Anticholinesterases: lipid solubility and enzyme interactions
THE CONTEXT
Carbamates and organophosphates inhibit acetylcholinesterase through enzyme interactions whose stability determines the duration of inhibition.
Lipid solubility
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A nonpolar tertiary amino group makes physostigmine lipid soluble.
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The quaternary group in neostigmine makes it lipid insoluble.
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Organophosphates are highly lipid soluble except echothiophate, which is water soluble.
Acetylcholinesterase sites and normal hydrolysis
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The active region of acetylcholinesterase forms a gorge containing an anionic site near glutamate 334 and an esteratic site formed by serine 203 and histidine 447.
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Acetylcholine is attracted electrostatically to the anionic site. Adjacent histidine activates serine-OH for nucleophilic attack, leading to acetylation of serine.
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The acetylated enzyme reacts with water to produce acetic acid and choline. The esteratic site is freed within a fraction of a millisecond.
Inhibitor binding and recovery
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Carbamates carbamylate the esteratic site, while organophosphates phosphorylate it.
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Carbamylated enzyme reacts slowly with water, producing reversible inhibition. Phosphorylated enzyme reacts extremely slowly or not at all, producing irreversible inhibition.
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Edrophonium and tacrine bind only to the anionic site without forming covalent bonds. Organophosphates bind only to the esteratic site and form strong covalent bonds.
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Edrophonium-inhibited enzyme recovers in less than 10 minutes. Weak hydrogen bonding permits recovery through diffusion of the inhibitor without its hydrolysis, explaining the brief action.
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The reactivation half-life of carbamylated enzyme is one-half to six hours, shorter than the time required to synthesize fresh enzyme protein.