Revisão Acesso aberto Revisado por pares

Phytocannabinoids: Origins and Biosynthesis

2020; Elsevier BV; Volume: 25; Issue: 10 Linguagem: Inglês

10.1016/j.tplants.2020.05.005

ISSN

1878-4372

Autores

Thies Gülck, Birger Lindberg Møller,

Tópico(s)

GABA and Rice Research

Resumo

Phytocannabinoids are bioactive terpenoids that were thought to be exclusive to Cannabis sativa, but have now also been discovered in Rhododendron species, some legumes, the liverwort genus Radula, and some fungi.Many cannabinoids display promising non-hallucinogenic bioactivities that are determined by the variable nature of the side chain and prenyl group defined by the enzymes involved in their synthesis.The biosynthesis of cannabinoids in C. sativa is fully elucidated, whereas the pathways in Rhododendron and Radula have only recently gained research attention.Cannabinoid biosynthesis is highly modular, enabling use of the modules identified in synthetic biology-based combinatorial approaches, as demonstrated by the generation of new-to-nature cannabinoids in Saccharomyces cerevisiae.The ecological functions of cannabinoids include protection against UV light and desiccation, as well as in plant defense. 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 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. 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.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar]. 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.Chanda D. et al.The endocannabinoid system: overview of an emerging multi-faceted therapeutic target.Prostaglandins Leukot. Essent. Fat. Acids. 2019; 140: 51-56Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. 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.Russo E.B. History of cannabis and its preparations in saga, science, and sobriquet.Chem. Biodivers. 2007; 4: 1614-1648Crossref PubMed Scopus (192) Google Scholar]. The mammalian brain has receptors that respond to compounds found in C. sativa. Accordingly, these receptors were named cannabinoid receptors (CBx) 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.Chanda D. et al.The endocannabinoid system: overview of an emerging multi-faceted therapeutic target.Prostaglandins Leukot. Essent. Fat. Acids. 2019; 140: 51-56Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. More than 113 different cannabinoids have been isolated from C. sativa and these are classified into distinct types: cannabigerols (CBGs), cannabichromenes (CBCs), cannabidiols (CBDs), (−)-Δ9-trans-tetrahydrocannabinols (Δ9-THCs), (−)-Δ8-trans-tetrahydrocannabinols (Δ8-THCs), cannabicyclols (CBLs), cannabielsoins (CBEs), cannabinols (CBNs), cannabinodiols (CBNDs), cannabitriols (CBTs), and the miscellaneous cannabinoids (Figure 2) [4.ElSohly M.A. Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids.Life Sci. 2005; 78: 539-548Crossref PubMed Scopus (509) Google Scholar]. C. sativa predominantly produces alkyl type cannabinoids that carry a monoterpene isoprenyl moiety (C10) and a pentyl side chain (C5) [1.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar]. The most abundant constituents are trans-Δ9-THC, CBD, CBC, and CBG, together with their respective acid forms (Δ9-THCA, CBDA, CBCA, and CBGA) [5.Happyana N. Kayser O. Monitoring metabolite profiles of Cannabis sativa L. trichomes during flowering period using 1H NMR-based metabolomics and real-time PCR.Planta Med. 2016; 82: 1217-1223Crossref PubMed Scopus (15) Google Scholar]. Cannabinoid biosynthetic pathways typically generate acidic cannabinoids (C22, 'pre-cannabinoids') as the final products [6.Sirikantaramas S. et al.Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes.Plant Cell Physiol. 