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| - Dehydroalanine-Based Inhibition of a Peptide Epimerase fromSpider Venom
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| - Ribosomally produced peptides that contain d-amino acids have been isolated from a number ofvertebrate and invertebrate sources. In each case, the d-amino acids are introduced by aposttranslational modification of a parent peptide containing only amino acids of the l-configuration.The only known enzyme to catalyze such a reaction is the peptide epimerase (also known as peptideisomerase) from the venom of the funnel web spider, Agelenopsis aperta. This enzyme interconvertstwo 48-amino-acid-long peptide toxins that differ only by the stereochemistry at a single serineresidue. In this paper we report the synthesis and testing of two pentapeptide analogues that containmodified amino acids at the site normally occupied by the substrate serine residue. When thel-chloroalanine-containing peptide 3 was incubated with the epimerase it was converted into thedehydroalanine-containing peptide 4 via an elimination of HCl. The dehydroalanine peptide 4 wasindependently synthesized and found to act as a potent inhibitor of the epimerase (IC50 = 0.5 μM).These results support a direct deprotonation/reprotonation mechanism in which a carbanionicintermediate is formed. The observed inhibition by 4 can be attributed to the sp2-hybridization ofthe α-carbon in the dehydroalanine unit that mimics the planar geometry of the anionicintermediate.
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