Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. ACS Synth Biol. 2024 May 17;13(5):1498-1512. doi: 10.1021/acssynbio.4c00039. 
Epub 2024 Apr 18.

Yeast Platforms for Production and Screening of Bioactive Derivatives of 
Rauwolscine.

Bradley SA(1), Hansson FG(1), Lehka BJ(1), Rago D(1), Pinho P(1), Peng H(1), 
Adhikari KB(1), Haidar AK(1), Hansen LG(1)(2), Volkova D(1), Holtz M(1), Muyo 
Abad S(1), Ma X(1), Koudounas K(3), Besseau S(3), Gautron N(3), Mélin C(3), Marc 
J(3), Birer Williams C(3), Courdavault V(3), Jensen ED(1), Keasling 
JD(1)(4)(5)(6)(7), Zhang J(1)(2), Jensen MK(1)(2).

Author information:
(1)Novo Nordisk Foundation Center for Biosustainability, Technical University of 
Denmark, 2800 Lyngby, Denmark.
(2)Biomia ApS, DK-2100 Copenhagen, Denmark.
(3)EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, 
F-37200 Tours, France.
(4)Joint BioEnergy Institute, Emeryville, California 94608,United States.
(5)Biological Systems and Engineering Division, Lawrence Berkeley National 
Laboratory, Berkeley, California 94720,United States.
(6)Department of Chemical and Biomolecular Engineering, Department of 
Bioengineering, University of California, Berkeley, California 94720, United 
States.
(7)Center for Synthetic Biochemistry, Institute for Synthetic Biology, Shenzhen 
Institutes of Advanced Technologies, Shenzhen 518055, China.

Monoterpene indole alkaloids (MIAs) make up a highly bioactive class of 
metabolites produced by a range of tropical and subtropical plants. The 
corynanthe-type MIAs are a stereochemically complex subclass with therapeutic 
potential against a large number of indications including cancer, psychotic 
disorders, and erectile dysfunction. Here, we report yeast-based cell factories 
capable of de novo production of corynanthe-type MIAs rauwolscine, yohimbine, 
tetrahydroalstonine, and corynanthine. From this, we demonstrate regioselective 
biosynthesis of 4 fluorinated derivatives of these compounds and de novo 
biosynthesis of 7-chlororauwolscine by coexpression of a halogenase with the 
biosynthetic pathway. Finally, we capitalize on the ability of these cell 
factories to produce derivatives of these bioactive scaffolds to establish a 
proof-of-principle drug discovery pipeline in which the corynanthe-type MIAs are 
screened for bioactivity on human drug targets, expressed in yeast. In doing so, 
we identify antagonistic and agonistic behavior against the human adrenergic G 
protein-coupled receptors ADRA2A and ADRA2B, and the serotonergic receptor 
5HT4b, respectively. This study thus demonstrates a proto-drug discovery 
pipeline for bioactive plant-inspired small molecules based on one-pot 
biocatalysis of natural and new-to-nature corynanthe-type MIAs in yeast.

DOI: 10.1021/acssynbio.4c00039
PMID: 38635307 [Indexed for MEDLINE]


2. Chem Biol Interact. 2018 Jun 25;290:37-43. doi: 10.1016/j.cbi.2018.05.006.
Epub  2018 May 19.

Simultaneous determination of intestinal permeability and potential drug 
interactions of complex mixtures using Caco-2 cells and high-resolution mass 
spectrometry: Studies with Rauwolfia serpentina extract.

Flynn TJ(1), Vohra SN(2).

Author information:
(1)Division of Applied Regulatory Toxicology, U.S. Food and Drug Administration, 
8301 Muirkirk Road, Laurel, MD, 20708, USA. Electronic address: 
tomflynn1@verizon.net.
(2)Division of Applied Regulatory Toxicology, U.S. Food and Drug Administration, 
8301 Muirkirk Road, Laurel, MD, 20708, USA. Electronic address: 
vohrasn@gmail.com.

