ChemBioChem p. 1129 - 1136 (2010)
Update date:2022-09-26
Topics:
Heck, Tobias
Reimer, Artur
Seebach, Dieter
Gardiner, James
Deniau, Gildas
Lukaszuk, Aneta
Kohler, Hans-Peter E.
Geueke, Birgit
We have previously shown that the β-aminopeptidases BapA from Sphingosinicella xenopeptidilytica and DmpA from Ochrobactrum anthropi can catalyze reactions with non-natural β3-peptides and β3-amino acid amides. Here we report that these exceptional enzymes are also able to utilize synthetic dipeptides with N-terminal β2-amino acid residues as substrates under aqueous conditions. The suitability of a β2-peptide as a substrate for BapA or DmpA was strongly dependent on the size of the Cα substituent of the N-terminal β2-amino acid. BapA was shown to convert a diastereomeric mixture of the β2-peptide H-β2hPhe- β2hAla-OH, but did not act on diastereomerically pure β2,β3-dipeptides containing an N-terminal β2-homoalanine. In contrast, DmpA was only active with the latter dipeptides as substrates. BapA-catalyzed transformation of the diastereomeric mixture of H-β2hPhe-β2hAla-OH proceeded along two highly S-enantioselective reaction routes, one leading to substrate hydrolysis and the other to the synthesis of coupling products. The synthetic route predominated even at neutral pH. A rise in pH of three log units shifted the synthesis-to-hydrolysis ratio (vS/vH) further towards peptide formation. Because the equilibrium of the reaction lies on the side of hydrolysis, prolonged incubation resulted in the cleavage of all peptides that carried an N-terminal β-amino acid of S configuration. After completion of the enzymatic reaction, only the S enantiomer of β2-homophenylalanine was detected (ee>99% for H-(S)-β2-hPhe-OH, E>500); this confirmed the high enantioselectivity of the reaction. Our findings suggest interesting new applications of the enzymes BapA and DmpA for the production of enantiopure β2-amino acids and the enantioselective coupling of N-terminal β2-amino acids to peptides.
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