Crotonase Catalysis Enables Flexible Production of Functionalized Prolines and Carbapenams
The biocatalytic versatility of wildtype and engineered carboxymethylproline synthases (CMPSs) is demonstrated by the preparation of functionalized 5-carboxymethylproline derivatives methylated at C-2, C-3, C-4, or C-5 of the proline ring from appropriately substituted amino acid aldehydes and malon...
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| Veröffentlicht in: | Journal of the American Chemical Society 2012-01, Vol.134 (1), p.471-479 |
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| container_issue | 1 |
| container_start_page | 471 |
| container_title | Journal of the American Chemical Society |
| container_volume | 134 |
| creator | Hamed, Refaat B Henry, Luc Gomez-Castellanos, J. Ruben Mecinović, Jasmin Ducho, Christian Sorensen, John L Claridge, Timothy D. W Schofield, Christopher J |
| description | The biocatalytic versatility of wildtype and engineered carboxymethylproline synthases (CMPSs) is demonstrated by the preparation of functionalized 5-carboxymethylproline derivatives methylated at C-2, C-3, C-4, or C-5 of the proline ring from appropriately substituted amino acid aldehydes and malonyl-coenzyme A. Notably, compounds with a quaternary center (at C-2 or C-5) were prepared in a stereoselective fashion by engineered CMPSs. The substituted-5-carboxymethyl-prolines were converted into the corresponding bicyclic β-lactams using a carbapenam synthetase. The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers. |
| doi_str_mv | 10.1021/ja208318d |
| format | Article |
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The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/ja208318d</identifier><identifier>PMID: 22091817</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Biocatalysis ; Carbapenems - biosynthesis ; Carbapenems - chemistry ; Carbapenems - metabolism ; Carbon-Carbon Lyases - chemistry ; Carbon-Carbon Lyases - genetics ; Carbon-Carbon Lyases - metabolism ; Methylation ; Models, Molecular ; Proline - biosynthesis ; Proline - chemistry ; Proline - metabolism ; Protein Conformation ; Protein Engineering - methods</subject><ispartof>Journal of the American Chemical Society, 2012-01, Vol.134 (1), p.471-479</ispartof><rights>Copyright © 2011 American Chemical Society</rights><rights>2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-5aaa9b291eb4ccd5d09b5627c45bd0402b4624ed233bceaa1f4e9dbc8d2ca3b33</citedby><cites>FETCH-LOGICAL-a314t-5aaa9b291eb4ccd5d09b5627c45bd0402b4624ed233bceaa1f4e9dbc8d2ca3b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/ja208318d$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/ja208318d$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22091817$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamed, Refaat B</creatorcontrib><creatorcontrib>Henry, Luc</creatorcontrib><creatorcontrib>Gomez-Castellanos, J. 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The substituted-5-carboxymethyl-prolines were converted into the corresponding bicyclic β-lactams using a carbapenam synthetase. The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers.</description><subject>Biocatalysis</subject><subject>Carbapenems - biosynthesis</subject><subject>Carbapenems - chemistry</subject><subject>Carbapenems - metabolism</subject><subject>Carbon-Carbon Lyases - chemistry</subject><subject>Carbon-Carbon Lyases - genetics</subject><subject>Carbon-Carbon Lyases - metabolism</subject><subject>Methylation</subject><subject>Models, Molecular</subject><subject>Proline - biosynthesis</subject><subject>Proline - chemistry</subject><subject>Proline - metabolism</subject><subject>Protein Conformation</subject><subject>Protein Engineering - methods</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtKw0AUQAdRbK0u_AHJRsRFdF55LSW0KhR0oRs34c4jkDKZqTMJWL_eqa1dubr3cg9ncRC6JPiOYEruV0BxyUipjtCUZBSnGaH5MZpijGlalDmboLMQVvHktCSnaEIprkhJiin6qL0bnIWgkxoGMJvQhWRuQRgdkoXRX13cklfv1CiHztnEtclitL87mO5bq-3TdDbiYFWUeAFrbaEP5-ikBRP0xX7O0Pti_lY_pcuXx-f6YZkCI3xIMwCoBK2IFlxKlSlciSynheSZUJhjKnhOuVaUMSE1AGm5rpSQpaISmGBshm523rV3n6MOQ9N3QWpjwGo3hqYiOeE5I0Ukb3ek9C4Er9tm7bse_KYhuNmWbA4lI3u1t46i1-pA_qWLwPUOABmalRt97BH-Ef0A3SR7og</recordid><startdate>20120111</startdate><enddate>20120111</enddate><creator>Hamed, Refaat B</creator><creator>Henry, Luc</creator><creator>Gomez-Castellanos, J. 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| source | MEDLINE; ACS Publications |
| subjects | Biocatalysis Carbapenems - biosynthesis Carbapenems - chemistry Carbapenems - metabolism Carbon-Carbon Lyases - chemistry Carbon-Carbon Lyases - genetics Carbon-Carbon Lyases - metabolism Methylation Models, Molecular Proline - biosynthesis Proline - chemistry Proline - metabolism Protein Conformation Protein Engineering - methods |
| title | Crotonase Catalysis Enables Flexible Production of Functionalized Prolines and Carbapenams |
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