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- W1449423006 abstract "Thiamine diphosphate (ThDP)-dependent enzymes enable the challenging stereoselective synthesis of α-hydroxy ketones via asymmetric C–C bond formation. However, the steric and chemical properties of the enzymes’ active sites often limit the product range, specifically the access to (S)-α-hydroxy ketones. Introduction of the S-pocket concept, which explains stereoselectivity by the orientation of the substrates prior to carboligation, paved the way for the design of S-selective ThDP-dependent enzymes, however, often only with moderate stereoselectivity. This thesis aimed for new concepts to design tailor-made S-selective variants to expand the toolbox of ThDP-dependent enzymes. After confirmation of the general validity of the Spocket concept by transfer to the new toolbox enzymes acetohydroxyacid synthase and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase (MenD), two novel strategies were developed to tailor ThDP-dependent enzymes with high S-selectivity: (i) suppression of the “R-pathway”, and (ii) creation of “thiamine enzyme hybrids”. The combination of the basic S-pocket concept with targeted destabilization of the R-pathway improved the S-selectivity of pyruvate decarboxylase (PDC) as well as new MenD variants enabling carboligations with up to > 99 % ee. The design of a hybrid substrate-binding site from an S-selective PDC variant with a large S-pocket and a benzaldehyde lyase with a large donor binding site combined the different selectivity-determining modules and thus solved the long-standing problem of S-selective benzoin synthesis starting from readily available benzaldehydes. The results demonstrate the high quality of current structure-function relationships as well as the robustness of ThDP-dependent enzymes towards active site mutations. S-Selectivity can be adjusted now by different strategies. Moreover, the hybridization approach might pave the way for a tailor-made design of ThDP-dependent enzymes with desired and novel carboligation activities. This work complemented the toolbox of ThDP-dependent enzymes by four wild-type enzymes and about 35 variants with characterized carboligation activity, which broadened the enzymatically accessible α-hydroxy ketone platform by novel functionalized mixed araliphatic α-hydroxy ketones as well as (S)-benzoins with excellent ees." @default.
- W1449423006 created "2016-06-24" @default.
- W1449423006 creator A5041525775 @default.
- W1449423006 date "2014-01-01" @default.
- W1449423006 modified "2023-09-27" @default.
- W1449423006 title "Tailor-made thiamine diphosphate-dependent enzymes for S-selective carboligation" @default.
- W1449423006 hasPublicationYear "2014" @default.
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