Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes

Peter L. Roach, Ian J. Clifton, Vilmos Fülöp, Karl Harlos, Geoffrey J. Barton, Janos Hajdu, Inger Andersson, Christopher Schofield, Jack E. Baldwin

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357 Citations (Scopus)

Abstract

Penicillin antibiotics are all produced from fermentation-derived penicillins because their chemical synthesis is not commercially viable. The key step in penicillin biosynthesis, in which both the beta-lactam and thiazolidine rings of the nucleus are created, is mediated by isopenicillin N synthase (IPNS), which binds ferrous iron and uses dioxygen as a cosubstrate. In a unique enzymatic step, with no chemical precedent, IPNS catalyses the transfer of four hydrogen atoms from its tripeptide substrate to dioxygen forming, in a single reaction, the complete bicyclic nucleus of the penicillins. We now report the structure of IPNS complexed with manganese, which reveals the active site is unusually buried within a 'jelly-roll' motif and lined by hydrophobic residues, and suggest how this structure permits the process of penicillin formation. Sequence analyses indicate IPNS, 1-aminocyclopropane-1-carboxylic acid oxidase and many of the 2-oxo-acid-dependent oxygenases contain a conserved jelly-roll motif, forming a new structural family of enzymes.

Original languageEnglish
Pages (from-to)700-704
Number of pages5
JournalNature
Volume375
Issue number6533
DOIs
Publication statusPublished - 22 Jun 1995

Keywords

  • Acremonium
  • Amino acid sequence
  • Aspergillus nidulans
  • Binding sites
  • Catalysis
  • Cloning, Molecular
  • Computer graphics
  • Crystallography, X-Ray
  • Manganese
  • Molecular sequence data
  • Oxidoreductases
  • Protein conformation
  • Recombinant proteins
  • Sequence homology, Amino acid

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    Roach, P. L., Clifton, I. J., Fülöp, V., Harlos, K., Barton, G. J., Hajdu, J., Andersson, I., Schofield, C., & Baldwin, J. E. (1995). Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes. Nature, 375(6533), 700-704. https://doi.org/10.1038/375700a0