Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The biosynthetic origin of psychoactive kavalactones in kava

Nature Plants volume 5, pages 867–878 (2019)Cite this article

Subjects

Abstract

Kava (Piper methysticum) is an ethnomedicinal shrub native to the Polynesian islands with well-established anxiolytic and analgesic properties. Its main psychoactive principles, kavalactones, form a unique class of polyketides that interact with the human central nervous system through mechanisms distinct from those of conventional psychiatric drugs. However, an unknown biosynthetic machinery and difficulty in chemical synthesis hinder the therapeutic use of kavalactones. In addition, kava also produces flavokavains, which are chalconoids with anticancer properties structurally related to kavalactones. Here, we report de novo elucidation of the key enzymes of the kavalactone and flavokavain biosynthetic network. We present the structural basis for the evolutionary development of a pair of paralogous styrylpyrone synthases that establish the kavalactone scaffold and the catalytic mechanism of a regio- and stereo-specific kavalactone reductase that produces a subset of chiral kavalactones. We further demonstrate the feasibility of engineering styrylpyrone production in heterologous hosts, thus opening a way to develop kavalactone-based non-addictive psychiatric therapeutics through synthetic biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Chemotypes of select Piper species and the bifurcation of kavalactone and flavokavain biosynthesis from common hydroxycinnamoyl-CoA precursors in kava.
Fig. 2: Mechanistic basis for the neofunctionalization of SPSs from ancestral CHS in kava.
Fig. 3: Functional characterization of kava OMTs.
Fig. 4: Functional characterization of PmKLR1.
Fig. 5: Functional characterization of the methylenedioxy-bridge-forming enzyme PmCYP719A26 (PmMTS1).
Fig. 6: The proposed kavalactone-biosynthetic network derived from phenylalanine.

Similar content being viewed by others

Data availability

The sequences of the genes reported in this article have been deposited in NCBI GenBank (accessions MK058492–MK058514). Protein expression plasmids are available from Addgene (see Supplementary Table 5). The raw sequencing reads have been submitted to NCBI SRA (accession PRJNA494686) and the de novo assembled transcriptome to NCBI TSA (accession GHAC00000000). Raw metabolomic LC–MS datasets have been uploaded to the GNPS-MassIVE database (accessions MSV000083272 and MSV000083274–MSV000083277). Protein structures have been deposited in Protein Data Bank (accessions 6OP5, 6CQB and 6NBR).

References

  1. Li, F.-S. & Weng, J.-K. Demystifying traditional herbal medicine with modern approach. Nat. Plants 3, 17109 (2017).

    Article  PubMed  Google Scholar 

  2. Parmar, V. S. et al. Phytochemistry of the genus Piper. Phytochemistry 46, 597–673 (1997).

    Article  CAS  Google Scholar 

  3. Mehmood, M. H. & Gilani, A. H. Pharmacological basis for the medicinal use of black pepper and piperine in gastrointestinal disorders. J. Med. Food 13, 1086–1096 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Bharadwaj, U. et al. Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene 34, 1341–1353 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chu, N. S. Effects of betel chewing on the central and autonomic nervous systems. J. Biomed. Sci. 8, 229–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Amonkar, A. J., Nagabhushan, M., D’Souza, A. V. & Bhide, S. V. Hydroxychavicol: a new phenolic antimutagen from betel leaf. Food Chem. Toxicol. 24, 1321–1324 (1986).

    Article  CAS  PubMed  Google Scholar 

  8. Jaramillo, M. A. & Manos, P. S. Phylogeny and patterns of floral diversity in the genus Piper (Piperaceae). Am. J. Bot. 88, 706–716 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Lebot, V. & Lèvesque, J. The origin and distribution of kava (Piper methysticum Forst. f., Piperaceae): a phytochemical approach. Allertonia 5, 223–281 (1989).