2005; 46: 1578-1582Crossref PubMed Scopus (98) Google Scholar]. Further modified cannabinoids are spontaneous breakdown or conversion products resulting from, for example, oxidation, decarboxylation and cyclization, or are formed during isolation [7.Flores-Sanchez I.J. Verpoorte R. Secondary metabolism in cannabis.Phytochem. Rev. 2008; 7: 615-639Crossref Scopus (93) Google Scholar]. These conversions take place because of the poor oxidative stability of alkylic cannabinoids, in particular Δ9-THC [1.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar]. C. sativa is the best-studied and most common and productive source of phytocannabinoids, but is not the only organism capable of synthesizing this group of bioactive natural products.Figure 2Overview of Cannabinoids Derived from an Orcinoid, Varinoid, Olivetoid, or Bibenzyl/Aralkyl Backbone.Show full captionBlack structures have been isolated from natural sources [1.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar]. Blue structures have not yet been found in planta. Abbreviations: CBC, cannabichromene;CBD, cannabidiol; CBE, cannabielsoin; CBG, cannabigerol; CBL, cannabicyclol; CBN, cannabinol; CBND, cannabinodiol; CBT, cannabitriol; Pr, prenyl; SC, side chain; Δ8-THC, Δ8-tetrahydrocannabinol; Δ9-THC, Δ9-tetrahydrocannabinol.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Black structures have been isolated from natural sources [1.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar]. Blue structures have not yet been found in planta. Abbreviations: CBC, cannabichromene; CBD, cannabidiol; CBE, cannabielsoin; CBG, cannabigerol; CBL, cannabicyclol; CBN, cannabinol; CBND, cannabinodiol; CBT, cannabitriol; Pr, prenyl; SC, side chain; Δ8-THC, Δ8-tetrahydrocannabinol; Δ9-THC, Δ9-tetrahydrocannabinol. Several Rhododendron species (Ericaceae) produce bioactive meroterpenoids with a cannabinoid backbone [8.Yang Y. xun et al.New chromane and chromene meroterpenoids from flowers of Rhododendron rubiginosum Franch. var. rubiginosum.Fitoterapia. 2018; 127: 396-401Crossref PubMed Scopus (4) Google Scholar]. Rhododendron cannabinoids typically belong to the CBC type decorated with an orcinol side chain (i.e., a methyl group). Rhododendron dauricum L. is native to Northeastern Asia and produces grifolic acid (GFA), daurichromenic acid (DCA), and confluentin (decarboxylated DCA), as well as rhododaurichromenic acids A and B. All these cannabinoids carry a sesquiterpene moiety [9.Taura F. et al.Daurichromenic acid and grifolic acid: phytotoxic meroterpenoids that induce cell death in cell culture of their producer Rhododendron dauricum.Plant Signal. Behav. 2018; 13e1422463Crossref PubMed Scopus (3) Google Scholar]. Rhododendron adamsii Rehder grows in the expanses of Eastern Siberia and Mongolia and is used in folk medicine for preparing a stimulating tonic and as an adaptogenic remedy [10.Rogachev A.D. et al.Some prenylated phenols of Rhododendron adamsii: isolation, modification and pharmacological tests.Chem. Sustain. Dev. 2009; 17: 185-193Google Scholar]. It produces cannabigerorcynic acid, cannabigerorcynic acid methylester, DCA, and chromane/chromene meroterpenoids [10.Rogachev A.D. et al.Some prenylated phenols of Rhododendron adamsii: isolation, modification and pharmacological tests.Chem. Sustain. Dev. 2009; 17: 185-193Google Scholar]. Rhododendron anthopogonoides Maxim. grows in Southern China and is used as expectorant and for the treatment of chronic bronchitis [11.Iwata N. Kitanaka S. Tetracyclic chromane derivatives from Rhododendron anthopogonoides.J. Nat. Prod. 2010; 73: 1203-1206Crossref PubMed Scopus (31) Google Scholar,12.Iwata N. Kitanaka S. New cannabinoid-like chromane and chromene derivatives from Rhododendron anthopogonoides.Chem. Pharm. Bull. 2011; 59: 1409-1412Crossref PubMed Scopus (20) Google Scholar]. Phytochemical studies revealed that it contains the cannabinoid-like chromane and