Elucidation of the mescaline biosynthetic pathway in peyote (Lophophora williamsii).
Lophophora williamsii
alkaloid biosynthesis
isoquinoline
mescaline
phenethylamine
psychedelics
Journal
The Plant journal : for cell and molecular biology
ISSN: 1365-313X
Titre abrégé: Plant J
Pays: England
ID NLM: 9207397
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
17
08
2023
received:
24
05
2023
accepted:
21
08
2023
medline:
23
10
2023
pubmed:
7
9
2023
entrez:
7
9
2023
Statut:
ppublish
Résumé
Peyote (Lophophora williamsii) is an entheogenic and medicinal cactus native to the Chihuahuan desert. The psychoactive and hallucinogenic properties of peyote are principally attributed to the phenethylamine derivative mescaline. Despite the isolation of mescaline from peyote over 120 years ago, the biosynthetic pathway in the plant has remained undiscovered. Here, we use a transcriptomics and homology-guided gene discovery strategy to elucidate a near-complete biosynthetic pathway from l-tyrosine to mescaline. We identified a cytochrome P450 that catalyzes the 3-hydroxylation of l-tyrosine to l-DOPA, a tyrosine/DOPA decarboxylase yielding dopamine, and four substrate-specific and regiospecific substituted phenethylamine O-methyltransferases. Biochemical assays with recombinant enzymes or functional analyses performed by feeding putative precursors to engineered yeast (Saccharomyces cerevisiae) strains expressing candidate peyote biosynthetic genes were used to determine substrate specificity, which served as the basis for pathway elucidation. Additionally, an N-methyltransferase displaying broad substrate specificity and leading to the production of N-methylated phenethylamine derivatives was identified, which could also function as an early step in the biosynthesis of tetrahydroisoquinoline alkaloids in peyote.
Substances chimiques
Mescaline
RHO99102VC
Phenethylamines
0
Tyrosine
42HK56048U
Methyltransferases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
635-649Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.
Références
Aragane, M., Sasaki, Y., Nakajima, J.I., Fukumori, N., Yoshizawa, M., Suzuki, Y. et al. (2011) Peyote identification on the basis of differences in morphology, mescaline content, and trnL/trnF sequence between Lophophora williamsii and L. diffusa. Journal of Natural Medicines, 65, 103-110.
Battersby, A.R., Binks, R. & Huxtable, R. (1967) Biosynthesis of cacti alkaloids. Tetrahedron Letters, 8, 563-565.
Battersby, A.R., Binks, R. & Huxtable, R. (1968) Biosynthesis of pellotine. Tetrahedron Letters, 58, 6111-6115.
Bender, E. (2022) Finding medical value in mescaline. Nature, 609, S90-S91.
Bharadwaj, R., Kumar, S.R., Sharma, A. & Sathishkumar, R. (2021) Plant metabolic gene clusters: evolution, organization, and their applications in synthetic biology. Frontiers in Plant Science, 12, 1-23.
Bruhn, J.G., De Smet, P.A.G.M., El-Seedi, H.R. & Beck, O. (2002) Mescaline use for 5700 years. The Lancet, 359, 2002.
Cassels, B.K. (2019) Alkaloids of the Cactaceae - the classics. Natural Product Communications, 14, 85-90.
Cassels, B.K. & Sáez-Briones, P. (2018) Dark classics in chemical neuroscience: mescaline. ACS Chemical Neuroscience, 9, 2448-2458.
Chan, C.B., Poulie, C.B.M., Wismann, S.S., Soelberg, J. & Kristensen, J.L. (2021) The alkaloids from Lophophora diffusa and other “false peyotes”. Journal of Natural Products, 84, 2398-2407.
Chavez, B.G., Srinivasan, P., Glockzin, K., Kim, N., Montero Estrada, O., Jirschitzka, J. et al. (2022) Elucidation of tropane alkaloid biosynthesis in Erythroxylum coca using a microbial pathway discovery platform. Proceedings of the National Academy of Sciences of the United States of America, 119, e2215372119.