    Google Scholar 

  10. Singh, Y. N. Kava: an overview. J. Ethnopharmacol. 37, 13–45 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Cairney, S., Maruff, P. & Clough, A. R. The neurobehavioural effects of kava. Aust. N. Z. J. Psychiatry 36, 657–662 (2002).

    Article  PubMed  Google Scholar 

  12. Sarris, J., LaPorte, E. & Schweitzer, I. Kava: a comprehensive review of efficacy, safety, and psychopharmacology. Aust. N. Z. J. Psychiatry 45, 27–35 (2011).

    Article  PubMed  Google Scholar 

  13. Lasme, P., Davrieux, F., Montet, D. & Lebot, V. Quantification of kavalactones and determination of kava (Piper methysticum) chemotypes using near-infrared reflectance spectroscopy for quality control in vanuatu. J. Agric. Food Chem. 56, 4976–4981 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Kava: A Review of the Safety of Traditional and Recreational Beverage Consumption (World Health Organization, 2016).

  15. Montague, Z. Stressed New Yorkers Take to Kava, ‘Nature’s Xanax’. The New York Times (21 July 2018); https://www.nytimes.com/2017/12/21/nyregion/stressed-new-yorkers-take-to-kava-natures-xanax.html

  16. Seifert, K. Kava: The NFL’s newest and safest painkiller. ESPN (21 July 2018); http://www.espn.com/blog/nflnation/post/_/id/256632

  17. Chua, H. C. et al. Kavain, the major constituent of the anxiolytic kava extract, potentiates GABAA receptors: functional characteristics and molecular mechanism. PLoS ONE 11, e0157700 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jamieson, D. D. & Duffield, P. H. The antinociceptive actions of kava components in mice. Clin. Exp. Pharmacol. Physiol. 17, 495–507 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Zi, X. & Simoneau, A. R. Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice. Cancer Res. 65, 3479–3486 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Zhou, P. et al. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways. FASEB J. 24, 4722–4732 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Abe, I. & Morita, H. Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases. Nat. Prod. Rep. 27, 809–838 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Lebot, V., Aradhya, M. K. & Manshardt, R. M. Geographic survey of genetic variation in kava (Piper methysticum Forst. f. and P. wichmannii C. DC.). Pac. Sci. 45, 169–185 (1991).

    Google Scholar 

  23. Torrens-Spence, M. P., Fallon, T. R. & Weng, J. K. A workflow for studying specialized metabolism in nonmodel eukaryotic organisms. Methods Enzymol. 576, 69–97 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Owen, C., Patron, N. J., Huang, A. & Osbourn, A. Harnessing plant metabolic diversity. Curr. Opin. Chem. Biol. 40, 24–30 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tatsis, E. C. & O’Connor, S. E. New developments in engineering plant metabolic pathways. Curr. Opin. Biotechnol. 42, 126–132 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Akiyama, T., Shibuya, M., Liu, H. M. & Ebizuka, Y. p‐Coumaroyltriacetic acid synthase, a new homologue of chalcone synthase, from Hydrangea macrophylla var. thunbergii. FEBS J. 263, 834–839 (1999).

    CAS  Google Scholar 

  27. Abe, I., Sano, Y., Takahashi, Y. & Noguchi, H. Site-directed mutagenesis of benzalacetone synthase: the role of PHE215 in plant type III polyketide synthases. J. Biol. Chem. 278, 25218–25226 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Burbulis, I. E., Iacobucci, M. & Shirley, B. W. A null mutation in the first enzyme of flavonoid biosynthesis does not affect male fertility in Arabidopsis. Plant Cell 8, 1013–1025 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Sainsbury, F. & Lomonossoff, G. P. Transient expressions of synthetic biology in plants. Curr. Opin. Plant Biol. 19, 1–7 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Murrell, B. et al. Detecting individual sites subject to episodic diversifying selection. PLoS Genet. 8, e1002764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jez, J. M. et al. Structural control of polyketide formation in plant-specific polyketide synthases. Chem. Biol. 7, 919–930 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Morita, H. et al. A structure-based mechanism for benzalacetone synthase from Rheum palmatum. Proc. Natl Acad. Sci. USA 107, 669–673 (2010).

