Open AccessMechanistic analysis of carbon–carbon bond formation by deoxypodophyllotoxin synthase
Author(s) -
Huibin Tang,
Mingzai Wu,
Hsiao-Yu Lin,
Meng-Ru Han,
Yueh-Hua Tu,
Zemin Yang,
TunCheng Chien,
Nei-Li Chan,
Weichen Chang
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2113770119
Subject(s) - chemistry , ring (chemistry) , stereochemistry , hydroxylation , deprotonation , reactivity (psychology) , hydrogen atom abstraction , carbocation , substrate (aquarium) , enzyme , medicinal chemistry , hydrogen , organic chemistry , medicine , ion , alternative medicine , pathology , oceanography , geology
Significance The completion of the tetracyclic core of etoposide, classified by the World Health Organization as an essential medicine, by the Fe/2OG oxygenase deoxypodophyllotoxin synthase follows a hybrid radical-polar pathway not previously seen in other members of this enzyme class. The implication of a substrate-based benzylic carbocation in this mechanism will inform ongoing efforts to create analogs of this important drug with improved or emergent properties and represents a new route for resolution of the initial substrate radical that is common to members of the class. This study adds to our understanding on a growing number of biochemical transformations in which carbocation intermediates are likely to be crucial.