Cannabinoid synthases and osmoprotective metabolites accumulate in the exudates of Cannabis sativa L. glandular trichomes

Rodziewicz, Paweł; Loroch, Stefan; Marczak, Łukasz; Sickmann, Albert; Kayser, Oliver

doi:10.1016/j.plantsci.2019.04.008

Cited by 49 publications

(38 citation statements)

References 72 publications

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“…The geranyl diphosphate (GPP) used for prenylation of olivetolic acid (OA) originates from the methylerythritol 4-phosphate (MEP) pathway, which typically operates in plastidial organelles in eukaryotic cells (normally chloroplasts) [96]. Oxidative cyclization and storage of the final products take place outside the gland cells in the resin cavity [97,98]. It remains to be resolved how the pathway intermediates are transported between the different compartments.…”

Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

“…The flavoproteins Δ 9 -tetrahydrocannabinolic acid synthase (THCAS) and cannabidiolic acid synthase (CBDAS) are secreted into the extracellular space and convert CBGA to Δ 9 -THCA and CBDA, respectively. These conversions proceed as oxidative cyclization reactions, via reduction of molecular oxygen (O 2 ), that generate hydrogen peroxide (H 2 O 2 ) as a side-product [97,103]. The reaction mechanism for cannabichromenic acid synthase (CBCAS) is most likely also dependent on FAD and O 2 even though the enzyme was initially reported to be independent of flavin cofactors and O 2 [104].…”

Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

“…All these oxidocyclases carry a secretion signal peptide and are exported to the extracellular resin space [6,103,107]. THCAS and CBDAS are catalytically active in the resin space, but it remains to be demonstrated whether their activity is exclusive to the extracellular space [97].…”

Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

“…The resin inside glandular trichomes of C. sativa, the apoplast of glandular scales in R. dauricum, and oil bodies in R. marginata are the storage environments and sites of the oxycyclase-catalyzed last step in the synthesis of cannabinoids [5,37,40,97]. 1 H NMR-based metabolomics of C. sativa trichomes revealed co-storage of the cannabinoids with an abundance of sugars, amino acids, choline, organic acids, and terpenes [5].…”

Section: Possible Storage Of High Amounts Of Cannabinoids In Natural mentioning

confidence: 99%

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Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

219

225

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Phytocannabinoids are bioactive natural products found in some flowering plants, liverworts, and fungi that can be beneficial for the treatment of human ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabinoids with desirable properties requires identification of the underlying genes and their expression in a suitable heterologous host. We provide an overview of the structural classification of phytocannabinoids based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Rhododendron, and Radula species. We also highlight the potential in planta roles of phytocannabinoids and the opportunity for synthetic biology approaches based on combinatorial biochemistry and protein engineering to produce cannabinoid derivatives with improved properties. Phytocannabinoids The term phytocannabinoid (see Glossary, also cannabinoid) defines meroterpenoids with a resorcinyl core typically decorated with a para-positioned isoprenyl, alkyl, or aralkyl side chain [1]. The alkyl side chain typically contains an odd number of carbon atoms, where orcinoids contain one carbon, varinoids three, and olivetoids five. Cannabinoids with an even number of carbon atoms in the side chain are known but rare. The term cannabinoid generally refers to molecules with a characteristic chemical structure; however, the term may also refer to pharmacological ligands of human endocannabinoid receptors [2]. In this review we use the chemical definition of cannabinoids. Phytocannabinoids occur in flowering plants, liverworts, and fungi (Figure 1, Key Figure). They were first isolated from Cannabis sativa L. (Cannabaceae), a plant with a long and controversial history of use and abuse [3]. The mammalian brain has receptors that respond to compounds found in C. sativa. Accordingly, these receptors were named cannabinoid receptors (CB x) and are the basis of the endocannabinoid system. Studies in human and animals demonstrated that the endocannabinoid system regulates a broad range of biological functions, including memory, mood, brain reward systems, and drug addiction, as well as metabolic processes such as lipolysis, glucose metabolism, and energy balance [2]. More than 113 different cannabinoids have been isolated from C. sativa and these are classified into distinct types: cannabigerols (CBGs), cannabichromenes (CBCs), cannabidiols (CBDs), (−)-Δ 9-trans-tetrahydrocannabinols (Δ 9-THCs), (−)-Δ 8-trans-tetrahydrocannabinols (Δ 8-THCs), cannabicyclols (CBLs), cannabielsoins (CBEs), cannabinols (CBNs), cannabinodiols (CBNDs), cannabitriols (CBTs), and the miscellaneous cannabinoids (Figure 2) [4]. C. sativa predominantly produces alkyl type cannabinoids that carry a monoterpene isoprenyl moiety (C10) and a pentyl side chain (C5) [1]. The most abundant constituents are trans-Δ 9-THC, CBD, CBC, and CBG, together with their respective acid forms (Δ 9-THCA, CBDA, CBCA, and CBGA) [5]. Cannabinoid biosynthetic pathways ty...

