Open AccessMechanism of the Stereoselective Catalysis of Diels–Alderase PyrE3 Involved in Pyrroindomycin Biosynthesis
Author(s) -
Bo Li,
Xingyi Guan,
Yang Song,
Yike Zou,
Wen Liu,
K. N. Houk
Publication year - 2022
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.2c00015
Subject(s) - chemistry , polyene , steric effects , stereoselectivity , stereochemistry , diene , catalysis , cycloaddition , mechanism (biology) , computational chemistry , organic chemistry , natural rubber , philosophy , epistemology
The biosynthesis of pyrroindomycins A and B features a complexity-building [4 + 2] cycloaddition cascade, which generates the spirotetramate core under the catalytic effects of monofunctional Diels-Alderases PyrE3 and PyrI4. We recently showed that the main functions of PyrI4 include acid catalysis and induced-fit/conformational selection. We now present quantum mechanical and molecular dynamics studies implicating a different mode of action by PyrE3, which prearranges an anionic polyene substrate into a high-energy reactive conformation at which an inverse-electron-demand Diels-Alder reaction can occur with a low barrier. Stereoselection is realized by strong binding interactions at the endo stereochemical relationship and a local steric constraint on the endo -1,3-diene unit. These findings, illustrating distinct mechanisms for PyrE3 and PyrI4, highlight how nature has evolved multiple ways to catalyze Diels-Alder reactions.