Yes / 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.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/17000 |
| Date | 12 December 2018 |
| Creators | Hamed, Refaat B., Gomez-Castellanos, J.R., Warhaut, H.L., Claridge, T.D.W., Schofield, C.J. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| 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/), CC-BY |
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