期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8130-8135
DOI：10.1073/pnas.1504951112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTerpenoids are the largest group of plant-specialized metabolites and include many valuable bioactive compounds, such as the blockbuster anticancer drugs vincristine and vinblastine, that are monoterpenoid indole alkaloids from the medicinal plant Catharanthus roseus (Madagascar periwinkle). A master regulator was discovered that activates the biosynthesis of the iridoids, the monoterpenoid precursors of vinblastine and vincristine, and the rate-limiting branch in their biosynthetic pathway. This master regulator can be used to boost production of iridoids and monoterpenoid indole alkaloids in C. roseus cell cultures and thus represents an interesting tool for the metabolic engineering of the sustainable production of these high-value compounds in cultures of the endogenous plant species. Plants make specialized bioactive metabolites to defend themselves against attackers. The conserved control mechanisms are based on transcriptional activation of the respective plant species-specific biosynthetic pathways by the phytohormone jasmonate. Knowledge of the transcription factors involved, particularly in terpenoid biosynthesis, remains fragmentary. By transcriptome analysis and functional screens in the medicinal plant Catharanthus roseus (Madagascar periwinkle), the unique source of the monoterpenoid indole alkaloid (MIA)-type anticancer drugs vincristine and vinblastine, we identified a jasmonate-regulated basic helix-loop-helix (bHLH) transcription factor from clade IVa inducing the monoterpenoid branch of the MIA pathway. The bHLH iridoid synthesis 1 (BIS1) transcription factor transactivated the expression of all of the genes encoding the enzymes that catalyze the sequential conversion of the ubiquitous terpenoid precursor geranyl diphosphate to the iridoid loganic acid. BIS1 acted in a complementary manner to the previously characterized ethylene response factor Octadecanoid derivative-Responsive Catharanthus APETALA2-domain 3 (ORCA3) that transactivates the expression of several genes encoding the enzymes catalyzing the conversion of loganic acid to the downstream MIAs. In contrast to ORCA3, overexpression of BIS1 was sufficient to boost production of high-value iridoids and MIAs in C. roseus suspension cell cultures. Hence, BIS1 might be a metabolic engineering tool to produce sustainably high-value MIAs in C. roseus plants or cultures.
