates that depend on both the type and the source of enzyme. Long-term incubation of high concentrations of purified cholinesterases (1-8 microM) with huperzine A did not show any chemical modification of huperzine A. A low dissociation constant KI was obtained for mammalian acetylcholinesterase-huperzine (20-40 nM) compared to mammalian butyrylcholinesterase-huperzine (20-40 microM). This indicates that the thermodynamic stability of huperzine-cholinesterase complex may depend on the number and type of aromatic amino acid residues in the catalytic pocket region of the cholinesterase molecule.
Ashani
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Walter Reed Army Institute of Research, Washington DC 20307.
Peggins
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D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004355:Drug Stability; D006736:Horses; D006801:Humans; D007700:Kinetics; D010261:Paraoxon / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014101:Torpedo
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C050426:huperzine A; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D010261:Paraoxon