# Phytocannabinoids Biosynthesis in Angiosperms, Fungi, and Liverworts and Their Versatile Role
## 3 Biosynthesis of Phytocannabinoids
### Liverworts  
It was reported that _Radula marignata_ possesses enzymes for GPP biosynthesis and helps in the biosynthesis of biphenyl cannabinoid. Moreover, the production of biphenyl CBGA analog (i.e., lunularic acid, perrottettinenic acid, and perrottettinene) needs precursor stilbene acid or dihydroastilbene acid, which is very rare, and compounds of this type were found in _Hydarnegacmophylla_ var. _thunbergii_ and liverworts such as _Marchantia polymorpha_ and _Convolvulus hystrix_ (Figure 7) [1; 17; 38]. Figure 7: Phytocannabinoids biosynthesis in liverworts. Abbreviations: C4H, cinnamate 4-hydroxyase; 4 CL, 4-cumarateCoA ligase; PAL, phenylalanine ammonia-lyase; TAL, tyrosine ammonia-lyase. Stilbene acid is synthesized from type III PKS via coumaoyl-CoA or dihydrocoumaoyl-CoA, CoA-activated precursors. Starter molecules are extended by malonyl-CoA with decarboxylation, followed by a condensation reaction, which produces polyketide intermediate, which synthesizes different core structures. Hydrangic acid is the starter molecule that acts as coumaoyl-CoA. It is extended utilizing malonyl-CoA (three units) as a C2 donor to synthesize tetraketide intermediate. These reactions are catalyzed via stilbene synthase (STS)-type PKS enzymes. Ketoreductase (KR) leads to polyketide reduction followed by STS-like C2 to C7 intramolecular aldol condensation, here retention of the carboxylic group produces hydrangic acid. KR is involved in the loss of the C5-hydroxyl group on the aromatic ring structure of hydrangic acid, contrary to the stilbene acid structure. In _R. marginata_, the precursor of stilbene acid or dihydrostilbene is derived from the coumaoyl CoA or cinnamoyl-CoA; type III PKS enzyme helps in chain elongation, later putative tetraketide cyclase or (dihydrostilbene acid cyclase, DHAC) helps in cyclization [1; 38; 39]. The lunularic acid precursor, prelunularic acid is produced by the type III PKS, named biphenyl synthase (BBS). Moreover, BBS catalyzes the reaction where dihydrocumaoyl-CoA serves as the starter molecule for the extension utilizing malonyl-CoA (3-units), which serves as the carbon donor. Later, cyclization occurs on reduced polyketide, with a lack of C5-hydroxyl group on the aromatic ring structure. Furthermore, type III PKS plays a crucial role in the biphenyl camabinoi and its analog synthesis by also catalyzing the carboxylate retaining reaction mechanism. KR is involved in the cyclization and assists proper ring formation. Thus, after cyclization, lunularic acid is synthesized [40; 41; 42]. Perrottetinic acid (PA) is synthesized in _R. marginate_[43]. The transcriptomic approach of liverworks bears the mRNA encoding for type III PKS (responsible for chain elongation), which were later recognized as STS. Furthermore, it also exhibits a 60% homology of the amino acid sequence to stilbene-carboxylate synthase in _Marchantia polymorpha_. Other enzymes, such as double-bond reductase (DBR)--aromatic PT and oxidoreductase (perrottetinic acid synthase, PAS), are also responsible for the production of PA. DBR catalyzes compounds that are precursors of phenylpropanol, and generates dihydrocinnamoyl-CoA. The production of biphenyl phytocannabinoid is dispersed across the liverworks cells in the same way as in cannabis and _Rhododend_. Therefore, DHAC and DBR reside in the cytosol, PT is localized in the plastids and PAS inside the oil body. Signal peptides act as the crucial indicators for the encoding genes selection [18; 39; 41; 44]. Another biphenyl _cis_-THC, (-)_-cis_-perrottettinene (_cis_-PET) was isolated from the liverwork _R. perrotettii_[45]. The _cis_ configuration in the cyclohexene ring in _cis_-PET is comparable with \(\Delta^{9}\)_-trans_-THC. PET resembles \(\Delta^{9}\)-THC in its 3D shape, and can bind to many of the same cannabinoid receptors (CBRs) as \(\Delta^{9}\)-THC. Interestingly, PET also reduces the level of prostaglandins in the brain--a compound with inflammatory properties that increase in response to \(\Delta^{9}\)-THC and may be responsible for adverse effects [17].