Cannabinoid Biosynthesis using Noncanonical Cannabinoid Synthases

We have found enzymes from the berberine-bridge enzyme (BBE) superfamily (IPR012951) that catalyze the oxidative cyclization of the monoterpene moiety in cannabigerolic acid (CBGA) to form cannabielsoic acid B (CBSA). The enzymes are from a variety of organisms and are previously uncharacterized. This is the first report that describes enzymes that did not originate from the Cannabis plant that catalyze the production of cannabinoids. Out of 72 homologues chosen from the enzyme superfamily, six orthologues were shown to accept CBGA as a substrate and catalyze the biosynthesis of CBSA. The six enzymes discovered in this study are the first report of heterologous expression of BBEs that did not originate from the Cannabis plant that catalyze the production of cannabinoids using CBGA as substrate. This study details a new avenue for discovering and producing natural and unnatural cannabinoids.