Enantioselective Synthesis of Pharmaceutically Active γ-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions

Biewenga, L., Thangavelu, S., Kunzendorf, A., Van Der Meer, J., Pijning, T., Tepper, P., Van Merkerk, R., Charnock, S. J., Thunnissen, A. W. H. & Poelarends, G. J., 1-Feb-2019, In : ACS Catalysis. 9, p. 1503-1513 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

Chiral γ-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, antidepressants and for the treatment of neuropathic pain. Here we report a one-pot two-step biocatalytic cascade route for synthesis of the pharmaceutically relevant enantiomers of γ-nitrobutyric acids, starting from simple precursors (acetaldehyde and nitroalkenes), using a tailor-made highly enantioselective artificial ‘Michaelase’ (4-oxalocrotonate tautomerase mutant L8Y/M45Y/F50A), an aldehyde dehydrogenase with a broad non-natural substrate scope, and a cofactor recycling system. We also report a three-step chemoenzymatic cascade route for the efficient chemical reduction of enzymatically prepared γ-nitrobutyric acids into GABA analogues in one pot, achieving high enantiopurity (e.r. up to 99:1) and high overall yields (up to 70%). This chemoenzymatic methodology offers a step-economic alternative route to important pharmaceutically active GABA analogues, and highlights the exciting opportunities available for combining chemocatalysts, natural enzymes, and designed artificial biocatalysts in multistep syntheses.
Original languageEnglish
Pages (from-to)1503-1513
Number of pages11
JournalACS Catalysis
Early online date7-Jan-2019
Publication statusPublished - 1-Feb-2019


  • Systems biocatalysis, cascades, "Michaelase", gamma-aminobutyric acids, gamma-nitrobutyric acids, enzyme engineering, pharmaceuticals, 4-OXALOCROTONATE TAUTOMERASE, MUTABILITY LANDSCAPES, ADDITION-REACTIONS, CATALYSIS, ACETALDEHYDE, REDUCTION, ALDEHYDES

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