Crystal Structures of BapA Complexes with β‐Lactam‐Derived Inhibitors Illustrate Substrate Specificity and Enantioselectivity of β‐Aminopeptidases |
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| Authors: | Dr Tobias Heck Dr Tobias Merz Artur Reimer Prof Dr Dieter Seebach Dr Daniel Rentsch Dr Christophe Briand Prof Dr Markus G Grütter Dr Hans‐Peter E Kohler Dr Birgit Geueke |
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| Affiliation: | 1. Eawag, Swiss Federal Institute of Aquatic Science and Technology, Department of Environmental Microbiology, überlandstrasse 133, 8600 Dübendorf (Switzerland);2. Present address Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014 St. Gallen (Switzerland);3. Biochemistry Institute, University of Zürich, Winterthurerstrasse 190, 8057 Zürich (Switzerland);4. Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, H?nggerberg HCI, Wolfgang‐Pauli‐Strasse 10, 8093 Zürich (Switzerland);5. Empa, Swiss Federal Laboratories for Materials Science and Technology, überlandstrasse 129, 8600 Dübendorf (Switzerland) |
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| 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 (Ki 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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| Keywords: | AEBSF ampicillin beta‐peptides Ntn hydrolases pefabloc SC |
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