chromene derivatives anthopogocyclolic acid, anthopogochromenic acid, cannabiorcichromenic acid, and cannabiorcicyclolic acid [11.Iwata N. Kitanaka S. Tetracyclic chromane derivatives from Rhododendron anthopogonoides.J. Nat. Prod. 2010; 73: 1203-1206Crossref PubMed Scopus (31) Google Scholar,12.Iwata N. Kitanaka S. New cannabinoid-like chromane and chromene derivatives from Rhododendron anthopogonoides.Chem. Pharm. Bull. 2011; 59: 1409-1412Crossref PubMed Scopus (20) Google Scholar]. Lastly, Rhododendron rubiginosum Franch. var. rubiginosum, a shrub endemic to Southwest China, was found to contain anthopogochromenes A and B, as well as rubiginosins A–G [8.Yang Y. xun et al.New chromane and chromene meroterpenoids from flowers of Rhododendron rubiginosum Franch. var. rubiginosum.Fitoterapia. 2018; 127: 396-401Crossref PubMed Scopus (4) Google Scholar]. The flowering plant Helichrysum umbraculigerum Less. (Asteraceae) from South Africa, the edible roots of Glycyrrhiza foetida Desf. (licorice; Fabaceae), and Amorpha fruticosa L. (bastard indigo; Fabaceae) contain so-called amorfrutins, bioactive compounds with a cannabinoid backbone [13.Fuhr L. et al.Amorfrutins are natural PPARγ agonists with potent anti-inflammatory properties.J. Nat. Prod. 2015; 78: 1160-1164Crossref PubMed Google Scholar,14.Pollastro F. et al.Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum.Fitoterapia. 2017; 123: 13-17Crossref PubMed Scopus (5) Google Scholar]. These cannabinoids carry an aralkyl side chain and are thus characterized as prenylated bibenzyls [1.Hanuš L.O. et al.Phytocannabinoids: a unified critical inventory.Nat. Prod. Rep. 2016; 33: 1357-1392Crossref PubMed Google Scholar,14.Pollastro F. et al.Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum.Fitoterapia. 2017; 123: 13-17Crossref PubMed Scopus (5) Google Scholar]. Liverworts (Marchantiophyta; also called 'hepatics') are prolific producers of compounds with a bibenzyl backbone, such as lunularic acid and vittatin [15.Métoyer B. et al.Chemotypes and biomarkers of seven species of new caledonian liverworts from the bazzanioideae subfamily.Molecules. 2018; 23: 1353Crossref Scopus (1) Google Scholar]. Cannabinoids with a bibenzyl structure have been isolated from Radula perrottetii Gottsche ex Steph., R. marginata Taylor ex Gottsche, and R. laxiramea Steph. (Radulaceae), liverworts that are native to the northern island of New Zealand. These bibenzyl analogs of Δ9-THC, (−)-cis-perrottetinene, and (−)-cis-perrottetinenic acid are noteworthy for their inverted stereoconfiguration compared to non-bryophyte cannabinoids [16.Chicca A. et al.Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high.Sci. Adv. 2018; 4eaat2166Crossref PubMed Scopus (12) Google Scholar, 17.Toyota M. et al.New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata.ChemInform. 2003; 34: 1390-1392Crossref Google Scholar, 18.Toyota M. et al.Bibenzyl cannabinoid and bisbibenzyl derivative from the liverwort Radula perrottetii.Phytochemistry. 1994; 37: 859-862Crossref Scopus (40) Google Scholar, 19.Hussain T. et al.Demystifying the liverwort Radula marginata, a critical review on its taxonomy, genetics, cannabinoid phytochemistry and pharmacology.Phytochem. Rev. 2019; 18: 953-965Crossref Scopus (2) Google Scholar]. Beyond plants, cannabinoids are present in a few fungal organisms. Mycorrhizal fungi of the genus Albatrellus (Albatrellaceae) produce GFA and the derivatives grifolin, neogrifolin, and confluentin [20.Hellwig V. et al.Activities of prenylphenol derivatives from fruitbodies of Albatrellus spp. on the human and rat vanilloid receptor 1 (VR1) and characterisation of the novel natural product, confluentin.Arch. Pharm. (Weinheim). 