Enzymatic Cyclization of Dioxidosqualene to Heterocyclic Triterpenes

Oxidosqualene cyclases normally produce triterpenes from 2,3-(S)-oxidosqualene (OS) but also can cyclize its minor companion (3S,22S)-2,3:22,23-dioxidosqualene (DOS). We explored DOS cyclization in plant triterpene synthesis using a recombinant lupeol synthase (LUP1) heterologously expressed in yeas...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2005-12, Vol.127 (51), p.18008-18009
Main Authors: Shan, Hui, Segura, Michael J. R, Wilson, William K, Lodeiro, Silvia, Matsuda, Seiichi P. T
Format: Article
Language:English
Subjects:
Alicyclic compounds, terpenoids, prostaglandins, steroids
Biological and medical sciences
Chemistry
Cyclization
Exact sciences and technology
Fundamental and applied biological sciences. Psychology
Intramolecular Transferases - chemistry
Intramolecular Transferases - metabolism
Mechanisms. Catalysis. Electron transfer. Models
Molecular biophysics
Organic chemistry
Physical chemistry in biology
Plant Proteins - chemistry
Plant Proteins - metabolism
Preparations and properties
Squalene - analogs & derivatives
Squalene - chemistry
Squalene - metabolism
Terpenoids
Triterpenes - chemical synthesis
Triterpenes - metabolism
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Summary:Oxidosqualene cyclases normally produce triterpenes from 2,3-(S)-oxidosqualene (OS) but also can cyclize its minor companion (3S,22S)-2,3:22,23-dioxidosqualene (DOS). We explored DOS cyclization in plant triterpene synthesis using a recombinant lupeol synthase (LUP1) heterologously expressed in yeast. Incubation of LUP1 with 3S,22S-DOS gave epoxydammaranes epimeric at C20 and a 17,24-epoxybaccharane in a 4:2:3 ratio. The products reflected a new mechanistic paradigm for DOS cyclization. The structures were determined by NMR and GC−MS, and recent errors in the epoxydammarane literature were rectified. Some DOS metabolites are likely candidates for regulating triterpenoid biosynthesis, while others may be precursors of saponin aglycones. Our in vivo experiments in yeast generated substantial amounts of DOS metabolites in a single enzymatic step, suggesting a seminal role for the DOS shunt pathway in the evolution of saponin synthesis. Quantum mechanical calculations revealed oxonium ion intermediates, whose reactivity altered the usual mechanistic patterns of triterpene synthesis. Further analysis indicated that the side chain of the epoxydammarenyl cation intermediate is in an extended conformation. The overall results establish new roles for DOS in triterpene synthesis and exemplify how organisms can increase the diversity of secondary metabolites without constructing new enzymes.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja055822g