Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases
There is a need to develop asymmetric routes to functionalised β-lactams, which remain the most important group of antibacterials. Here we describe biocatalytic and protein engineering studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective production of functionalised c...
| Hoofdauteurs: | , , , , , |
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| Formaat: | Journal article |
| Gepubliceerd in: |
Springer Nature
2019
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| _version_ | 1826271467689476096 |
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| author | Hamed, R Gomez-Castellanos, J Henry, L Warhaut, S Claridge, T Schofield, C |
| author_facet | Hamed, R Gomez-Castellanos, J Henry, L Warhaut, S Claridge, T Schofield, C |
| author_sort | Hamed, R |
| collection | OXFORD |
| description | There is a need to develop asymmetric routes to functionalised β-lactams, which remain the most important group of antibacterials. Here we describe biocatalytic and protein engineering studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective production of functionalised carbapenams with three contiguous chiral centres. Structurally-guided substitutions of wildtype carboxymethylproline synthases enable tuning of their C-N and C-C bond forming capacity to produce 5-carboxymethylproline derivatives substituted at C-4 and C-6, from amino acid aldehyde and malonyl-CoA derivatives. Use of tandem enzyme incubations comprising an engineered carboxymethylproline synthase and an alkylmalonyl-CoA forming enzyme (i.e. malonyl-CoA synthetase or crotonyl-CoA carboxylase reductase) can improve stereocontrol and expand the product range. Some of the prepared 4,6-disubstituted-5-carboxymethylproline derivatives are converted to bicyclic β-lactams by carbapenam synthetase catalysis. The results illustrate the utility of tandem enzyme systems involving engineered crotonases for asymmetric bicyclic β-lactam synthesis. |
| first_indexed | 2024-03-06T21:57:07Z |
| format | Journal article |
| id | oxford-uuid:4d4a33af-4ab3-46ff-a766-0d6d1ecdda92 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T21:57:07Z |
| publishDate | 2019 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:4d4a33af-4ab3-46ff-a766-0d6d1ecdda922022-03-26T15:54:41ZBiocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonasesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4d4a33af-4ab3-46ff-a766-0d6d1ecdda92Symplectic Elements at OxfordSpringer Nature2019Hamed, RGomez-Castellanos, JHenry, LWarhaut, SClaridge, TSchofield, CThere is a need to develop asymmetric routes to functionalised β-lactams, which remain the most important group of antibacterials. Here we describe biocatalytic and protein engineering studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective production of functionalised carbapenams with three contiguous chiral centres. Structurally-guided substitutions of wildtype carboxymethylproline synthases enable tuning of their C-N and C-C bond forming capacity to produce 5-carboxymethylproline derivatives substituted at C-4 and C-6, from amino acid aldehyde and malonyl-CoA derivatives. Use of tandem enzyme incubations comprising an engineered carboxymethylproline synthase and an alkylmalonyl-CoA forming enzyme (i.e. malonyl-CoA synthetase or crotonyl-CoA carboxylase reductase) can improve stereocontrol and expand the product range. Some of the prepared 4,6-disubstituted-5-carboxymethylproline derivatives are converted to bicyclic β-lactams by carbapenam synthetase catalysis. The results illustrate the utility of tandem enzyme systems involving engineered crotonases for asymmetric bicyclic β-lactam synthesis. |
| spellingShingle | Hamed, R Gomez-Castellanos, J Henry, L Warhaut, S Claridge, T Schofield, C Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title | Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title_full | Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title_fullStr | Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title_full_unstemmed | Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title_short | Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases |
| title_sort | biocatalytic production of bicyclic β lactams with three contiguous chiral centres using engineered crotonases |
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