2003; 336: 119-126Crossref PubMed Scopus (46) Google Scholar,21.Hashimoto T. et al.Isolation, synthesis and biological activity of grifolic acid dervivatives from the inedible mushroom Albatrellus dispansus.Heterocycles. 2005; 65: 2431-2439Crossref Scopus (25) Google Scholar]. Furthermore, Cylindrocarpon olidum (Nectriaceae) produces cannabiorcichromenic acid and the halogenated cannabinoid 8-chlorocannabiorcichromenic acid [22.Quaghebeur K. et al.Cannabiorci- and 8-chlorocannabiorcichromenic acid as fungal antagonists from Cylindrocarpon olidum.Phytochemistry. 1994; 37: 159-161Crossref PubMed Scopus (21) Google Scholar]. C. sativa accumulates phytocannabinoids and terpenes in glandular trichomes located all over the aerial parts of the plant and in highest density on the female flowers [7.Flores-Sanchez I.J. Verpoorte R. Secondary metabolism in cannabis.Phytochem. Rev. 2008; 7: 615-639Crossref Scopus (93) Google Scholar,23.Happyana N. et al.Analysis of cannabinoids in laser-microdissected trichomes of medicinal Cannabis sativa using LCMS and cryogenic NMR.Phytochemistry. 2013; 87: 51-59Crossref PubMed Scopus (73) Google Scholar]. No glandular trichomes are found on the root surfaces, and the root tissue therefore does not accumulate phytocannabinoids [24.Elhendawy M.A. et al.Chemical and biological studies of Cannabis sativa roots. Med.Cannabis Cannabinoids. 2018; 1: 104-111Crossref Google Scholar]. Glandular trichomes may be classified as sessile trichomes or stalked trichomes. Stalked glandular trichomes were recently shown to develop from sessile trichomes [25.Livingston S.J. et al.Cannabis glandular trichomes alter morphology and metabolite content.Plant J. 2020; 101: 37-56Crossref PubMed Scopus (2) Google Scholar]. Glandular trichomes accumulate cannabinoids in a balloon-shaped cavity that is filled by secretory vesicles [25.Livingston S.J. et al.Cannabis glandular trichomes alter morphology and metabolite content.Plant J. 2020; 101: 37-56Crossref PubMed Scopus (2) Google Scholar, 26.Hammond C.T. Mahlberg P.G. Morphogenesis of capitate glandular hairs of Cannabis sativa (Cannabaceae).Am. J. Bot. 1977; 64: 1023-1031Crossref Google Scholar, 27.Mahlberg P.G. Kim E. Cuticle development on glandular trichomes of Cannabis sativa (Cannabaceae).Am. J. Bot. 2017; 78: 1113-1122Crossref Google Scholar, 28.Mahlberg P. Kim E. Accumulation of cannabinoids in glandular trichomes of Cannabis (Cannabaceae).J. Ind. Hemp. 2004; 9: 15-36Crossref Scopus (31) Google Scholar]. When a trichome ruptures, for example during high ambient temperatures or as a result of herbivory, its contents form a sticky coating on the plant surface that is orchestrated by the viscous, non-crystallizing properties of cannabinoids [29.Garrett E.R. Hunt C.A. Physicochemical properties, solubility, and protein binding of Δ9-tetrahydrocannabinol.J. Pharm. Sci. 1974; 63: 1056-1064Abstract Full Text PDF PubMed Google Scholar]. The noxious substance glues the mandibles and legs of potential herbivores and prevents desiccation, resembling the waxy glaze of cacti and other succulents from dry environments [30.Mauseth J.D. Structure–function relationships in highly modified shoots of cactaceae.Ann. Bot. 2006; 98: 901-926Crossref PubMed Scopus (135) Google Scholar]. The amount of cannabinoids formed correlates positively with increased temperatures and imposed heat stress, as well as with low soil moisture and poor mineral nutrient content [31.Murari G. et al.Influence of environmental conditions on tetrahydrocannabinol (Δ9-TCH) in different cultivars of Cannabis sativa L.Electron. J. Environ. Agric. Food Chem. 1983; 5: 195-201Google Scholar,32.Bazzaz F.A. et al.Photosynthesis and cannabinoid content of temperate and tropical populations of Cannabis sativa.Biochem. Syst. Ecol. 1975; 3: 15-18Crossref Scopus (14) Google Scholar]. The latter was indicated by a negative correlation between mineral supply