Show simple item record

dc.contributor.authorHamed, Refaat B.*
dc.contributor.authorGomez-Castellanos, J.R.*
dc.contributor.authorWarhaut, H.L.*
dc.contributor.authorClaridge, T.D.W.*
dc.contributor.authorSchofield, C.J.*
dc.date.accessioned2019-04-30T14:53:34Z
dc.date.available2019-04-30T14:53:34Z
dc.date.issued2019-01-24
dc.identifier.citationHamed 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.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17000
dc.descriptionYesen_US
dc.description.abstractThere 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.en_US
dc.language.isoenen_US
dc.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/)en_US
dc.subjectβ-lactamsen_US
dc.subjectAntibacterialsen_US
dc.subjectCrotonasesen_US
dc.subjectAntibioticsen_US
dc.subjectCarbapenemsen_US
dc.titleBiocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonasesen_US
dc.status.refereedYesen_US
dc.date.Accepted2018-12-12
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.identifier.doihttps://doi.org/10.1038/s42004-018-0106-z
refterms.dateFOA2019-04-30T14:53:34Z


Item file(s)

Thumbnail
Name:
hamed_et_al_2019.pdf
Size:
2.253Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record