Journal
ACS CATALYSIS
Volume 9, Issue 2, Pages 1503-1513Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.8b04299
Keywords
systems biocatalysis; cascades; Michaelase; gamma-aminobutyric acids; gamma-nitrobutyric acids; enzyme engineering; pharmaceuticals
Categories
Funding
- Netherlands Organization of Scientific Research (VICI grant) [724.016.002]
- European Research Council (PoC grant) [713483]
- European Union [635595]
- European Research Council (ERC) [713483] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available