and cannabinoid production [33.Bernstein N. et al.Impact of N, P, K, and humic acid supplementation on the chemical profile of medical cannabis (Cannabis sativa L).Front. Plant Sci. 2019; 10: 736Crossref PubMed Scopus (5) Google Scholar,34.Coffman C.B. Gentner W.A. Cannabinoid profile and elemental uptake of Cannabis sativa L. as influenced by soil characteristics.Agron. J. 1975; 67: 491Crossref Google Scholar]. Cannabinoid production may also provide an evolutionary advantage by functioning as sun-screens that absorb biologically destructive UV-B radiation (280–315 nm) [35.Eichhorn Bilodeau S. et al.An update on plant photobiology and implications for cannabis production.Front. Plant Sci. 2019; 10: 296Crossref PubMed Scopus (8) Google Scholar]. Significantly increased cannabinoid production was measured in Cannabis flowers after UV-B-induced stress [35.Eichhorn Bilodeau S. et al.An update on plant photobiology and implications for cannabis production.Front. Plant Sci. 2019; 10: 296Crossref PubMed Scopus (8) Google Scholar]. Thus phytocannabinoids convey various biologically beneficial properties. Compared with the in planta roles of cannabinoids in C. sativa, little is known about the function of cannabinoids in Rhododendron species. Rhododendrons are separated into two major groups, elepidotes and lepidotes. Elepidotes are large-leaved rhododendrons that are devoid of scales on their leaves. Lepidote rhododendrons have small leaves covered by glandular scales [36.Desch C. Hartford W. The rhododendron leaf scale.J. Am. Rhododendron Soc. 1983; 37 (https://scholar.lib.vt.edu/ejournals/JARS/v37n2/v37n2-desch.htm)Google Scholar]. The scales are located predominantly on the abaxial leaf surface, but are also present on the adaxial side (ratio ca 20:1) [36.Desch C. Hartford W. The rhododendron leaf scale.J. Am. Rhododendron Soc. 1983; 37 (https://scholar.lib.vt.edu/ejournals/JARS/v37n2/v37n2-desch.htm)Google Scholar]. These multicellular morphological features of epidermal origin consist of a stalk and a circular expanded cap [36.Desch C. Hartford W. The rhododendron leaf scale.J. Am. Rhododendron Soc. 1983; 37 (https://scholar.lib.vt.edu/ejournals/JARS/v37n2/v37n2-desch.htm)Google Scholar]. The leaf scales contain lipophilic globules that contain specialized metabolites such as terpenes, and function in insect deterrence [37.Doss R.P. Role of glandular scales of lepidote rhododendrons in insect resistance.J. Chem. Ecol. 1984; 10: 1787-1798Crossref PubMed Scopus (11) Google Scholar]. R. dauricum produces DCA that accumulates in the apoplast of the glandular scales, presumably serving as a chemical defense barrier based on its antimicrobial activities, together with its precursor grifolic acid (GA) and the reaction side-product H2O2 [38.Iijima M. et al.Identification and characterization of daurichromenic acid synthase active in anti-HIV biosynthesis.Plant Physiol. 2017; 174: 2213-2230Crossref PubMed Scopus (8) Google Scholar]. Liverworts (Marchantiophyta) possess oil bodies – membrane-bound cell organelles containing suspensions of terpenoids and aromatic oils in a carbohydrate- or protein-enriched matrix [39.Asakawa Y. Ludwiczuk A. Chemical constituents of bryophytes: structures and biological activity.J. Nat. Prod. 2018; 81: 641-660Crossref PubMed Scopus (37) Google Scholar]. The morphology of the oil bodies is used to distinguish the different Marchantiophyta species, and oil bodies have been proposed to serve several ecological functions [40.He X. et al.The oil bodies of liverworts: unique and important organelles in land plants.CRC. Crit. Rev. Plant Sci. 2013; 32: 293-302Crossref Scopus (34) Google Scholar]. Liverworts are in general not damaged by fungi and bacteria, insect larvae and adults, or slugs, snails, and small mammals [39.Asakawa Y. Ludwiczuk