Tabersonine

ACS Chem Neurosci. 2015 Jun 17;6(6):879-88.

Tabersonine Inhibits Amyloid Fibril Formation and Cytotoxicity of Aβ(1-42).[Pubmed: 25874995 ]

The misfolding and aggregation of amyloid beta (Aβ) peptides into amyloid fibrils are key events in the amyloid cascade hypothesis for the etiology of Alzheimer's disease (AD).
METHODS AND RESULTS:
Using thioflavin-T (ThT) fluorescence assay, atomic force microscopy, circular dichroism, size exclusion chromatography, surface plasmon resonance (SPR), and cytotoxicity tests, we demonstrate that Tabersonine, an ingredient extracted from the bean of Voacanga africana, disrupts Aβ(1-42) aggregation and ameliorates Aβ aggregate-induced cytotoxicity. A small amount of Tabersonine (e.g., 10 μM) can effectively inhibit the formation of Aβ(1-42) (e.g., 80 μM) fibrils or convert mature fibrils into largely innocuous amorphous aggregates. SPR results indicate that Tabersonine binds to Aβ(1-42) oligomers in a dose-dependent way. Molecular dynamics (MD) simulations further confirm that Tabersonine can bind to oligomers such as the pentamer of Aβ(1-42). Tabersonine preferentially interact with the β-sheet grooves of Aβ(1-42) containing aromatic and hydrophobic residues. The various binding sites and modes explain the diverse inhibitory effects of Tabersonine on Aβ aggregation.
CONCLUSIONS:
Given that Tabersonine is a natural product and a precursor for vincristine used in cancer chemotherapy, the biocompatibility and small size essential for permeating the blood-brain barrier make it a potential therapeutic drug candidate for treating AD.

Phytochemistry. 2003 Sep;64(2):401-9.

Jasmonate-induced epoxidation of tabersonine by a cytochrome P-450 in hairy root cultures of Catharanthus roseus.[Pubmed: 12943756]

Methyl jasmonate, a chemical inducer of secondary metabolism, was shown to promote Tabersonine 2 biosynthesis in hairy root cultures of Catharanthus roseus.
METHODS AND RESULTS:
Tabersonine 6,7-epoxidase activity was detected in total protein extract of jasmonate-induced hairy root cultures using labeled 14C-Tabersonine 2. This enzyme converted Tabersonine 2 to lochnericine 3 by selective epoxidation at positions 6 and 7 via a reaction dependent on NADPH and molecular oxygen. Carbon monoxide, clotrimazole, miconazole, and cytochrome C were shown to be strong inhibitors of the enzyme.
CONCLUSIONS:
The activity was found in microsomes, indicating that Tabersonine 6,7-epoxidase was a cytochrome P-450-dependent monooxygenase.

Proc Natl Acad Sci U S A. 2015 May 12;112(19):6224-9.

Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast.[Pubmed: 25918424 ]

Antitumor substances related to vinblastine and vincristine are exclusively found in the Catharanthus roseus (Madagascar periwinkle), a member of the Apocynaceae plant family, and continue to be extensively used in cancer chemotherapy. Although in high demand, these valuable compounds only accumulate in trace amounts in C. roseus leaves. Vinblastine and vincristine are condensed from the monoterpenoid indole alkaloid (MIA) precursors catharanthine and vindoline. Although catharanthine biosynthesis remains poorly characterized, the biosynthesis of vindoline from the MIA precursor Tabersonine is well understood at the molecular and biochemical levels.
METHODS AND RESULTS:
This study uses virus-induced gene silencing (VIGS) to identify a cytochrome P450 [CYP71D1V2; Tabersonine 3-oxygenase (T3O)] and an alcohol dehydrogenase [ADHL1; Tabersonine 3-reductase (T3R)] as candidate genes involved in the conversion of Tabersonine or 16-methoxyTabersonine to 3-hydroxy-2,3-dihydroTabersonine or 3-hydroxy-16-methoxy-2,3-dihydroTabersonine, which are intermediates in the vindorosine and vindoline pathways, respectively. Biochemical assays with recombinant enzymes confirm that product formation is only possible by the coupled action of T3O and T3R, as the reaction product of T3O is an epoxide that is not used as a substrate by T3R.
CONCLUSIONS:
The T3O and T3R transcripts were identified in a C. roseus database representing genes preferentially expressed in leaf epidermis and suggest that the subsequent reaction products are transported from the leaf epidermis to specialized leaf mesophyll idioblast and laticifer cells to complete the biosynthesis of these MIAs. With these two genes, the complete seven-gene pathway was engineered in yeast to produce vindoline from Tabersonine.