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A Cyclobutanone Analogue Mimics Penicillin in Binding to Isopenicillin N Synthase
Author(s) -
Stewart Amanda C.,
Clifton Ian J.,
Adlington Robert M.,
Baldwin Jack E.,
Rutledge Peter J.
Publication year - 2007
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700176
Subject(s) - stereochemistry , cyclobutanone , chemistry , atp synthase , natural product , active site , enzyme , carboxylate , substrate (aquarium) , hydrolase , salt bridge , biosynthesis , cyclase , hydrogen bond , biochemistry , molecule , biology , organic chemistry , ring (chemistry) , ecology , gene , mutant
A carbocyclic analogue of the β‐lactam antibiotic isopenicillin N (IPN) has been synthesised and cocrystallised with isopenicillin N synthase (IPNS), the central enzyme in the biosynthesis of penicillin antibiotics. The crystal structure of the IPNS‐cyclobutanone complex reveals an active site environment similar to that seen in the enzyme–product complex generated by turnover of the natural substrate within the crystalline protein. The IPNS–cyclobutanone structure demonstrates that the product analogue is tethered to the protein by hydrogen bonding and salt bridge interactions with its carboxylate groups, as seen previously for the natural substrate and product. Furthermore, the successful cocrystallisation of this analogue with IPNS provides firm structural evidence for the utility of such cyclobutanone derivatives as hydrolytically stable analogues of bicyclic β‐lactams.