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

Nature. 1995 Jun 22;375(6533):700-4. doi: 10.1038/375700a0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acremonium / enzymology
  • Amino Acid Sequence
  • Aspergillus nidulans / genetics
  • Binding Sites
  • Catalysis
  • Cloning, Molecular
  • Computer Graphics
  • Crystallography, X-Ray
  • Manganese / chemistry
  • Molecular Sequence Data
  • Oxidoreductases / chemistry*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Protein Conformation
  • Recombinant Proteins
  • Sequence Homology, Amino Acid

Substances

  • Recombinant Proteins
  • Manganese
  • Oxidoreductases
  • isopenicillin N synthetase

Associated data

  • GENBANK/S67953
  • GENBANK/U04434
  • GENBANK/X73314
  • SWISSPROT/P05116
  • SWISSPROT/P05326
  • SWISSPROT/P11935
  • SWISSPROT/P24397