Chen, C., Chen, H., Zhang, Y., Thomas, H.R., Frank, M.H., He, Y. et al. (2020) TBtools: an integrative toolkit developed for interactive analyses of big biological data. Molecular Plant, 13, 1194-1202.
Chen, S., Zhou, Y., Chen, Y. & Gu, J. (2018) Fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 34, i884-i890.
Choi, K.B., Morishige, T., Shitan, N., Yazaki, K. & Sato, F. (2002) Molecular cloning and characterization of coclaurine N-methyltransferase from cultured cells of Coptis japonica. Journal of Biological Chemistry, 277, 830-835.
Daniel, B., Konrad, B., Toplak, M., Lahham, M., Messenlehner, J., Winkler, A. et al. (2017) The family of berberine bridge enzyme-like enzymes: a treasure-trove of oxidative reactions. Archives of Biochemistry and Biophysics, 632, 88-103.
Dastmalchi, M., Chang, L., Chen, R., Yu, L., Chen, X., Hagel, J.M. et al. (2019a) Purine permease-type benzylisoquinoline alkaloid transporters in opium poppy. Plant Physiology, 181, 916-933.
Dastmalchi, M., Chen, X., Hagel, J.M., Chang, L., Chen, R., Ramasamy, S. et al. (2019b) Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy. Nature Chemical Biology, 14, 738-743.
Dinis-Oliveira, R.J., Pereira, C.L. & da Silva, D.D. (2018) Pharmacokinetic and pharmacodynamic aspects of peyote and mescaline: clinical and forensic repercussions. Current Molecular Pharmacology, 12, 184-194.
Dusséaux, S., Thomas Wajn, W., Liu, Y., Ignea, C. & Kampranis, S.C. (2020) Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids. Proceedings of the National Academy of Sciences of the United States of America, 117, 31789-31799.
Dyck, E. & Farrell, P. (2018) Psychedelics and psychotherapy in Canada: Humphry Osmond and Aldous Huxley. History of Psychology, 21, 240-253.
Edgar, R.C. (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics, 5, 1-19.
Farrow, S.C., Hagel, J.M., Beaudoin, G.A.W., Burns, D.C. & Facchini, P.J. (2015) Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy. Nature Chemical Biology, 11, 728-732.
Fernández-Calderón, F., Cleland, C.M. & Palamar, J.J. (2018) Polysubstance use profiles among electronic dance music party attendees in New York City and their relation to use of new psychoactive substances. Addictive Behaviors, 78, 85-93.
Grabherr, M.G., Haas, B.J., Yassour, M., Levin, J.Z., Thompson, D.A., Amit, I. et al. (2011) Full-length transcriptome assembly from RNA-seq data without a reference genome. Nature Biotechnology, 29, 644-652.
Hagel, J.M. & Facchini, P.J. (2018) Expanding the roles for 2-oxoglutarate-dependent oxygenases in plant metabolism. Natural Product Reports, 35, 721-734.
Hatlestad, G.J., Sunnadeniya, R.M., Akhavan, N.A., Gonzalez, A., Goldman, I.L., McGrath, J.M. et al. (2012) The beet R locus encodes a new cytochrome P450 required for red betalain production. Nature Genetics, 44, 816-820.
Hernández-Hernández, T., Brown, J.W., Schlumpberger, B.O., Eguiarte, L.E. & Magallón, S. (2014) Beyond aridification: multiple explanations for the elevated diversification of cacti in the New World succulent biome. New Phytologist, 202, 1382-1397.
Huang, R., O'Donnell, A.J., Barboline, J.J. & Barkman, T.J. (2016) Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes. Proceedings of the National Academy of Sciences of the United States of America, 113, 10613-10618.
