Inhibition of Papain by N‐Acyl‐aminoacetaldehydes and N‐Acyl‐aminopropanones

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Abstract
N‐Acyl‐aminoacetaldehydes are potent inhibitors of the proteolytic enzyme, papain. Although they exist predominantly in their hydrated form in aqueous solution only the aldehyde is an effective inhibitor. The binding constants for related amides and methyl ketones confirm that it is principally the lower steric requirement of the aldehyde rather than its increased electrophilicity which is responsible for its powerful inhibitory properties. Using nuclear magnetic resonance spectroscopy, evidence is provided for an N‐acetyl‐aminoacetaldehyde‐papain complex. Using a cross‐saturation technique evidence is also provided for a hemithioacetal, formed from the aldehyde and the active‐site thiol group. Hemithioacetal formation has also been detected between N‐benzoyl‐aminoacetaldehyde and papain. This provides the first direct evidence for a tetrahedral adduct with papain and supports the proposed involvement of such intermediates in papain‐catalysed hydrolyses.