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Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

Section: Cannabinoid Biosynthesis In Cannabis Sativamentioning

confidence: 99%

Section: Possible Storage Of High Amounts Of Cannabinoids In Natural mentioning

confidence: 99%

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Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

219

225

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“…Therapeutic activity of Cannabis is associated with a class of secondary metabolites commonly identified as cannabinoids 6 , 7 . Mature plants are prolific producers of these compounds, which are predominantly synthesised in capitate stalked trichomes and subsequently accumulate as exudates within their storage cavities 8 . The United States Food and Drug Administration (FDA) recently approved the first Cannabis -based medicine 9 , a purified plant extract containing the cannabinoid cannabidiol (CBD).…”

Section: Introductionmentioning

confidence: 99%

An extreme-phenotype genome‐wide association study identifies candidate cannabinoid pathway genes in Cannabis

Welling

Лю

Kretzschmar

et al. 2020

Sci Rep

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Cannabis produces a class of isoprenylated resorcinyl polyketides known as cannabinoids, a subset of which are medically important and exclusive to this plant. The cannabinoid alkyl group is a critical structural feature that governs therapeutic activity. Genetic enhancement of the alkyl side-chain could lead to the development of novel chemical phenotypes (chemotypes) for pharmaceutical end-use. However, the genetic determinants underlying in planta variation of cannabinoid alkyl side-chain length remain uncharacterised. Using a diversity panel derived from the Ecofibre Cannabis germplasm collection, an extreme-phenotype genome-wide association study (XP-GWAS) was used to enrich for alkyl cannabinoid polymorphic regions. Resequencing of chemotypically extreme pools revealed a known cannabinoid synthesis pathway locus as well as a series of chemotype-associated genomic regions. One of these regions contained a candidate gene encoding a β-keto acyl carrier protein (ACP) reductase (BKR) putatively associated with polyketide fatty acid starter unit synthesis and alkyl side-chain length. Association analysis revealed twenty-two polymorphic variants spanning the length of this gene, including two nonsynonymous substitutions. The success of this first reported application of XP-GWAS for an obligate outcrossing and highly heterozygote plant genus suggests that this approach may have generic application for other plant species.

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Biosynthesis and Chemical Modifications of Minor Cannabinoids

Nguyen

Kayser

2020

Encyclopedia of Life Sciences

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Minor cannabinoids are cannabinoids at very low abundances in Cannabis sativa L. essential oils (<0.5% of dried weight). The pharmacological properties of minor cannabinoids have never been determined or validated in clinical assays or in rational in vitro and in vivo assays. Due to this lack of biological and pharmacological information, minor cannabinoids have great potential as future drug candidates. The biosynthesis of minor cannabinoids is not clear in C. sativa L., but, likely, chemical conversion in the trichomes influenced by light, temperature and ultraviolet (UV) radiation is the main catalytic mode. This chemical conversion may explain the high chemodiversity and low structural stability. Key Concepts Minor cannabinoids are at very low abundance in Cannabis sativa L. Chemical diversity of essential oil is a consequence of chemical transformation. The role of minor cannabinoids in planta is unknown and needs further investigations. Minor cannabinoids can be considered as future candidates in drug discovery. Minor cannabinoids are found in other species (plant, moss, fungus) and chemical diversity is not limited to Cannabaceae only.

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Cannabinoid synthases and osmoprotective metabolites accumulate in the exudates of Cannabis sativa L. glandular trichomes

Cited by 49 publications

References 72 publications

Phytocannabinoids: Origins and Biosynthesis

Phytocannabinoids: Origins and Biosynthesis

An extreme-phenotype genome‐wide association study identifies candidate cannabinoid pathway genes in Cannabis

Biosynthesis and Chemical Modifications of Minor Cannabinoids

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