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    Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases

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    Publication date
    2019-01-24
    Author
    Hamed, Refaat B.
    Gomez-Castellanos, J.R.
    Warhaut, H.L.
    Claridge, T.D.W.
    Schofield, C.J.
    Keyword
    β-lactams
    Antibacterials
    Crotonases
    Antibiotics
    Carbapenems
    Rights
    (c) 2019 The Authors. This is an Open Access article distributed under a Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)
    Peer-Reviewed
    Yes
    
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    Abstract
    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. Structurallyguided 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 alkylmalonylCoA 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.
    URI
    http://hdl.handle.net/10454/17000
    Version
    Published version
    Citation
    Hamed RB, Gomez-Castellano JR, Henry L et al (2019) Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases. Communications Chemistry. 2: 7.
    Link to publisher’s version
    https://doi.org/10.1038/s42004-018-0106-z
    Type
    Article
    Collections
    Life Sciences Publications

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