    Article  PubMed  Google Scholar 

  33. Austin, M. B. & Noel, J. P. The chalcone synthase superfamily of type III polyketide synthases. Nat. Prod. Rep. 20, 79–110 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Moinuddin, S. G. A. et al. Insights into lignin primary structure and deconstruction from Arabidopsis thaliana COMT (caffeic acid O-methyl transferase) mutant Atomt1. Org. Biomol. Chem. 8, 3928–3946 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Eckermann, C. et al. Stilbenecarboxylate biosynthesis: a new function in the family of chalcone synthase-related proteins. Phytochemistry 62, 271–286 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Gosch, C., Halbwirth, H. & Stich, K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry 71, 838–843 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Narváez-Cuenca, C.-E., Vincken, J.-P. & Gruppen, H. Identification and quantification of (dihydro) hydroxycinnamic acids and their conjugates in potato by UHPLC–DAD–ESI-MSn. Food Chem. 130, 730–738 (2012).

    Article  CAS  Google Scholar 

  38. Harbaum, B. et al. Identification of flavonoids and hydroxycinnamic acids in pak choi varieties (Brassica campestris L. ssp. chinensis var. communis) by HPLC–ESI-MSn and NMR and their quantification by HPLC–DAD. J. Agric. Food Chem. 55, 8251–8260 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Li, Y. et al. Methysticin and 7,8-dihydromethysticin are two major kavalactones in kava extract to induce CYP1A1. Toxicol. Sci. 124, 388–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Ikezawa, N. et al. Molecular cloning and characterization of CYP719, a methylenedioxy bridge-forming enzyme that belongs to a novel P450 family, from cultured Coptis japonica cells. J. Biol. Chem. 278, 38557–38565 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Lau, W. & Sattely, E. S. Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science 349, 1224–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chemler, J. A. & Koffas, M. A. G. Metabolic engineering for plant natural product biosynthesis in microbes. Curr. Opin. Biotechnol. 19, 597–605 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Beckert, C. et al. Styrylpyrone biosynthesis in Equisetum arvense. Phytochemistry 44, 275–283 (1997).

    Article  CAS  Google Scholar 

  44. Anarat-Cappillino, G. & Sattely, E. S. The chemical logic of plant natural product biosynthesis. Curr. Opin. Plant Biol. 19, 51–58 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weng, J.-K. & Noel, J. P. The remarkable pliability and promiscuity of specialized metabolism. Cold Spring Harb. Symp. Quant. Biol. 77, 309–320 (2012).

    Article  PubMed  Google Scholar 

  46. Weng, J.-K., Philippe, R. N. & Noel, J. P. The rise of chemodiversity in plants. Science 336, 1667–1670 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grabherr, M. G. et al. Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat. Biotechnol. 29, 644–652 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Haas, B. J. et al. De novo transcript sequence reconstruction from RNA-seq using the Trinity platform for reference generation and analysis. Nat. Protoc. 8, 1494–1512 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Simão, F. A., Waterhouse, R. M., Ioannidis, P., Kriventseva, E. V. & Zdobnov, E. M. BUSCO: assessing genome assembly and annotation completeness with single-copy orthologs. Bioinformatics 31, 3210–3212 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 12, 323 (2011).

    Article  CAS  Google Scholar 

  52. Priyam, A. et al. Sequenceserver: a modern graphical user interface for custom BLAST databases. Preprint at https://www.biorxiv.org/content/10.1101/033142v1 (2015).

