The biosynthetic origin of psychoactive kavalactones in kava

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...

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Veröffentlicht in:Nat. Plants 2019-08, Vol.5 (8), p.867-878
Hauptverfasser: Pluskal, Tomáš, Torrens-Spence, Michael P., Fallon, Timothy R., De Abreu, Andrea, Shi, Cindy H., Weng, Jing-Ke
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container_end_page 878
container_issue 8
container_start_page 867
container_title Nat. Plants
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creator Pluskal, Tomáš
Torrens-Spence, Michael P.
Fallon, Timothy R.
De Abreu, Andrea
Shi, Cindy H.
Weng, Jing-Ke
description 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. Kava ( Piper methysticum ), an ethnomedicinal shrub native to the Polynesian islands, produces psychoactive kavalactones and anticancer flavokavains. Structures of key enzymes in their biosynthetic network may enable heterologous production.
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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. Kava ( Piper methysticum ), an ethnomedicinal shrub native to the Polynesian islands, produces psychoactive kavalactones and anticancer flavokavains. 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subjects 101/58
38
45/91
631/449/2667
631/449/2669
82/16
82/80
82/83
Analgesics
Anticancer properties
Biomedical and Life Sciences
Biosynthesis
Cancer
Central nervous system
Chemical synthesis
Enzymes
Flavonoids - metabolism
Genes
Kava - enzymology
Kava - metabolism
Lactones - metabolism
Life Sciences
Nervous system
Plant Sciences
Polyketides
Psychotropic Drugs - metabolism
Reductases
title The biosynthetic origin of psychoactive kavalactones in kava
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