Dataset Information

Potent, Irreversible Inhibition of Human Carboxylesterases by Tanshinone Anhydrides Isolated from Salvia miltiorrhiza ("Danshen").

ABSTRACT: The roots of Salvia miltiorrhiza ("Danshen") have been used in Chinese herbal medicine for centuries for a host of different conditions. While the exact nature of the active components of this material are unknown, large amounts of tanshinones are present in extracts derived from these samples. Recently, the tanshinones have been demonstrated to be potent human carboxylesterase (CE) inhibitors, with the ability to modulate the biological activity of esterified drugs. During the course of these studies, we also identified more active, irreversible inhibitors of these enzymes. We have purified, identified, and synthesized these molecules and confirmed them to be the anhydride derivatives of the tanshinones. These compounds are exceptionally potent inhibitors ( Ki < 1 nM) and can inactivate human CEs both in vitro and in cell culture systems and can modulate the metabolism of the esterified drug oseltamivir. Therefore, the coadministration of Danshen extracts with drugs that contain the ester chemotype should be minimized since, not only is transient inhibition of CEs observed with the tanshinones, but also prolonged irreversible inhibition arises via interaction with the anhydrides.

SUBMITTER: Hatfield MJ

PROVIDER: S-EPMC6263802 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Potent, Irreversible Inhibition of Human Carboxylesterases by Tanshinone Anhydrides Isolated from Salvia miltiorrhiza ("Danshen").

Hatfield M Jason MJ Binder Randall J RJ Gannon Rowan R Fratt Ellie M EM Bowling John J Potter Philip M PM

Journal of natural products 20181023 11

The roots of Salvia miltiorrhiza ("Danshen") have been used in Chinese herbal medicine for centuries for a host of different conditions. While the exact nature of the active components of this material are unknown, large amounts of tanshinones are present in extracts derived from these samples. Recently, the tanshinones have been demonstrated to be potent human carboxylesterase (CE) inhibitors, with the ability to modulate the biological activity of esterified drugs. During the course of these s ...[more]

PMID: 30351923

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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

Potent, Irreversible Inhibition of Human Carboxylesterases by Tanshinone Anhydrides Isolated from Salvia miltiorrhiza ("Danshen").

Publications

Potent, Irreversible Inhibition of Human Carboxylesterases by Tanshinone Anhydrides Isolated from Salvia miltiorrhiza ("Danshen").

Similar Datasets

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