A. Chemical constituents of bryophytes: structures and biological activity.J. Nat. Prod. 2018; 81: 641-660Crossref PubMed Scopus (37) Google Scholar]. The compounds found in oil bodies bring forth characteristic pungent, odiferous, and/or bitter-tasting compounds that display a wide range of bioactivities [39.Asakawa Y. Ludwiczuk A. Chemical constituents of bryophytes: structures and biological activity.J. Nat. Prod. 2018; 81: 641-660Crossref PubMed Scopus (37) Google Scholar]. It is noteworthy that most sesqui- and di-terpenoids produced by liverworts show cis configuration, in contrast to those found in most higher plants, which have trans configuration [41.Asakawa Y. Chemical Constituents of the Hepaticae (Progress in the Chemistry of Organic Natural Products Vol. 42). Springer, 1982Google Scholar], although sesqui- and di-terpenoids in the Eremophila genus and Solanum spp. are exceptions [42.Wubshet S.G. et al.Identification of PTP1B and α-glucosidase inhibitory serrulatanes from Eremophila spp. by combined use of dual high-resolution PTP1B and α-glucosidase inhibition profiling and HPLC–HRMS–SPE–NMR.J. Nat. Prod. 2016; 79: 1063-1072Crossref PubMed Scopus (30) Google Scholar, 43.Tahtah Y. et al.High resolution PTP1B inhibition profiling combined with high-performance liquid chromatography–high-resolution mass spectrometry–solid-phase extraction–nuclear magnetic resonance spectroscopy: proof-of-concept and antidiabetic constituents in crude extract of Eremophila lucida.Fitoterapia. 2016; 110: 52-58PubMed Google Scholar, 44.Gericke O. et al.Biosynthesis of diterpenoids in Eremophila.BMC Plant Biol. 2020; 20: 91Crossref PubMed Scopus (0) Google Scholar, 45.Matsuba Y. et al.Biosynthesis of the diterpenoid lycosantalonol via nerylneryl diphosphate in Solanum lycopersicum.PLoS One. 2015; 10e0119302Crossref PubMed Scopus (17) Google Scholar]. In addition, the proposed ecological functions of oil bodies include resilience to cold temperatures, excessive light, UV radiation, and desiccation [40.He X. et al.The oil bodies of liverworts: unique and important organelles in land plants.CRC. Crit. Rev. Plant Sci. 2013; 32: 293-302Crossref Scopus (34) Google Scholar,46.Pressel S. et al.Effects of de- and rehydration in desiccation-tolerant liverworts: a cytological and physiological study.Int. J. Plant Sci. 2009; 170: 182-199Crossref Scopus (28) Google Scholar]. Liverworts are unable to biosynthesize abscisic acid. Instead, they produce the bibenzylic dihydrostilbenoid lunularic acid that has plant hormone activity [47.Pryce R.J. Lunularic acid, a common endogenous growth inhibitor of liverworts.Planta. 1971; 97: 354-357Crossref PubMed Scopus (33) Google Scholar]. The ecological function of perrottetinenic acid and perrottetinene is unclear, but might resemble those of cannabinoids in C. sativa. An extensive review on liverworts with a focus on Radula marginata taxonomy, genetics, cannabinoid phytochemistry, and pharmacology was recently published by Hussain et al. [19.Hussain T. et al.Demystifying the liverwort Radula marginata, a critical review on its taxonomy, genetics, cannabinoid phytochemistry and pharmacology.Phytochem. Rev. 2019; 18: 953-965Crossref Scopus (2) Google Scholar]. Mosses (Bryophyta) and hornworts (Anthocerotophyta) do not possess oil bodies [40.He X. et al.The oil bodies of liverworts: unique and important organelles in land plants.CRC. Crit. Rev. Plant Sci. 2013; 32: 293-302Crossref Scopus (34) Google Scholar,48.Asakawa Y. Recent advances in phytochemistry of bryophytes-acetogenins, terpenoids and bis(bibenzyl)s from selected Japanese, Taiwanese, New Zealand, Argentinean and European liverworts.Phytochemistry. 2001; 56: 297-312Crossref PubMed Scopus (138) Google Scholar]. Cannabis preparations have been used as medicines since ancient times [3.Russo E.B. History of cannabis and its preparations in saga, science, and sobriquet.Chem. Biodivers. 