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| Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation |
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| Author(s): Roach PL, Clifton IJ, Hensgens CMH, Shibata N, Schofield CJ, Hajdu J, Baldwin JE |
| Source: NATURE Volume: 387 Issue: 6635 Pages: 827-830 Published: JUN 19 1997 |
| Times Cited: 207 References: 30 |
| Abstract: The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin(1). Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of a tripeptide, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV), and dioxygen to form isopenicillin N and two water molecules(2). Mechanistic studies suggest the reaction is initiated by ligation of the substrate thiolate to the iron centre, and proceeds through an enzyme-bound monocyclic intermediate(3,4) (Fig. 1), Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 Angstrom resolution. Based on the structure, we propose a mechanism for penicillin formation that involves ligation of ACV to the iron centre, creating a vacant iron coordination site into which dioxygen can bind. Subsequently, iron-dioxygen and iron-ore species remove the requisite hydrogens from ACV without the direct assistance of protein residues (Fig. 2). The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis. |
| Document Type: Article |
| Language: English |
Addresses:
1. UNIV OXFORD, DYSON PERRINS LAB, OXFORD OX1 3QY, ENGLAND
2. UNIV OXFORD, OXFORD CTR MOL SCI, OXFORD OX1 3QY, ENGLAND
3. UNIV UPPSALA, CTR BIOMED, DEPT BIOCHEM, S-75123 UPPSALA, SWEDEN |
| Publisher: MACMILLAN MAGAZINES LTD, PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: XF144 |
| ISSN: 0028-0836 |
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