title: Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes.
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.
authors.affiliation: Dyson Perrins Laboratory, University of Oxford, UK.
authors.forename: P L
authors.initials: PL
authors.lastname: Roach
authors.forename: I J
authors.initials: IJ
authors.lastname: Clifton
authors.forename: V
authors.initials: V
authors.lastname: Fülöp
authors.forename: K
authors.initials: K
authors.lastname: Harlos
authors.forename: G J
authors.initials: GJ
authors.lastname: Barton
authors.forename: J
authors.initials: J
authors.lastname: Hajdu
authors.forename: I
authors.initials: I
authors.lastname: Andersson
authors.forename: C J
authors.initials: CJ
authors.lastname: Schofield
authors.forename: J E
authors.initials: JE
authors.lastname: Baldwin
mesh_terms: D000164:Acremonium / Q000201:enzymology; D000595:Amino Acid Sequence; D001233:Aspergillus nidulans / Q000235:genetics; D001665:Binding Sites; D002384:Catalysis; D003001:Cloning, Molecular; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D008345:Manganese / Q000737:chemistry; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011994:Recombinant Proteins; D017386:Sequence Homology, Amino Acid
chemical_list: D011994:Recombinant Proteins; D008345:Manganese; D010088:Oxidoreductases; C038370:isopenicillin N synthetase