Premium
Inverting the Regioselectivity of the Berberine Bridge Enzyme by Employing Customized Fluorine‐Containing Substrates
Author(s) -
Resch Verena,
Lechner Horst,
Schrittwieser Joerg H.,
Wallner Silvia,
Gruber Karl,
Macheroux Peter,
Kroutil Wolfgang
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201201895
Subject(s) - regioselectivity , moiety , chemistry , substrate (aquarium) , combinatorial chemistry , stereochemistry , selectivity , fluorine , ring (chemistry) , structural isomer , organic chemistry , catalysis , oceanography , geology
Fluorine is commonly applied in pharmaceuticals to block the degradation of bioactive compounds at a specific site of the molecule. Blocking of the reaction center of the enzyme‐catalyzed ring closure of 1,2,3,4‐tetrahydrobenzylisoquinolines by a fluoro moiety allowed redirecting the berberine bridge enzyme (BBE)‐catalyzed transformation of these compounds to give the formation of an alternative regioisomeric product namely 11‐hydroxy‐functionalized tetrahydroprotoberberines instead of the commonly formed 9‐hydroxy‐functionalized products. Alternative strategies to change the regioselectivity of the enzyme, such as protein engineering, were not applicable in this special case due to missing substrate–enzyme interactions. Medium engineering, as another possible strategy, had clear influence on the regioselectivity of the reaction pathway, but did not lead to perfect selectivity. Thus, only substrate tuning by introducing a fluoro moiety at one potential reactive carbon center switched the reaction to the formation of exclusively one regioisomer with perfect enantioselectivity.