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Crystal Structures of BapA Complexes with β-Lactam-Derived Inhibitors Illustrate Substrate Specificity and Enantioselectivity of β-Aminopeptidases


Heck, Tobias; Merz, Tobias; Reimer, Artur; Seebach, Dieter; Rentsch, Daniel; Briand, Christophe; Grütter, Markus G; Kohler, Hans-Peter E; Geueke, Birgit (2012). Crystal Structures of BapA Complexes with β-Lactam-Derived Inhibitors Illustrate Substrate Specificity and Enantioselectivity of β-Aminopeptidases. ChemBioChem, 13(14):2137-215.

Abstract

β-Aminopeptidases have exclusive biocatalytic potential because they react with peptides composed of β-amino acids, which serve as building blocks for the design of non-natural peptidomimetics. We have identified the β-lactam antibiotic ampicillin and the ampicillin-derived penicilloic acid as novel inhibitors of the β-aminopeptidase BapA from Sphingosinicella xenopeptidilytica (K(i) values of 0.69 and 0.74 mM, respectively). We report high-resolution crystal structures of BapA in noncovalent complexes with these inhibitors and with the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride. All three inhibitors showed similar binding characteristics; the aromatic moiety extended into a hydrophobic binding pocket of the active site, and the free amino group formed a salt bridge with Glu133 of BapA. The exact position of the inhibitors and structural details of the ligand binding pocket illustrate the specificity and the enantioselectivity of BapA-catalyzed reactions with β-peptide substrates.

Abstract

β-Aminopeptidases have exclusive biocatalytic potential because they react with peptides composed of β-amino acids, which serve as building blocks for the design of non-natural peptidomimetics. We have identified the β-lactam antibiotic ampicillin and the ampicillin-derived penicilloic acid as novel inhibitors of the β-aminopeptidase BapA from Sphingosinicella xenopeptidilytica (K(i) values of 0.69 and 0.74 mM, respectively). We report high-resolution crystal structures of BapA in noncovalent complexes with these inhibitors and with the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride. All three inhibitors showed similar binding characteristics; the aromatic moiety extended into a hydrophobic binding pocket of the active site, and the free amino group formed a salt bridge with Glu133 of BapA. The exact position of the inhibitors and structural details of the ligand binding pocket illustrate the specificity and the enantioselectivity of BapA-catalyzed reactions with β-peptide substrates.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2012
Deposited On:09 Oct 2012 15:52
Last Modified:05 Apr 2016 15:59
Publisher:Wiley-Blackwell
ISSN:1439-4227
Publisher DOI:https://doi.org/10.1002/cbic.201200393
PubMed ID:22961926

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