Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes.
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.
Roach
P L
PL
Dyson Perrins Laboratory, University of Oxford, UK.
Clifton
I J
IJ
Fülöp
V
V
Harlos
K
K
Barton
G J
GJ
Hajdu
J
J
Andersson
I
I
Schofield
C J
CJ
Baldwin
J E
JE
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
D011994:Recombinant Proteins; D008345:Manganese; D010088:Oxidoreductases; C038370:isopenicillin N synthetase