Terpene Synthases from Cannabis Sativa

 In Cannabis Education, Health, Medical Marijuana

Cannabis sativa, referred to here as cannabis, has been used for millennia as a medicine and recreational intoxicant. The species Cannabis sativa comprises both marijuana and hemp. Medicinal cannabis is highly valued for its pharmacologically active cannabinoids, a class of terpenophenolic metabolites unique to cannabis. These compounds are primarily found in the resin produced in the glandular trichomes of pistillate (female) inflorescences. Cannabis resin also contains a variety of monoterpenes and sesquiterpenes (Fig 1), which are responsible for much of the scent of cannabis flowers and contribute characteristically to the unique flavor qualities of cannabis products. Similarly, terpenes in hop (Humulus lupulus), a close relative of cannabis, are an important flavoring component in the brewing industry. Differences between the pharmaceutical properties of different cannabis strains have been attributed to interactions (or an ‘entourage effect’) between cannabinoids and terpenes [6, 7]. For example, the sesquiterpene β-caryophyllene interacts with mammalian cannabinoid receptors [8]. As a result, medicinal compositions have been proposed to incorporate blends of cannabinoids and terpenes [9]. Terpenes may contribute anxiolytic, antibacterial, anti-inflammatory, and sedative effects [6].

The inflorescence (left) with a high density of glandular trichomes was at five weeks post onset of flowering. Non-inflorescence leaves (right) have lower density of glandular trichomes. Structures of representative cannabis resin components are shown in white: monoterpenes (top row), sesquiterpenes (middle row), and cannabinoids (bottom row). GBGA = cannabigerolic acid; THCA = tetrahydrocannabinolic acid; CBDA = cannabidiolic acid.

Terpene biosynthesis in plants involves two pathways to produce the general 5-carbon isoprenoid diphosphate precursors of all terpenes, the plastidial methylerythritol phosphate (MEP) pathway and the cytosolic mevalonate (MEV) pathway. These pathways ultimately control the different substrate pools available for terpene synthases (TPS). The MEP pathway is comprised of seven steps that convert pyruvate and glyceraldehyde-3-phosphate into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) (Fig 2A). Enzymes thought to be critical for flux regulation through this pathway include the first two and final two steps: 1-deoxy-D-xylulose 5-phosphate synthase, 1-deoxy-D-xylulose 5-phosphate reductase, 4-hydroxy-3-methylbut-2-enyl diphosphate synthase, and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase [10, 11]. The MEV pathway converts three units of acetyl-CoA to IPP, which is then isomerized to DMAPP by IPP isomerase. A rate-limiting step in this six-step pathway is 3-hydroxy-3-methylglutaryl-CoA reductase, which produces mevalonate [12]. IPP and DMAPP are condensed into longer-chain isoprenoid diphosphates by prenyltransferases, which include geranyl diphosphate (GPP) synthase (GPPS) and farnesyl diphosphate (FPP) synthase (FPPS). GPPS and FPPS condense one unit of IPP and one or two units of DMAPP to form 10- and 15-carbon linear trans-isoprenoid diphosphates, respectively. GPP is the 10-carbon precursor of monoterpenes and is typically derived from 5-carbon isoprenoid diphosphate units of the MEP pathway. GPP is also a building block in the biosynthesis of cannabinoids [13, 14]. FPP is the 15-carbon precursor of sesquiterpenes and is commonly produced from 5-carbon isoprenoid diphosphate units of the cytosolic mevalonate (MEV) pathway. GPPSs exist as homo- or heterodimeric enzymes. In hops, the closest known relative of cannabis, heterodimeric GPPSs can produce both GPP and the 20-carbon geranylgeranyl diphosphate (GGPP), with the ratio of large to small G(G)PPS subunits controlling the product outcome [15, 16, 17]. The linear isoprenoid diphosphates GPP and FPP are substrates for monoterpene synthases (mono-TPS) and sesquiterpene synthases (sesqui-TPS), respectively, which diversify these precursors into a large number of different mono- and sesquiterpenes.


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