  53. Xiao, M. et al. Transcriptome analysis based on next-generation sequencing of non-model plants producing specialized metabolites of biotechnological interest. J. Biotechnol. 166, 122–134 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kumar, S., Stecher, G. & Tamura, K. MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. Mol. Biol. Evol. 33, 1870–1874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jones, D. T., Taylor, W. R. & Thornton, J. M. The rapid generation of mutation data matrices from protein sequences. Comput. Appl. Biosci. 8, 275–282 (1992).

    CAS  PubMed  Google Scholar 

  57. Pond, S. L. K., Frost, S. D. W. & Muse, S. V. HyPhy: hypothesis testing using phylogenies. Bioinformatics 21, 676–679 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Gibson, D. G. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat. Methods 6, 343–345 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Tropea, J. E., Cherry, S. & Waugh, D. S. Expression and purification of soluble His(6)-tagged TEV protease. Methods Mol. Biol. 498, 297–307 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Viola, R. E., Cook, P. F. & Cleland, W. W. Stereoselective preparation of deuterated reduced nicotinamide adenine nucleotides and substrates by enzymatic synthesis. Anal. Biochem. 96, 334–340 (1979).

    Article  CAS  PubMed  Google Scholar 

  61. Earley, K. W. et al. Gateway-compatible vectors for plant functional genomics and proteomics. Plant J. 45, 616–629 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Clough, S. J. & Bent, A. F. Floral dip: a simplified method for Agrobacterium-mediated transformation of Arabidopsis thaliana. Plant J. 16, 735–743 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Czechowski, T., Stitt, M., Altmann, T., Udvardi, M. K. & Scheible, W.-R. Genome-wide identification and testing of superior reference genes for transcript normalization in Arabidopsis. Plant Physiol. 139, 5–17 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pluskal, T., Castillo, S., Villar-Briones, A. & Oresic, M. MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinforma. 11, 395 (2010).

    Article  CAS  Google Scholar 

  65. Xia, J., Sinelnikov, I. V., Han, B. & Wishart, D. S. MetaboAnalyst 3.0—making metabolomics more meaningful. Nucleic Acids Res. 43, W251–W257 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dührkop, K., Shen, H., Meusel, M., Rousu, J. & Böcker, S. Searching molecular structure databases with tandem mass spectra using CSI:FingerID. Proc. Natl Acad. Sci. USA 112, 12580–12585 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dührkop, K. et al. SIRIUS 4: a rapid tool for turning tandem mass spectra into metabolite structure information. Nat. Methods 16, 299–302 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Battye, T. G. G., Kontogiannis, L., Johnson, O., Powell, H. R. & Leslie, A. G. W. /it iMOSFLM: a new graphical interface for diffraction-image processing with /it MOSFLM. Acta Crystallogr. D 67, 271–281 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Evans, P. Scaling and assessment of data quality. Acta Crystallogr. D 62, 72–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. McCoy, A. J. Solving structures of protein complexes by molecular replacement with Phaser. Acta Crystallogr. D 63, 32–41 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kelley, L. A., Mezulis, S., Yates, C. M., Wass, M. N. & Sternberg, M. J. E. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 10, 845–858 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Oliveira, S. H. P. et al. KVFinder: steered identification of protein cavities as a PyMOL plugin. BMC Bioinforma. 15, 197 (2014).

    Article  CAS  Google Scholar 

  75. Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455–461 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sainsbury, F., Thuenemann, E. C. & Lomonossoff, G. P. pEAQ: versatile expression vectors for easy and quick transient expression of heterologous proteins in plants. Plant Biotechnol. J. 7, 682–693 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Peyret, H. & Lomonossoff, G. P. The pEAQ vector series: the easy and quick way to produce recombinant proteins in plants. Plant Mol. Biol. 83, 51–58 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Hoekema, A., Hirsch, P. R., Hooykaas, P. J. J. & Schilperoort, R. A. A binary plant vector strategy based on separation of vir- and T-region of the Agrobacterium tumefaciens Ti-plasmid. Nature 303, 179 (1983).