2007; 4: 1614-1648Crossref PubMed Scopus (192) Google Scholar,49.Russo E.B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.Br. J. Pharmacol. 2011; 163: 1344-1364Crossref PubMed Scopus (511) Google Scholar]. They have been investigated for their antimicrobial activity against bacteria and fungi, and were found to be effective against a range of infectious diseases in humans and to represent potent antibiotics. Many fungi can metabolize cannabinoids [50.Binder M. Meisenberg G. Microbial transformation of cannabinoids.Eur. J. Appl. Microbiol. Biotechnol. 1978; 5: 37-50Crossref Scopus (5) Google Scholar], and this may reflect why cannabinoids seem to be effective only against a few fungal pathogens such as Phomopsis ganjae [51.McPartland J. Pathogenicity of Phomopsis ganjae on Cannabis sativa and the fungistatic effect of cannabinoids produced by the host.Mycopathologia. 1984; 87: 149-153Crossref Scopus (11) Google Scholar]. Their distinct pharmacological potential is commercially relevant. An increasing number of countries are relaxing their legislation around C. sativa and its phytocannabinoids. As a result, the global industry around legal cannabis-derived products is growing rapidly, and is likely to represent a projected US$ 57 billion market by 2027 [52.Pellechia T. Legal cannabis industry poised for big growth, in North America and around the world.Forbes. 2018; (Published online March 1, 2018. https://www.forbes.com/sites/thomaspellechia/2018/03/01/double-digit-billions-puts-north-america-in-the-worldwide-cannabis-market-lead/#)Google Scholar]. Cannabis extracts possess antimicrobial activity against the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus, as well as against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, but exhibits no activity towards the pathogenic fungi Candida albicans and Aspergillus niger [53.Ali E. Almagboul A. Antimicrobial activity of Cannabis sativa L.J. Chinese Med. 2012; 3: 61-64Crossref Google Scholar]. When tested individually, the major cannabinoids CBG, CBD, CBC, Δ9-THC, and CBN display antibiotic activity against methicillin-resistant Staphylococcus aureus [54.Appendino G. et al.Antibacterial cannabinoids from Cannabis sativa: a structure–activity study.J. Nat. Prod. 2008; 71: 1427-1430Crossref PubMed Scopus (259) Google Scholar]. Δ9-THC and CBD exhibit bactericidal effect against Gram-positive staphylococci and streptococci in the 1–5 μg/ml range, but not against Gram-negative bacteria [55.Van Klingeren B. Ten Ham M. Antibacterial activity of delta9-tetrahydrocannabinol and cannabidiol.Antonie Van Leeuwenhoek. 1976; 42: 9-12Crossref PubMed Scopus (24) Google Scholar]. This indicates that components of the complex cannabis extracts other than Δ9-THC and CBD, such as some of the terpenoids, are responsible for the bactericidal effects towards Gram-negative bacteria. DCA and GFA from Albatrellus dispansus also displayed antimicrobial activity against Gram-positive bacteria [21.Hashimoto T. et al.Isolation, synthesis and biological activity of grifolic acid dervivatives from the inedible mushroom Albatrellus dispansus.Heterocycles. 2005; 65: 2431-2439Crossref Scopus (25) Google Scholar]. This activity is attributed to the presence of a prenyl group in DCA and GFA because the resorcinolic core alone shows no antimicrobial activity [54.Appendino G. et al.Antibacterial cannabinoids from Cannabis sativa: a structure–activity study.J. Nat. Prod. 2008; 71: 1427-1430Crossref PubMed Scopus (259) Google Scholar]. Interestingly, the prenyl moieties show structural similarities to bioactive monoterpenes. In human, cannabinoids display a variety of bioactivities owing to their interaction

Referência(s)