Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation
The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of a tripeptide, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (...
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| Veröffentlicht in: | Nature (London) 1997-06, Vol.387 (6635), p.827-830 |
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| creator | ROACH, P. L CLIFTON, I. J HENSGENS, C. M. H SHIBATA, N SCHOFIELD, C. J HAJDU, J BALDWIN, J. E |
| description | The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. 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. 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. Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 A 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-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues. The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis. |
| doi_str_mv | 10.1038/42990 |
| format | Article |
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L ; CLIFTON, I. J ; HENSGENS, C. M. H ; SHIBATA, N ; SCHOFIELD, C. J ; HAJDU, J ; BALDWIN, J. E</creator><creatorcontrib>ROACH, P. L ; CLIFTON, I. J ; HENSGENS, C. M. H ; SHIBATA, N ; SCHOFIELD, C. J ; HAJDU, J ; BALDWIN, J. E</creatorcontrib><description>The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. 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. 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. Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 A 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-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues. The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/42990</identifier><identifier>PMID: 9194566</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing</publisher><subject>Analytical, structural and metabolic biochemistry ; Antibiotics ; Aspergillus nidulans ; Binding Sites ; Biological and medical sciences ; Biosynthesis ; Chemical reactions ; Chemistry ; Crystallography, X-Ray ; Crystals ; Enzymes ; Enzymes and enzyme inhibitors ; Ferrous Compounds - chemistry ; Ferrous Compounds - metabolism ; Fundamental and applied biological sciences. Psychology ; Hydrogen Bonding ; Iron ; Microorganisms ; Models, Molecular ; Oligopeptides - chemistry ; Oligopeptides - metabolism ; Oxidoreductases ; Oxidoreductases - chemistry ; Oxidoreductases - metabolism ; Oxygen - metabolism ; Penicillin ; Penicillins - biosynthesis ; Protein Conformation</subject><ispartof>Nature (London), 1997-06, Vol.387 (6635), p.827-830</ispartof><rights>1997 INIST-CNRS</rights><rights>Copyright Macmillan Journals Ltd. 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E</creatorcontrib><title>Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation</title><title>Nature (London)</title><addtitle>Nature</addtitle><description>The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. 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. 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. Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 A 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-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues. The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Antibiotics</subject><subject>Aspergillus nidulans</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Biosynthesis</subject><subject>Chemical reactions</subject><subject>Chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Crystals</subject><subject>Enzymes</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Ferrous Compounds - chemistry</subject><subject>Ferrous Compounds - metabolism</subject><subject>Fundamental and applied biological sciences. 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L</au><au>CLIFTON, I. J</au><au>HENSGENS, C. M. H</au><au>SHIBATA, N</au><au>SCHOFIELD, C. J</au><au>HAJDU, J</au><au>BALDWIN, J. E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation</atitle><jtitle>Nature (London)</jtitle><addtitle>Nature</addtitle><date>1997-06-19</date><risdate>1997</risdate><volume>387</volume><issue>6635</issue><spage>827</spage><epage>830</epage><pages>827-830</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. 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. 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. Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 A 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-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues. The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis.</abstract><cop>London</cop><pub>Nature Publishing</pub><pmid>9194566</pmid><doi>10.1038/42990</doi><tpages>4</tpages></addata></record> |
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| ispartof | Nature (London), 1997-06, Vol.387 (6635), p.827-830 |
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| subjects | Analytical, structural and metabolic biochemistry Antibiotics Aspergillus nidulans Binding Sites Biological and medical sciences Biosynthesis Chemical reactions Chemistry Crystallography, X-Ray Crystals Enzymes Enzymes and enzyme inhibitors Ferrous Compounds - chemistry Ferrous Compounds - metabolism Fundamental and applied biological sciences. Psychology Hydrogen Bonding Iron Microorganisms Models, Molecular Oligopeptides - chemistry Oligopeptides - metabolism Oxidoreductases Oxidoreductases - chemistry Oxidoreductases - metabolism Oxygen - metabolism Penicillin Penicillins - biosynthesis Protein Conformation |
| title | Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation |
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