Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa

Marks, M. David; Tian, Li; Wenger, Jonathan P.; Omburo, Stephanie N.; Soto-Fuentes, Wilfredo; He, Ji; Gang, David R.; Weiblen, George D.; Dixon, Richard A.

doi:10.1093/jxb/erp210

Cited by 116 publications

(105 citation statements)

References 61 publications

(77 reference statements)

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“…Many of the genes involved in photosynthesis and carbon fixation are expressed at significant (although not particularly high) levels in the Solanum trichome types investigated, in contrast to what has been observed in some other species (Turner et al, 2000;Gang et al, 2001;Deschamps et al, 2006;Gunnewich et al, 2007;Marks et al, 2009). Therefore, it is likely that at least some of the carbon required for the synthesis of the specialized metabolites found in Solanum glandular trichomes may be fixed within the trichome secretory cells.…”

Section: Resultsmentioning

confidence: 77%

Comparative Functional Genomic Analysis ofSolanumGlandular Trichome Types

et al. 2010

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Glandular trichomes play important roles in protecting plants from biotic attack by producing defensive compounds. We investigated the metabolic profiles and transcriptomes to characterize the differences between different glandular trichome types in several domesticated and wild Solanum species: Solanum lycopersicum (glandular trichome types 1, 6, and 7), Solanum habrochaites (types 1, 4, and 6), Solanum pennellii (types 4 and 6), Solanum arcanum (type 6), and Solanum pimpinellifolium (type 6). Substantial chemical differences in and between Solanum species and glandular trichome types are likely determined by the regulation of metabolism at several levels. Comparison of S. habrochaites type 1 and 4 glandular trichomes revealed few differences in chemical content or transcript abundance, leading to the conclusion that these two glandular trichome types are the same and differ perhaps only in stalk length. The observation that all of the other species examined here contain either type 1 or 4 trichomes (not both) supports the conclusion that these two trichome types are the same. Most differences in metabolites between type 1 and 4 glands on the one hand and type 6 glands on the other hand are quantitative but not qualitative. Several glandular trichome types express genes associated with photosynthesis and carbon fixation, indicating that some carbon destined for specialized metabolism is likely fixed within the trichome secretory cells. Finally, Solanum type 7 glandular trichomes do not appear to be involved in the biosynthesis and storage of specialized metabolites and thus likely serve another unknown function, perhaps as the site of the synthesis of protease inhibitors.Trichomes are epidermal structures widely conserved across the plant kingdom (Kim and Mahlberg, 1991;Wagner, 1991;Alonso et al., 1992;Yu et al., 1992;Kolb and Muller, 2003;Valkama et al., 2003;Giuliani and Bini, 2008). These structures perform important biological functions, such as discouraging herbivory, attracting pollinators, and maintaining a boundary layer (Nihoul, 1993;Van Dam and Hare, 1998;Kennedy, 2003;Moyano et al., 2003;Simmons and Gurr, 2005;Liu et al., 2006;Horgan et al., 2007;Gonzalez et al., 2008;Romero et al., 2008;Nonomura et al., 2009;Kang et al., 2010). Many of these functions are the result of the specialized nature of glandular trichomes (glands) as sites for the synthesis and storage of biologically active specialized metabolites (Alonso et al

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Section: Resultsmentioning

confidence: 77%

Comparative Functional Genomic Analysis ofSolanumGlandular Trichome Types

et al. 2010

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“…This divergence may reflect the taxonomical distance of hop (Cannabinaceae) from Leguminosae or the difference in enzymatic functions such as different substrate preference. Partial sequence of prenyltransferase putatively involved in cannabinoid biosynthesis has also been found in Cannabis sativa (Cannabinaceae) EST data (34), and this partial sequence is similar to HlPT1. However, the possibility cannot be eliminated that other membranebound prenyltransferases, from the p-hydroxybenzoate prenyltransferase family involved in the biosynthesis of ubiquinone (35,36) and naphthoquinone (19), serve another evolutional origin for those divergent prenyltransferases from other aromatic substrates.…”

Section: Discussionmentioning

confidence: 78%

Molecular Characterization of a Membrane-bound Prenyltransferase Specific for Isoflavone from Sophora flavescens

