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Stereoselective Production of Dimethyl-Substituted Carbapenams via Engineered Carbapenem Biosynthesis Enzymes

Research Authors
Refaat Bakr Hamed, Luc Henry, Timothy D. W. Claridge, and Christopher J. Schofield
Research Department
Research Journal
ACS Catalysis
Research Publisher
American Chemical Society
Research Rank
1
Research Vol
NULL
Research Website
http://pubs.acs.org/doi/abs/10.1021/acscatal.6b02509?journalCode=accacs
Research Year
2017
Research Member
Research Abstract

Stereoselective biocatalysis by crotonase superfamily enzymes is exemplified by use of engineered 5-carboxymethylproline synthases (CMPSs) for preparation of functionalized 5-carboxymethylproline (5-CMP) derivatives methylated at two positions (i.e. C2/C6, C3/C6 and C5/C6), including products with a quaternary centre, from appropriately-substituted-amino acid aldehydes and C-2 epimeric methylmalonyl-CoA. The enzymatically-produced disubstituted 5-CMPs were converted by carbapenam synthetase into methylated bicyclic Β-lactams, which manifest improved hydrolytic stability compared to the unsubstituted carbapenams. The results highlight the use of modi-fied carbapenem biosynthesis enzymes for production of new carbapenams with improved properties.