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The 2-oxoglutarate-dependent dioxygenase superfamily participates in tanshinone production in Salvia miltiorrhiza.

ABSTRACT: Highly oxidized tanshinones are pharmacological ingredients extracted from the medicinal model plant Salvia miltiorrhiza and are mainly used to treat cardiovascular diseases. Previous studies have confirmed that cytochrome P450 mono-oxygenases (CYP450s) have a key function in the biosynthesis of tanshinones; however, no solid evidence links oxidation to the 2-oxoglutarate-dependent dioxygenase (2OGD) superfamily. Here, we identified 132 members of the DOXB and DOXC subfamilies of 2OGD by scanning the 2OG-FeII Oxy domain using a genome-wide strategy in S. miltiorrhiza. The DOXC class was phylogenetically divided into twelve clades. Combining phylogenetic relationships, differential expression and co-expression from various organs and tissues revealed that two 2OGDs were directly related to flavonoid metabolism, and that 13 2OGDs from different clades were predicted to be involved in tanshinone biosynthesis. Based on this insight into tanshinone production, we experimentally detected significant decreases in miltirone, cryptotanshinone, and tanshinone IIA (0.16-, 0.56-, and 0.56-fold, respectively) in 2OGD5 RNAi transgenic lines relative to the control lines using a metabonomics analysis. 2OGD5 was found to play a crucial role in the downstream biosynthesis of tanshinones following the hydroxylation of CYPs. Our results highlight the evolution and diversification of 2OGD superfamily members and suggest that they contribute to the complexity of tanshinone metabolites.

SUBMITTER: Xu Z

PROVIDER: S-EPMC5447875 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The 2-oxoglutarate-dependent dioxygenase superfamily participates in tanshinone production in Salvia miltiorrhiza.

Xu Zhichao Z Song Jingyuan J

Journal of experimental botany 20170401 9

Highly oxidized tanshinones are pharmacological ingredients extracted from the medicinal model plant Salvia miltiorrhiza and are mainly used to treat cardiovascular diseases. Previous studies have confirmed that cytochrome P450 mono-oxygenases (CYP450s) have a key function in the biosynthesis of tanshinones; however, no solid evidence links oxidation to the 2-oxoglutarate-dependent dioxygenase (2OGD) superfamily. Here, we identified 132 members of the DOXB and DOXC subfamilies of 2OGD by scannin ...[more]

PMID: 28398557

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Project description:Plant natural products have been co-opted for millennia by humans for various uses such as flavor, fragrances, and medicines. These compounds often are only produced in relatively low amounts and are difficult to chemically synthesize, limiting access. While elucidation of the underlying biosynthetic processes might help alleviate these issues (e.g., via metabolic engineering), investigation of this is hindered by the low levels of relevant gene expression and expansion of the corresponding enzymatic gene families. However, the often-inducible nature of such metabolic processes enables selection of those genes whose expression pattern indicates a role in production of the targeted natural product.Here, we combine metabolomics and transcriptomics to investigate the inducible biosynthesis of the bioactive diterpenoid tanshinones from the Chinese medicinal herb, Salvia miltiorrhiza (Danshen). Untargeted metabolomics investigation of elicited hairy root cultures indicated that tanshinone production was a dominant component of the metabolic response, increasing at later time points. A transcriptomic approach was applied to not only define a comprehensive transcriptome (comprised of 20,972 non-redundant genes), but also its response to induction, revealing 6,358 genes that exhibited differential expression, with significant enrichment for up-regulation of genes involved in stress, stimulus and immune response processes. Consistent with our metabolomics analysis, there appears to be a slower but more sustained increased in transcript levels of known genes from diterpenoid and, more specifically, tanshinone biosynthesis. Among the co-regulated genes were 70 transcription factors and 8 cytochromes P450, providing targets for future investigation.Our results indicate a biphasic response of Danshen terpenoid metabolism to elicitation, with early induction of sesqui- and tri- terpenoid biosynthesis, followed by later and more sustained production of the diterpenoid tanshinones. Our data provides a firm foundation for further elucidation of tanshinone and other inducible natural product metabolism in Danshen.

Dataset Information

The 2-oxoglutarate-dependent dioxygenase superfamily participates in tanshinone production in Salvia miltiorrhiza.

Publications

The 2-oxoglutarate-dependent dioxygenase superfamily participates in tanshinone production in Salvia miltiorrhiza.

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