6FPS

Crystal structure of 4-oxalocrotonate tautomerase triple mutant L8Y/M45Y/F50A

Summary for 6FPS

• Entry DOI: 10.2210/pdb6fps/pdb
• Descriptor: 2-hydroxymuconate tautomerase, PHOSPHATE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: 2-hydroxymuconate tautomerase, isomerase
• Biological source: Pseudomonas putida (Arthrobacter siderocapsulatus)
• Total number of polymer chains: 18
• Total formula weight: 123086.31

Authors

Pijning, T.,Thunnissen, A.M.W.H. (deposition date: 2018-02-12, release date: 2019-03-06, Last modification date: 2024-01-17)

Primary citation

Biewenga, L.,Saravanan, T.,Kunzendorf, A.,van der Meer, J.Y.,Pijning, T.,Tepper, P.G.,van Merkerk, R.,Charnock, S.J.,Thunnissen, A.W.H.,Poelarends, G.J.
Enantioselective Synthesis of Pharmaceutically Active gamma-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions.
ACS Catal, 9:1503-1513, 2019

PubMed Abstract: Chiral γ-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 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.

PubMed: 30740262
DOI: 10.1021/acscatal.8b04299

Experimental method

X-RAY DIFFRACTION (1.9 Å)