Triptolide binds covalently to a 90kDa nuclear protein. Role of epoxides in binding and activity

McCallum, Christine; Kwon, Suzy; Leavitt, Penny; Shen, Dong‐Ming; Liu, Wensheng; Gurnett, Anne

doi:10.1016/j.imbio.2007.02.002

Cited by 29 publications

(22 citation statements)

References 18 publications

(23 reference statements)

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“…It has been shown that 20 exerts its biological effects via inhibition and covalent modification of Cys342 of the transcription factor TFIIA ( 24 ). 47–49 In a manner that predicted the particular epoxide that is modified by the enzyme, the probe reacted with the 12,13-epoxide of 20 to yield 21 . 49 Likewise, 22 , a covalent proteasome inhibitor with an epoxy ketone functionality, gave 23 under the same conditions.…”

Section: Resultsmentioning

confidence: 99%

Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action

et al. 2016

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New methods are urgently needed to find novel natural products as structural leads for the development of new drugs against emerging diseases such as cancer and multiresistant bacterial infections. Here we introduce a reactivity-guided drug discovery approach for electrophilic natural products, a therapeutically relevant class of natural products that covalently modify their cellular targets, in crude extracts. Using carefully designed halogenated aromatic reagents, the process furnishes derivatives that are UV-active and highly conspicuous via mass spectrometry by virtue of an isotopically unique bromine or chlorine tag. In addition to the identification of high-value metabolites, the process facilitates the difficult task of structure elucidation by providing derivatives that are primed for X-ray crystallographic analysis. We show that a cysteine probe efficiently and chemoselectively labels enone-, β-lactam-, and β-lactone-based electrophilic natural products (parthenolide, andrographolide, wortmannin, penicillin G, salinosporamide), while a thiophenol probe preferentially labels epoxide-based electrophilic natural products (triptolide, epoxomicin, eponemycin, cyclomarin, salinamide). Using the optimized method, we were able to detect and isolate the epoxide-bearing natural product tirandalydigin from Salinispora and thereby link an orphan gene cluster to its gene product.

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Section: Resultsmentioning

confidence: 99%

Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action

et al. 2016

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“…However, an in vitro transcription assay showed that triptolide does not have the ability to directly interact and inhibit the elongating RNA polymerase II complex under the experimental conditions. Actually, a 90 kDa nuclear protein has recently been identified to bind triptolide (39). We thus suspect that this protein could be a general transcription factor not present in our reconstituted RNA polymerase II-mediated transcription assay.…”

Section: Discussionmentioning

confidence: 96%

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Vispé

DeVries

Créancier

et al. 2009

Molecular Cancer Therapeutics

159

135

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Triptolide, a natural product extracted from the Chinese plant Tripterygium wilfordii, possesses antitumor properties. Despite numerous reports showing the proapoptotic capacity and the inhibition of NF-κB-mediated transcription by triptolide, the identity of its cellular target is still unknown. To clarify its mechanism of action, we further investigated the effect of triptolide on RNA synthesis in the human non-small cell lung cancer cell line A549. Triptolide inhibited both total RNA and mRNA de novo synthesis, with the primary action being on the latter pool. We used 44K human pan-genomic DNA microarrays and identified the genes primarily affected by a short treatment with triptolide. Among the modulated genes, up to 98% are down-regulated, encompassing a large array of oncogenes including transcription factors and cell cycle regulators. We next observed that triptolide induced a rapid depletion of RPB1, the RNA polymerase II main subunit that is considered a hallmark of a transcription elongation blockage. However, we also show that triptolide does not directly interact with the RNA polymerase II complex nor does it damage DNA. We thus conclude that triptolide is an original pharmacologic inhibitor of RNA polymerase activity, affecting indirectly the transcription machinery, leading to a rapid depletion of short-lived mRNA, including transcription factors, cell cycle regulators such as CDC25A, and the oncogenes MYC and Src. Overall, the data shed light on the effect of triptolide on transcription, along with its novel potential applications in cancers, including acute myeloid leukemia, which is in part driven by the aforementioned oncogenic factors. [Mol Cancer Ther 2009;8(10):2780-90]

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“…al. (50) demonstrated that TRP binds irreversibly and specifically to an unidentified 90-kD nuclear protein. Another study reported the binding of TRP to a 110-kD calcium channel protein involved in polycystic kidney disease, PC2 or polycystin-2 (51).…”

Section: Discussionmentioning

confidence: 99%

Triptolide Inhibits Proliferation and Migration of Colon Cancer Cells by Inhibition of Cell Cycle Regulators and Cytokine Receptors

Johnson

Wang

Evers

2011

Journal of Surgical Research

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Background-Phytochemicals are an important source of emerging preventive and therapeutic agents for cancer. Triptolide/PG490, an extract of the Chinese herb Tripterygium wilfordii Hook F, is a potent anti-inflammatory agent that also possesses anticancer activity. While its antiproliferative effects are well-established, the potential anti-migratory effects of triptolide have not been characterized.

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Triptolide binds covalently to a 90kDa nuclear protein. Role of epoxides in binding and activity

Cited by 29 publications

References 18 publications

Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action

Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Triptolide Inhibits Proliferation and Migration of Colon Cancer Cells by Inhibition of Cell Cycle Regulators and Cytokine Receptors

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