Figure 2.

Schematic depiction of cannabinoid and exemplar mono‐, sesqui‐, and diterpenoid biosynthesis. The isoprenoid and prenyl precursors for cannabigerolic acid (CBGA), are provided by the hexanoate and 2‐C‐methyl‐D‐erythritol 4‐phosphate (MEP) pathways, respectively. Geranyl diphosphate (GPP), is a key intermediate metabolite and building block for both cannabinoid and terpenoid biosynthesis. The seven‐step mevalonate (MVA) pathway converts pyruvate and glyceraldehyde‐3‐phosphate (G‐3‐P) into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Key catalytic enzymes controlling flux through this pathway include the first two steps, 1‐deoxy‐D‐xylulose 5‐phosphate synthase (DXS) and 1‐deoxy‐D‐xylulose 5‐phosphate reductase (DXR). In the six‐step MEP pathway, three units of acetyl coenzyme A (CoA) are converted to IPP, which is isomerized with DMAPP by IPP isomerase. The enzyme catalysing the synthesis of MEV, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGR), is considered to control flux through this pathway. The number of consecutive condensations of the five‐carbon monomer isopentenyl diphosphate (IPP) to its isomer, dimethylallyl diphosphate (DMAPP) is indicated by 1x, 2x, 3x. Longer‐chain isoprenoids, GPP, farnesyl diphosphate (FPP) and geranyl geranyl diphosphate (GGPP), are the products of IPP and DMAPP condensation catalysed by GPP synthase, FPP synthase and GGPP synthase, respectively. GPP, FPP and geranyl‐geranyl diphosphate (GGPP) are the precursors for mono‐, sequi‐, and di‐terpines, respectively. The final steps catalysing the synthesis of major active cannabinoids, cannabichromenic acid (CBCA), cannabidiolic acid (CBDA) and Δ⁹‐tetrahydrocannabinolic acid (THCA), are oxidocyclases, CBCA synthase (CBCAS), CBDA synthase (CBDAS) and THCA synthase (THCAS). Components of Figure 2 are derived from 29. AAE, acyl‐activating enzyme; CBD: cannabidiol; CYP76F39, α/β‐santalene monooxygenase; GPP synthase small subunit; OLS, olivetol synthase; P450: haemoprotein cytochrome P450; PT, prenyltransferase; STS, santalene synthase; TS, gamma‐terpinene synthase; TXS, taxadiene synthase