Sasaki

Tsurumaru

Yamamoto

et al. 2011

Journal of Biological Chemistry

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Prenylated isoflavones are secondary metabolites that are mainly distributed in legume plants. They often possess divergent biological activities such as anti-bacterial, anti-fungal, and anti-oxidant activities and thus attract much attention in food, medicinal, and agricultural research fields. Prenyltransferase is the key enzyme in the biosynthesis of prenylated flavonoids by catalyzing a rate-limiting step, i.e. the coupling process of two major metabolic pathways, the isoprenoid pathway and shikimate/polyketide pathway. However, so far only two genes have been isolated as prenyltransferases involved in the biosynthesis of prenylated flavonoids, namely naringenin 8-dimethylallyltransferase from Sophora flavescens (SfN8DT-1) specific for some limited flavanones and glycinol 4-dimethylallyltransferase from Glycine max (G4DT), specific for pterocarpan substrate. We have in this study isolated two novel genes coding for membrane-bound flavonoid prenyltransferases from S. flavescens, an isoflavone-specific prenyltransferase (SfG6DT) responsible for the prenylation of the genistein at the 6-position and a chalcone-specific prenyltransferase designated as isoliquiritigenin dimethylallyltransferase (SfiLDT). These prenyltransferases were enzymatically characterized using a yeast expression system. Analysis on the substrate specificity of chimeric enzymes between SfN8DT-1 and SfG6DT suggested that the determinant region for the specificity of the flavonoids was the domain neighboring the fifth transmembrane ␣-helix of the prenyltransferases.

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“…Several Betv1-protein family members function as enzymes in plant natural product biosynthesis (23). High numbers of ESTs corresponding to the DABB protein (9 ESTs) and the Betv1-like protein (6 ESTs) were found in the cannabis trichome EST dataset reported by Marks et al (11).…”

Section: Resultsmentioning

confidence: 96%

“…Several groups have attempted to identify the PKS that synthesizes OA, but the enzymatic basis for this reaction remains unclear (10,11). Taura et al (10) assayed a type III PKS cloned from cannabis leaves and found that it produces olivetol and α-pyrones [pentyl diacetic acid lactone (PDAL) and hexanoyl triacetic acid lactone (HTAL)] but not OA (Fig.…”

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confidence: 99%

Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides

Gagne

Stout²,

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

256

236

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Δ 9 -Tetrahydrocannabinol (THC) and other cannabinoids are responsible for the psychoactive and medicinal properties of Cannabis sativa L. (marijuana). The first intermediate in the cannabinoid biosynthetic pathway is proposed to be olivetolic acid (OA), an alkylresorcinolic acid that forms the polyketide nucleus of the cannabinoids. OA has been postulated to be synthesized by a type III polyketide synthase (PKS) enzyme, but so far type III PKSs from cannabis have been shown to produce catalytic byproducts instead of OA. We analyzed the transcriptome of glandular trichomes from female cannabis flowers, which are the primary site of cannabinoid biosynthesis, and searched for polyketide cyclase-like enzymes that could assist in OA cyclization. Here, we show that a type III PKS (tetraketide synthase) from cannabis trichomes requires the presence of a polyketide cyclase enzyme, olivetolic acid cyclase (OAC), which catalyzes a C2-C7 intramolecular aldol condensation with carboxylate retention to form OA. OAC is a dimeric α+β barrel (DABB) protein that is structurally similar to polyketide cyclases from Streptomyces species. OAC transcript is present at high levels in glandular trichomes, an expression profile that parallels other cannabinoid pathway enzymes. Our identification of OAC both clarifies the cannabinoid pathway and demonstrates unexpected evolutionary parallels between polyketide biosynthesis in plants and bacteria. In addition, the widespread occurrence of DABB proteins in plants suggests that polyketide cyclases may play an overlooked role in generating plant chemical diversity.natural products | phytocannabinoid | terpenophenolic | aldolase | ferredoxin-like

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Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa

Cited by 116 publications

References 61 publications

Comparative Functional Genomic Analysis ofSolanumGlandular Trichome Types

Comparative Functional Genomic Analysis ofSolanumGlandular Trichome Types

Molecular Characterization of a Membrane-bound Prenyltransferase Specific for Isoflavone from Sophora flavescens

Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides

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