Simultaneous engineering of an enzyme's entrance tunnel and active site: the case of monoamine oxidase MAO-N

Chemical Science
Guangyue LiManfred T Reetz

Abstract

A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.

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Citations

Jan 3, 2019·Angewandte Chemie·Christian Curado-CarballadaSílvia Osuna
Feb 26, 2020·Scientific Reports·Natalia KwiatosStanisław Bielecki
May 22, 2018·Chemical Communications : Chem Comm·Miguel A Maria-SolanoSílvia Osuna
Feb 2, 2021·Chembiochem : a European Journal of Chemical Biology·Yuxue LiuZongbao Kent Zhao
May 26, 2021·Scientific Reports·Yael Baruch-Shpigler, David Avnir
Jun 19, 2021·Chemical Society Reviews·Dong YiUwe T Bornscheuer
Dec 7, 2018·Journal of the American Chemical Society·Piia KokkonenMartin Hof
Aug 28, 2021·Biotechnology Advances·Jing FengBian Wu

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Methods Mentioned

BETA
X-ray

Software Mentioned

GBSA
Autodock
Accelrys Studio
MM
AMBER16

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