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Publication Abstract from PubMed

Chiral gamma-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, as 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 gamma-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 gamma-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.

Enantioselective Synthesis of Pharmaceutically Active gamma-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions.,Biewenga L, Saravanan T, Kunzendorf A, van der Meer JY, Pijning T, Tepper PG, van Merkerk R, Charnock SJ, Thunnissen AWH, Poelarends GJ ACS Catal. 2019 Feb 1;9(2):1503-1513. doi: 10.1021/acscatal.8b04299. Epub 2019, Jan 7. PMID:30740262^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.