Caco-2 cells are a commonly used model for estimating the intestinal 
bioavailability of single chemical entity pharmaceuticals. Caco-2 cells, when 
induced with calcitriol, also express other biological functions such as phase I 
(CYP) and phase II (glucuronosyltransferases) drug metabolizing enzymes which 
are relevant to drug-supplement interactions. Intestinal bioavailability is an 
important factor in the overall safety assessment of products consumed orally. 
Foods, including herbal dietary supplements, are complex substances with 
multiple chemical components. Because of potential interactions between 
components of complex mixtures, more reliable safety assessments can be obtained 
by studying the commercial products "as consumed" rather than by testing 
individual chemical components one at a time. The present study evaluated the 
apparent intestinal permeability (Papp) of a model herbal extract, Rauwolfia 
serpentina, using both whole plant extracts and the individual purified 
Rauwolfia alkaloids. All test compounds, endpoint substrates, and their 
metabolites were quantified using liquid chromatography and high-resolution mass 
spectrometry. The Papp values for individual Rauwolfia alkaloids were comparable 
whether measured individually or as components of the complete extract. Both 
Rauwolfia extract and all individual Rauwolfia alkaloids except yohimbine 
inhibited CYP3A4 activity (midazolam 1'-hydroxylation). Both Rauwolfia extract 
and all individual Rauwolfia alkaloids except corynanthine and reserpic acid 
significantly increased glucuronosyltransferase activity (glucuronidation of 
4-methylumbelliferone). The positive control, ketoconazole, significantly 
inhibited both CYP3A4 and glucuronosyltransferase activities. These findings 
suggest that the Caco-2 assay is capable of simultaneously identifying both 
bioavailability and potentially hazardous intestinal drug-supplement 
interactions in complex mixtures.

Published by Elsevier B.V.

DOI: 10.1016/j.cbi.2018.05.006
PMID: 29782822 [Indexed for MEDLINE]


3. Biotechnol J. 2018 Nov;13(11):e1700696. doi: 10.1002/biot.201700696. Epub 2018
 Apr 26.

Transient Expression of Human Cytochrome P450s 2D6 and 3A4 in Nicotiana 
benthamiana Provides a Possibility for Rapid Substrate Testing and Production of 
Novel Compounds.

Sheludko YV(1)(2), Gerasymenko IM(1)(2), Warzecha H(1).

Author information:
(1)Plant Biotechnology and Metabolic Engineering, Technische Universität 
Darmstadt, Darmstadt, 64287, Germany.
(2)Institute of Cell Biology and Genetic Engineering, National Academy of 
Science of Ukraine, 03143, Kiev, Ukraine.

Employment of transient expression of foreign genes for bioconversion of 
pharmaceutically valuable low-molecular-weight compounds, including plant 
secondary metabolites, is an enticing trend still scantily explored in plant 
biotechnology. In the present work, an efficient protocol for rapid assessment 
of synthetic and plant-derived metabolites as potential substrates for human 
P450s (CYP2D6 and CYP3A4) via Agrobacterium-mediated transient expression in 
Nicotiana benthamiana is put forth. Animal P450s with broad substrate 
specificity are promising candidates for transformation of diverse metabolites. 
The efficiency of P450s in heterologous surroundings is not always satisfactory 
and depends on the availability of an associated electron-transfer enzyme. 
Plants represent an attractive assortment of prospective hosts for foreign P450s 
expression. The optimal composition of genetic blocks providing the highest 
transient expression efficiency is designed, an effective substrate 
administration scheme is validated, and biological activity of the investigated 
P450s against loratadine and several indole alkaloids with different molecular 
scaffold structures is tested. A novel indole alkaloid, 11-hydroxycorynanthine, 
is isolated from N. benthamiana plants transiently expressing CYP2D6 and 
supplemented with corynanthine, and its structure was elucidated. The proposed 
technique might be of value in realization of combinatorial biosynthesis concept 
comprising the junction of heterologous enzymes and substrates in different 
metabolic surroundings.

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI: 10.1002/biot.201700696
PMID: 29637719 [Indexed for MEDLINE]


4. Anal Bioanal Chem. 2016 Jan;408(1):177-90. doi: 10.1007/s00216-015-9093-4.
Epub  2015 Oct 17.

Quantification and characterization of alkaloids from roots of Rauwolfia 
serpentina using ultra-high performance liquid chromatography-photo diode 
array-mass spectrometry.

Sagi S(1), Avula B(1), Wang YH(1), Khan IA(2)(3)(4).

