Premium
Effects of Active‐Site Modification and Quaternary Structure on the Regioselectivity of Catechol‐ O ‐Methyltransferase
Author(s) -
Law Brian J. C.,
Bennett Matthew R.,
Thompson Mark L.,
Levy Colin,
Shepherd Sarah A.,
Leys David,
Micklefield Jason
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201508287
Subject(s) - regioselectivity , catechol , chemistry , catechol o methyl transferase , active site , vanillin , alkylation , protein quaternary structure , stereochemistry , enzyme , combinatorial chemistry , biochemistry , protein subunit , catalysis , allele , gene
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.