    Article  CAS  Google Scholar 

  79. Charpentier, B., Bardey, V., Robas, N. & Branlant, C. The EIIGlc protein is involved in glucose-mediated activation of Escherichia coli gapA and gapB-pgk transcription. J. Bacteriol. 180, 6476–6483 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Olins, P. O. & Rangwala, S. H. A novel sequence element derived from bacteriophage T7 mRNA acts as an enhancer of translation of the lacZ gene in Escherichia coli. J. Biol. Chem. 264, 16973–16976 (1989).

    CAS  PubMed  Google Scholar 

  81. Chen, Y.-J. et al. Characterization of 582 natural and synthetic terminators and quantification of their design constraints. Nat. Methods 10, 659–664 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Khlebnikov, A., Datsenko, K. A., Skaug, T., Wanner, B. L. & Keasling, J. D. Homogeneous expression of the P(BAD) promoter in Escherichia coli by constitutive expression of the low-affinity high-capacity AraE transporter. Microbiology 147, 3241–3247 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Mumberg, D., Müller, R. & Funk, M. Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds. Gene 156, 119–122 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Brachmann, C. B. et al. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast 14, 115–132 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Ferrer, J. L., Jez, J. M., Bowman, M. E., Dixon, R. A. & Noel, J. P. Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis. Nat. Struct. Biol. 6, 775–784 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Smith Family Foundation, Edward N. and Della L. Thome Memorial Foundation, the Family Larsson-Rosenquist Foundation and the National Science Foundation (grant no. CHE-1709616). T.P. is a Simons Foundation Fellow of the Helen Hay Whitney Foundation. J.-K.W is supported by the Beckman Young Investigator Program, Pew Scholars Program in the Biomedical Sciences (grant no. 27345) and the Searle Scholars Program (grant no. 15-SSP-162). This work is on the basis of research conducted at the Northeastern Collaborative Access Team (NE-CAT) beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6 M detector on NE-CAT 24-ID-C beam line is funded by an NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. RNA-seq service was provided free of charge by the Beijing Genome Institute in exchange for an evaluation of their BGISEQ-500 sequencing platform. We thank B. Marotta for an introduction to kava, C. Nguyen and F. A. Samatey for advice regarding crystallography, G. Fink for providing yeast strains and expression vectors and Weng lab members for constructive comments.

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    Tomáš Pluskal, Michael P. Torrens-Spence, Timothy R. Fallon, Andrea De Abreu, Cindy H. Shi & Jing-Ke Weng

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Timothy R. Fallon, Andrea De Abreu, Cindy H. Shi & Jing-Ke Weng

Authors
  1. Tomáš Pluskal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael P. Torrens-Spence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy R. Fallon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea De Abreu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cindy H. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing-Ke Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.P. and J.-K.W. designed experiments. T.P. performed most of the experiments. M.P.T.-S. assisted with cloning and crystallography. T.R.F. assisted with transcriptome assembly and LC–MS analyses. A.D.A. cloned genes and purified proteins. C.H.S. constructed expression vectors. T.P. analysed data. T.P. and J.-K.W. wrote the paper.

Corresponding author

Correspondence to Jing-Ke Weng.

Ethics declarations

Competing interests

T.P. and J.-K.W. have filed a patent application on metabolic engineering of kavalactones and flavokavains using the enzymes discovered in this study. J.-K.W. is a co-founder, a member of the Scientific Advisory Board and a shareholder of DoubleRainbow Biosciences, which develops biotechnologies related to natural products. All other authors have no competing interests.

Additional information

Peer review information: Nature Plants thanks Fernando Geu-Flores and Reuben Peters and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–12, Supplementary Notes 1–7, Supplementary Tables 1–5 and Supplementary References.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pluskal, T., Torrens-Spence, M.P., Fallon, T.R. et al. The biosynthetic origin of psychoactive kavalactones in kava. Nat. Plants 5, 867–878 (2019). https://doi.org/10.1038/s41477-019-0474-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41477-019-0474-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing