A Conformational Switch in the Catalytic Lysine Governs the Stereochemical Outcome of DERA-Catalyzed Aldol Addition

A conformational switch of the catalytic lysine in DERA from Geobacillus (DERAGs) is linked to enantioselectivity, including the Ser185→Gly variant that inverts S- to R-selectivity.

• Why it matters: Enantioselective DERA aldol additions are valuable for making chiral drug intermediates, but how specific mutations control stereochemical outcome is not well understood.
• What they did: High-resolution apo crystal structures of wild-type DERAGs and enantiocomplementary variants T12I/S185A and S185G were combined with biochemistry, biocatalysis, and molecular dynamics to analyze lysine conformations and a conserved amino-acid mechanism.
• The result: The catalytic lysine adopts two conformations, and a conserved amino acid regulates enantioselectivity; the same stereochemical basis is conserved in DERA from Escherichia coli.

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