Abstract
The marine natural product manoalide (MLD), a potent irreversible inhibitor of bee venom phospholipase A 2 (PLA 2), was shown to produce a chromophore ( λ max = 437 nm) during incubation with the enzyme. MLD also developed an identical chromophore when incubated with free lysine (Lys), cysteine (Cys) or tryptophan (Trp) but not with their N- α-amino-blocked analogs. These results suggest that the chromophore product was dependent on the presence of two nucleophilic groups which react by an ordered mechanism rather than by simple random collision. Lys polymers prevented MLD from inhibiting PLA 2, whereas monomeric Lys did not. The optimal active polymer of Lys appeared to be a tetralysine (L 4) peptide, and a degree of selectivity was obtained when the Lys residues were in a 1,4-Lys arrangement. The rate of chromophore development with PLA 2 and the rate of inactivation of PLA 2 by MLD appear to be independent processes. Based on these data, it is possible that the irreversible inactivation of PLA 2 may involve an ordered reaction with a peptide sequence in PLA 2 containing a 1,4-Lys arrangement.
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