Ibarra-Laclette, E., Zamudio-Hernández, F., Pérez-Torres, C.A., Albert, V.A., Ramírez-Chávez, E., Molina-Torres, J. et al. (2015) De novo sequencing and analysis of Lophophora williamsii transcriptome, and searching for putative genes involved in mescaline biosynthesis. BMC Genomics, 16, 1-14.
Kyzar, E.J., Nichols, C.D., Gainetdinov, R.R., Nichols, D.E. & Kalueff, A.V. (2017) Psychedelic drugs in biomedicine. Trends in Pharmacological Sciences, 38, 992-1005.
Langmead, B. & Salzberg, S.L. (2012) Fast gapped-read alignment with bowtie 2. Nature Methods, 9, 357-359.
Lee, E.-J. & Facchini, P. (2010) Norcoclaurine synthase is a member of the pathogenesis-related 10/bet v1 protein family. Plant Cell, 22, 3489-3503.
Leete, E. & Braunstein, J.D. (1969) Biosynthesis of anhalonidine: origin of the two-carbon unit. Tetrahedron Letters, 10, 451-452.
Li, B. & Dewey, C.N. (2011) RSEM: accurate transcript quantification from RNA-seq data with or without a reference genome. BMC Bioinformatics, 12, 1471-2105.
Li, M.Z. & Elledge, S.J. (2012) SLIC: A method for sequence- and ligation-independent cloning. In: Methods in Molecular Biology. N.J: Clifton, pp. 51-59.
Lovett, J.V., Hoult, A.H.C. & Christen, O. (1994) Biologically active secondary metabolites of barley. IV. Hordenine production by different barley lines. Journal of Chemical Ecology, 20, 1945-1954.
Lundström, J. & Agurell, S. (1969) A complete biosynthetic sequence from tyrosine to mescaline in two cactus species. Tetrahedron Letters, 10, 3371-3374.
Ma, X., Panjikar, S., Koepke, J., Loris, E. & Stöckigt, J. (2006) The structure of Rauvolfia serpentina strictosidine synthase is a novel six-bladed β-propeller fold in plant proteins. Plant Cell, 18, 907-920.
Menéndez-Perdomo, I.M. & Facchini, P.J. (2020) Isolation and characterization of two O-methyltransferases involved in benzylisoquinoline alkaloid biosynthesis in sacred lotus (Nelumbo nucifera). The Journal of Biological Chemistry, 295, 1598-1612.
Moreno-Pedraza, A., Rosas-Román, I., Garcia-Rojas, N.S., Guillén-Alonso, H., Ovando-Vázquez, C., Díaz-Ramírez, D. et al. (2019) Elucidating the distribution of plant metabolites from native tissues with laser desorption low-temperature plasma mass spectrometry imaging. Analytical Chemistry, 91, 2734-2743.
Morris, J.S., Dastmalchi, M., Li, J., Chang, L., Chen, X., Hagel, J.M. et al. (2016) Plug-and-play benzylisoquinoline alkaloid biosynthetic gene discovery in engineered yeast. Methods in Enzymology, 575, 143-178.
Morris, J.S. & Facchini, P.J. (2019) Molecular origins of functional diversity in benzylisoquinoline alkaloid methyltransferases. Frontiers in Plant Science, 10, 1-22.
Morris, J.S., Groves, R.A., Hagel, J.M. & Facchini, P.J. (2018) An N-methyltransferase from Ephedra sinica catalyzing the formation of ephedrine and pseudoephedrine enables microbial phenylalkylamine production. The Journal of Biological Chemistry, 293, 13364-13376.
Morris, J.S., Yu, L. & Facchini, P.J. (2020) A single residue determines substrate preference in benzylisoquinoline alkaloid N-methyltransferases. Phytochemistry, 170, 112193.
Nett, R.S., Lau, W. & Sattely, E.S. (2020) Discovery and engineering of colchicine alkaloid biosynthesis. Nature, 584, 148-153.
