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

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journal contribution
posted on 28.12.2016, 00:00 by Refaat B. Hamed, Luc Henry, Timothy D. W. Claridge, Christopher J. Schofield
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 center, 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 manifestly improved hydrolytic stability compared to the unsubstituted carbapenams. The results highlight the use of modified carbapenem biosynthesis enzymes for production of carbapenams with improved properties.