Author information:
(1)National Center for Natural Products Research, Research Institute of 
Pharmaceutical Sciences, The University of Mississippi, 1558 University Circle, 
University, MS, 38677, USA.
(2)National Center for Natural Products Research, Research Institute of 
Pharmaceutical Sciences, The University of Mississippi, 1558 University Circle, 
University, MS, 38677, USA. ikhan@olemiss.edu.
(3)Division of Pharmacognosy, Department of BioMolecular Sciences, School of 
Pharmacy, The University of Mississippi, University, MS, 38677, USA. 
ikhan@olemiss.edu.
(4)Department of Pharmacognosy, College of Pharmacy, King Saud University, 
Riyadh, Saudi Arabia. ikhan@olemiss.edu.

A new UHPLC-UV method has been developed for the simultaneous analysis of seven 
alkaloids [ajmaline (1), yohimbine (2), corynanthine (3), ajmalicine (4), 
serpentine (5), serpentinine (6), and reserpine (7)] from the root samples of 
Rauwolfia serpentina (L.) Benth. ex Kurz. The chromatographic separation was 
achieved using a reversed phase C18 column with a mobile phase of water and 
acetonitrile, both containing 0.05% formic acid. The seven compounds were 
completely separated within 8 min at a flow rate of 0.2 mL/min with a 2-μL 
injection volume. The method is validated for linearity, accuracy, 
repeatability, limits of detection (LOD), and limits of quantification (LOQ). 
Seven plant samples and 21 dietary supplements claiming to contain Rauwolfia 
roots were analyzed and content of total alkaloids (1-7) varied, namely, 
1.57-12.1 mg/g dry plant material and 0.0-4.5 mg/day, respectively. The results 
indicated that commercial products are of variable quality. The developed 
analytical method is simple, economic, fast, and suitable for quality control 
analysis of Rauwolfia samples and commercial products. The UHPLC-QToF-mass 
spectrometry with electrospray ionization (ESI) interface method is described 
for the confirmation and characterization of alkaloids from plant samples. This 
method involved the detection of [M + H](+) or M(+) ions in the positive mode.

DOI: 10.1007/s00216-015-9093-4
PMID: 26476922 [Indexed for MEDLINE]


5. Drug Test Anal. 2016 Mar-Apr;8(3-4):357-69. doi: 10.1002/dta.1849. Epub 2015
Sep  22.

Pharmaceutical quantities of yohimbine found in dietary supplements in the USA.

Cohen PA(1)(2), Wang YH(3), Maller G(4), DeSouza R(4), Khan IA(3).

Author information:
(1)Harvard Medical School, Boston, Massachusetts.
(2)Cambridge Health Alliance, Somerville, MA.
(3)National Center for Natural Products Research, Research Institute of 
Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS, 
38677, USA.
(4)Cornell University, Ithaca, New York.

In the USA, botanical dietary supplements are presumed to be safe, but this is 
not necessarily always the case. Extracts of the evergreen tree yohimbe, 
Pausinystalia johimbe, though banned in many countries, are sold in hundreds of 
dietary supplements in the USA. We analyzed 49 brands of supplements labelled as 
containing yohimbe or yohimbine available for sale from seven major retailers in 
the USA. Supplements were analyzed using ultra high-performance liquid 
chromatography coupled to photodiode and quadrupole time-of-flight mass 
spectrometry detectors for quantity of three alkaloids found in P. johimbe 
(yohimbine, rauwolscine, and corynanthine). The alkaloids were confirmed on the 
basis of retention time, ultraviolet spectra, and mass spectra against reference 
standards. The quantity of the most active alkaloid, yohimbine, per recommended 
serving ranged from none detected to 12.1 mg. Thirty-nine percent of the 
supplements (19/49) did not contain rauwolscine and corynanthine suggesting that 
the yohimbine was either from highly processed plant extract or synthetic in 
origin. Only 11 supplement brands (22%, 11/49) listed a specific quantity of 
yohimbine on the label. Most of these were inaccurately labelled (actual content 
ranged from 23% to 147% of the content on the label). Eighteen percent (9/49) of 
the supplements' labels did not provide any information about yohimbine's 
adverse effects. Of the 49 yohimbine supplement brands sold at seven major 
retail chains in the USA, only 4.1% (2/49) provided consumers with both accurate 
information about the quantity of yohimbine as well as information about 
yohimbine's known adverse effects. Copyright © 2015 John Wiley & Sons, Ltd.

Copyright © 2015 John Wiley & Sons, Ltd.

DOI: 10.1002/dta.1849
PMID: 26391406 [Indexed for MEDLINE]