Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase

Angewandte Chemie
Brian J C LawJason Micklefield

Abstract

Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack of regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta- or para-methylated catechols. X-ray crystallography further revealed how the active-site residues and quaternary structure govern regioselectivity. Finally, analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin.

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Citations

Feb 13, 2016·Journal of the American Chemical Society·Anna-Winona StruckJason Micklefield
Aug 24, 2016·The Journal of Physical Chemistry. B·Garima Jindal, Arieh Warshel
Apr 4, 2017·Chembiochem : a European Journal of Chemical Biology·Joanna C SadlerGlenn A Burley
May 24, 2018·Angewandte Chemie·Matthew R BennettJason Micklefield
May 28, 2020·Chembiochem : a European Journal of Chemical Biology·Iain J W McKeanGlenn A Burley
May 14, 2020·Angewandte Chemie·Abigail J HerbertJason Micklefield
Sep 9, 2019·International Journal of Biological Macromolecules·Wei LiYinggang Luo
Feb 19, 2021·Journal of Agricultural and Food Chemistry·Seul Hoo LeeKyung-Jin Kim
Jan 17, 2021·Angewandte Chemie·Elvira RomeroChristian Schnepel
Apr 24, 2021·Chembiochem : a European Journal of Chemical Biology·Qingyun TangUwe T Bornscheuer
May 25, 2021·Biochemistry and Biophysics Reports·Aminu UsmanBrendan S Wilhelmi
Jul 20, 2021·Green Chemistry : an International Journal and Green Chemistry Resource : GC·Joanna C Sadler, Stephen Wallace
Aug 31, 2018·The Journal of Physical Chemistry. B·David Adrian SaezEsteban Vöhringer-Martinez
Apr 21, 2018·ACS Chemical Biology·Qi ZhangEvripidis Gavathiotis
Nov 3, 2021·Chembiochem : a European Journal of Chemical Biology·Jack J SangsterJuan Mangas-Sanchez

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Methods Mentioned

BETA
X‐ray

Software Mentioned

COMT

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