Cannabinoid Biosynthesis using Noncanonical Cannabinoid Synthases

Abstract

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.

Biosynthesis of Nature-Inspired Unnatural Cannabinoids

“…This is unsurprising as these secondary metabolites originally isolated from plants were used as a deterrent against herbivory or even as a UV screen that filters UV-B radiation that are biologically harmful [ 89 ]. Recently, Go et al illustrated that possibility by screening a library of 72 orthologues obtained from the EFI-EST webtool using CBGA as the substrate and found six orthologues from various sources that catalyze the formation of cannabielsoic acid (CBEA), a rare cannabinoid found in low abundance in C. sativa [ 90 ]. This is the first report of using non-canonical flavoproteins outside of the Cannabis plant to catalyze the formation of a minor cannabinoid.…”