Biosynthesis of cannabigerol and cannabigerolic acid: the gateways to further cannabinoid production

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Abstract
Cannabinoids are a therapeutically valuable class of secondary metabolites with a vast number of substituents. The native cannabinoid biosynthetic pathway of Cannabis sativa generates cannabigerolic acid, the common substrate to multiple cannabinoid synthases. The bioactive decarboxylated analogue of this compound, cannabigerol, represents an alternate gateway into the cannabinoid space either as a substrate to non-canonical cannabinoid synthase homologues or to synthetic chemical reactions. Herein, we describe the identification and repurposing of the aromatic prenyl transferase, AtaPT, which when coupled with native enzymes of C. sativa can form an E. coli production system for cannabigerolic acid in cell lysates, and cannabigerol in whole cells. Engineering of AtaPT, guided by structural analysis, was performed to enhance its kinetics towards cannabigerolic acid production for subsequent use in a proof-of-concept lysate system. For the first time, we show a synthetic biology platform for cannabigerol biosynthesis in E. coli cells by employing AtaPT under an optimised microbial system. Our results have therefore set the foundation for sustainable production of well researched and rarer cannabinoids in an E. coli chassis.
Funding Information
  • EPSRC/BBSRC
  • EP (S01778X/1)
  • BBSRC/EPSRC Synthetic Biology Research Centre (BB/M017702/1)
  • University of California, San Francisco
  • UK Biotechnology and Biological Sciences Research Council
  • BBSRC
  • NIH (P41-GM103311)
  • EPSRC/BBSRC
  • EP (S01778X/1)
  • BBSRC/EPSRC Synthetic Biology Research Centre (BB/M017702/1)
  • University of California, San Francisco
  • UK Biotechnology and Biological Sciences Research Council
  • BBSRC
  • NIH (P41-GM103311)

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