A cyclobutanone analogue mimics penicillin in binding to isopenicillin N synthase.
A carbocyclic analogue of the beta-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 beta-lactams.
Stewart
Amanda C
AC
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
Clifton
Ian J
IJ
Adlington
Robert M
RM
Baldwin
Jack E
JE
Rutledge
Peter J
PJ
D001665:Binding Sites; D018360:Crystallography, X-Ray; D003503:Cyclobutanes / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000737:chemistry*; D010406:Penicillins / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
D003503:Cyclobutanes; D010406:Penicillins; D010088:Oxidoreductases; C038370:isopenicillin N synthetase; C006414:penicillin N