Document Type
Article
Publication Version
Published Version
Publication Date
4-2008
Journal or Book Title
Journal of the American Chemical Society
Volume
130
Issue
16
First Page
5400
Last Page
5401
DOI
10.1021/ja710524w
Abstract
Terpene synthases often catalyze complex reactions involving intricate series of carbocation intermediates. The resulting, generally cyclical, structures provide initial hydrocarbon frameworks that underlie the astonishing structural diversity of the enormous class of terpenoid natural products (>50,000 known), and these enzymes often mediate the committed step in their particular biosynthetic pathway. Accordingly, how terpene synthases specify product outcome has drawn a great deal of attention. In previous work, we have shown that mutational introduction of a hydroxyl group at specific positions within diterpene synthase active sites can "short circuit" complex cyclization and/or rearrangement reactions, resulting in the production of "simpler"' diterpenes. Here we demonstrate that the converse change, substitution of an Ile for Thr at the relevant position in a native pimaradiene synthase, leads to a dramatic increase in reaction complexity. Product outcome is shifted from the tricyclic pimaradiene to a rearranged tetracycle, aphidicol-15-ene. Thus, the nature of the residue at this position acts as a true switch for product outcome. In addition, the ability of aliphatic residue substitution to enable a more complex reaction emphasizes the importance of substrate conformation imposed by a largely inert active site. Furthermore, the profound plasticity of diterpene synthases exemplified by this single residue switch for product outcome is consistent with the screening/diversity-oriented hypothesis of natural products metabolism.
Copyright Owner
American Chemical Society
Copyright Date
2008
Language
en
File Format
application/pdf
Recommended Citation
Morrone, Dana; Xu, Meimei; Fulton, D. Bruce; Determan, Mara K.; and Peters, Reuben J., "Increasing Complexity of a Diterpene Synthase Reaction with a Single Residue Switch" (2008). Biochemistry, Biophysics and Molecular Biology Publications. 7.
https://lib.dr.iastate.edu/bbmb_ag_pubs/7
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Natural Products Chemistry and Pharmacognosy Commons
Comments
Reprinted with permission from Journal of the American Chemical Society 130 (2008): 5400, doi:10.1021/ja710524w. Copyright 2008 American Chemical Society