Crystal Structure of Carbapenem Synthase (CarC)
The proposed biosynthetic pathway to the carbapenem antibiotics proceeds via epimerization/desaturation of a carbapenam in an unusual process catalyzed by an iron- and 2-oxoglutarate-dependent oxygenase, CarC. Crystal structures of CarC complexed with Fe(II) and 2-oxoglutarate reveal it to be hexame...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-06, Vol.278 (23), p.20843-20850 |
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| container_end_page | 20850 |
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| container_issue | 23 |
| container_start_page | 20843 |
| container_title | The Journal of biological chemistry |
| container_volume | 278 |
| creator | Clifton, Ian J. Doan, Linh X. Sleeman, Mark C. Topf, Maya Suzuki, Hikokazu Wilmouth, Rupert C. Schofield, Christopher J. |
| description | The proposed biosynthetic pathway to the carbapenem antibiotics proceeds via epimerization/desaturation of a carbapenam in an unusual process catalyzed by an iron- and 2-oxoglutarate-dependent oxygenase, CarC. Crystal structures of CarC complexed with Fe(II) and 2-oxoglutarate reveal it to be hexameric (space group C2221), consistent with solution studies. CarC monomers contain a double-stranded β-helix core that supports ligands binding a single Fe(II) to which 2-oxoglutarate complexes in a bi-dentate manner. A structure was obtained with l-N-acetylproline acting as a substrate analogue. Quantum mechanical/molecular mechanical modeling studies with stereoisomers of carbapenams and carbapenems were used to investigate substrate binding. The combined work will stimulate further mechanistic studies and aid in the engineering of carbapenem biosynthesis. |
| doi_str_mv | 10.1074/jbc.M213054200 |
| format | Article |
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Crystal structures of CarC complexed with Fe(II) and 2-oxoglutarate reveal it to be hexameric (space group C2221), consistent with solution studies. CarC monomers contain a double-stranded β-helix core that supports ligands binding a single Fe(II) to which 2-oxoglutarate complexes in a bi-dentate manner. A structure was obtained with l-N-acetylproline acting as a substrate analogue. Quantum mechanical/molecular mechanical modeling studies with stereoisomers of carbapenams and carbapenems were used to investigate substrate binding. 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The combined work will stimulate further mechanistic studies and aid in the engineering of carbapenem biosynthesis.</description><subject>Binding Sites</subject><subject>Carbapenems - biosynthesis</subject><subject>Crystallography</subject><subject>Iron - chemistry</subject><subject>Ketoglutaric Acids - chemistry</subject><subject>Oxidoreductases - chemistry</subject><subject>Oxidoreductases - metabolism</subject><subject>Pectobacterium carotovorum - enzymology</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>Substrate Specificity</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtLw0AQhxdRbK1ePUoOInpIu488NkcJvqDioQreln1MzErS1N1E6X_vSgo9OQwM_PhmGD6EzgmeE5wni0-l58-UMJwmFOMDNCWYs5il5P0QTTGmJC5oyifoxPtPHCopyDGaEJoRwnk2RYvSbX0vm2jVu0H3g4Ooq6JSOiU3sIY2Wm3XfS09RNchLG9O0VElGw9nuzlDb_d3r-VjvHx5eCpvl7FOcNHH1LAq4zJ0JTmmRqmCSJMyk0MSMoqZIrLINA0x5FmhOTGFJqkyjKYGazZDV-Pdjeu-BvC9aK3X0DRyDd3gRc5YwkjKAzgfQe067x1UYuNsK91WECz-FImgSOwVhYWL3eVBtWD2-M5JAC5HoLYf9Y91IJTtdA2toDkXlAmKecICxkcMgoZvC054bWGtwYQV3QvT2f9e-AXNJ37o</recordid><startdate>20030606</startdate><enddate>20030606</enddate><creator>Clifton, Ian J.</creator><creator>Doan, Linh X.</creator><creator>Sleeman, Mark C.</creator><creator>Topf, Maya</creator><creator>Suzuki, Hikokazu</creator><creator>Wilmouth, Rupert C.</creator><creator>Schofield, Christopher J.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20030606</creationdate><title>Crystal Structure of Carbapenem Synthase (CarC)</title><author>Clifton, Ian J. ; Doan, Linh X. ; Sleeman, Mark C. ; Topf, Maya ; Suzuki, Hikokazu ; Wilmouth, Rupert C. ; Schofield, Christopher J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-2d3f68a68afa802dbb91ad53d7e48af203b1a96c291ae769c81d9c15bd325d0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Binding Sites</topic><topic>Carbapenems - biosynthesis</topic><topic>Crystallography</topic><topic>Iron - chemistry</topic><topic>Ketoglutaric Acids - chemistry</topic><topic>Oxidoreductases - chemistry</topic><topic>Oxidoreductases - metabolism</topic><topic>Pectobacterium carotovorum - enzymology</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clifton, Ian J.</creatorcontrib><creatorcontrib>Doan, Linh X.</creatorcontrib><creatorcontrib>Sleeman, Mark C.</creatorcontrib><creatorcontrib>Topf, Maya</creatorcontrib><creatorcontrib>Suzuki, Hikokazu</creatorcontrib><creatorcontrib>Wilmouth, Rupert C.</creatorcontrib><creatorcontrib>Schofield, Christopher J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clifton, Ian J.</au><au>Doan, Linh X.</au><au>Sleeman, Mark C.</au><au>Topf, Maya</au><au>Suzuki, Hikokazu</au><au>Wilmouth, Rupert C.</au><au>Schofield, Christopher J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crystal Structure of Carbapenem Synthase (CarC)</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-06-06</date><risdate>2003</risdate><volume>278</volume><issue>23</issue><spage>20843</spage><epage>20850</epage><pages>20843-20850</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The proposed biosynthetic pathway to the carbapenem antibiotics proceeds via epimerization/desaturation of a carbapenam in an unusual process catalyzed by an iron- and 2-oxoglutarate-dependent oxygenase, CarC. 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| identifier | ISSN: 0021-9258 |
| ispartof | The Journal of biological chemistry, 2003-06, Vol.278 (23), p.20843-20850 |
| issn | 0021-9258 1083-351X |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Binding Sites Carbapenems - biosynthesis Crystallography Iron - chemistry Ketoglutaric Acids - chemistry Oxidoreductases - chemistry Oxidoreductases - metabolism Pectobacterium carotovorum - enzymology Protein Structure, Secondary Protein Structure, Tertiary Substrate Specificity |
| title | Crystal Structure of Carbapenem Synthase (CarC) |
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