## 1 Introduction  
Over a thousand of the molecules produced in _Cannabis sativa_ plants have been reported in the literature, including more than a hundred cannabinoids (CBs) [1]. The antinociceptive and appetite-stimulating properties of CBs have been studied thoroughly, as well as their association with relieving the symptoms associated with different diseases such as multiple sclerosis and the relief of chemotherapy side effects [2; 3; 4; 5]. The most studied CBs are \(\Delta\)9-tetrahydroocannabinol (THC), which has psychoactive potential, and cannabidiol (CBD), which acts on human endocannabinoid receptors to modulate pain and is already contained in many pharmaceutical products available on the market, such as Sativex and Bediol [6; 7; 8]. Other therapeutic properties of specific CBs that could be administrated in a purified form are still under investigation and offer a promising alternative for different human pathology applications [5]. In planta, phytocannabinoids are produced in glandular trichomes via fatty acid and terpenoid precursors [9]. The genes and enzymes implicated in the cannabinoid pathway were characterized by several plant biologists shortly after the sequencing of the _C. sativa_ genome [9; 10; 11; 12]. The first step in the CB biosynthetic pathway is the formation of olivetolic acid (OA) from malonyl-CoA and hexanoyl-CoA, through a two-step reaction performed by a type-III polykeletic synthase named tetraketide synthase (CsTKS) followed by a cyclase named olivetolic acid cyclase (CsOAC), both of which are localized in the cytosol or cells from the glandular trichomes (Figure 1). The enzymes belonging to the type-III polykeletic synthase (PKS) superfamily are responsible for producing a wide array of central frameworks that are found in specialized plant metabolites of significant medicinal value. These metabolites encompass various categories, such as flavonoids, stilbenes, chromomes, pyrones, phloroglucinols, resorcinols, xanthones, acridones, and quinolones [13; 14]. Examples of PKS include chalcone synthase, which accepts \(p\)-coumaroyl-CoA as the starter substrate to catalyze three successive condensations with malonyl-CoA to generate naringenin chalcone [15; 16] and stilbene synthase, which generates resveratrol [17]. The polykeletic synthase from _C. sativa_ (also named tetraketide synthase or olivetol synthase) was characterized and has been shown to be dependent on OAC for the formation of OA (Figure 1) [9]. The 3D structure of CsOAC is most accurately described as a dimeric \(\alpha+\beta\) barrel (DABB) protein, with similarities to other plant DABBs, especially those implicated in stress responses and to the DABB proteins found in _Streptomyces_ bacteria [9]. The aromatic precursor OA is a resorcinol carrying an alkyl chain (named alkylresorcinolic acid), which is condensed with a monoterenoid moiety (geranyl diphosphate, GPP) to yield the general structure of the most well-known CBs, as reported in feeding studies of 13C-labeled glucose in the early 1960s [18; 19]. Although not all CBs are derived from the OA precursor, it remains the most widely characterized pathway in _C. sativa_[20]. The preynl moiety of GPP is transferred to OA by an aromatic preynltransferase (CsAPT) to form cannabinoid acid (CBGA) (Figure 1). This core intermediate is the backbone of the remaining reaction, which diverges to form cannabidiolic acid (CBDA) and tetrahydroconnabinolic acid (THCA) through CBDA-synthase (CBDAS) and THCA-synthase (THCAS), respectively (Figure 1), as well as other CBs such as cannabichromeic acid (CBCA) via cannabichromeic acid cyclase (CBCAS) [9; 11; 21; 22]. The neutral phytocannabinoids THC and CBD are generated from cannabinoid acids by non-enzymatic decarboxylation and are often produced upon exposure to light or heat (Figure 1) [21].