Nguyen, T.D. & Dang, T.T.T. (2021) Cytochrome P450 enzymes as key drivers of alkaloid chemical diversification in plants. Frontiers in Plant Science, 12, 682181.
Ogunbodede, O., McCombs, D., Trout, K., Daley, P. & Terry, M. (2010) New mescaline concentrations from 14 taxa/cultivars of Echinopsis spp. (Cactaceae) (“San Pedro”) and their relevance to shamanic practice. Journal of Ethnopharmacology, 131, 356-362.
Pyne, M.E., Kevvai, K., Grewal, P.S., Narcross, L., Choi, B., Bourgeois, L. et al. (2020) A yeast platform for high-level synthesis of natural and unnatural tetrahydroisoquinoline alkaloids. Nature Communications, 11, 3337.
Qu, Y., Safonova, O. & De Luca, V. (2019) Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. The Plant Journal, 97, 257-266.
Rosenberg, H. & Stohs, S.J. (1974) The utilization of tyrosine for mescaline and protein biosynthesis in Lophophora williamsii. Phytochemistry, 13, 1861-1863.
Shahsavarani, M., Utomo, J.C., Kumar, R., Paz-Galeano, M., Garza-García, J.J.O., Mai, Z. et al. (2023) Improved protein glycosylation enabled heterologous biosynthesis of monoterpenoid indole alkaloids and their unnatural derivatives in yeast. Metabolic engineering communications, 16, e00215.
Sommer, T., Hübner, H., El Kerdawy, A., Gmeiner, P., Pischetsrieder, M. & Clark, T. (2017) Identification of the beer component hordenine as food-derived dopamine D2 receptor agonist by virtual screening a 3D compound database. Scientific Reports, 7, 1-12.
Srinivasan, P. & Smolke, C.D. (2021) Engineering cellular metabolite transport for biosynthesis of computationally predicted tropane alkaloid derivatives in yeast. Proceedings of the National Academy of Sciences of the United States of America, 118, e2104460118.
Sunnadeniya, R., Bean, A., Brown, M., Akhavan, N., Hatlestad, G., Gonzalez, A. et al. (2016) Tyrosine hydroxylation in betalain pigment biosynthesis is performed by cytochrome P450 enzymes in beets (Beta vulgaris). PLoS One, 11, 1-16.
Terry, M., Steelman, K.L., Guilderson, T., Dering, P. & Rowe, M.W. (2006) Lower Pecos and Coahuila peyote: new radiocarbon dates. Journal of Archaeological Science, 33, 1017-1021.
Torrens-Spence, M.P., Lazear, M., Von Guggenberg, R., Ding, H. & Li, J. (2014) Investigation of a substrate-specifying residue within Papaver somniferum and Catharanthus roseus aromatic amino acid decarboxylases. Phytochemistry, 106, 37-43.
Wang, Y.-J., Huang, J.-P., Tian, T., Yan, Y., Chen, Y., Yang, J. et al. (2022) Discovery and engineering of the cocaine biosynthetic pathway. Journal of the American Chemical Society, 144, 22000-22007.
Zheng, J., Meinhardt, L.W., Goenaga, R., Zhang, D. & Yin, Y. (2021) The chromosome-level genome of dragon fruit reveals whole-genome duplication and chromosomal co-localization of betacyanin biosynthetic genes. Horticulture Research, 8, 63.
Zhou, J.W., Luo, H.Z., Jiang, H., Jian, T.K., Chen, Z.Q. & Jia, A.Q. (2018) Hordenine: a novel quorum sensing inhibitor and antibiofilm agent against Pseudomonas aeruginosa. Journal of Agricultural and Food Chemistry, 66, 1620-1628.
Zhou, J.W., Ruan, L.Y., Chen, H.J., Luo, H.Z., Jiang, H., Wang, J.S. et al. (2019) Inhibition of quorum sensing and virulence in Serratia marcescens by hordenine. Journal of Agricultural and Food Chemistry, 67, 784-795.