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

Author:

Kearsey Lewis J1,Yan Cunyu2,Prandi Nicole3,Toogood Helen S1,Takano Eriko124ORCID,Scrutton Nigel S124ORCID

Affiliation:

1. Manchester Institute of Biotechnology and School of Chemistry, University of Manchester , Manchester M1 7DN, UK

2. BBSRC/EPSRC Synthetic Biology Research Centre SYNBIOCHEM, University of Manchester , Manchester M1 7DN, UK

3. Manchester Institute of Biotechnology and School of Chemistry, University of Manchester

4. EPSRC/BBSRC Future Biomanufacturing Research Hub, The University of Manchester , Manchester M1 7DN, UK

Abstract

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 (CBGA), the common substrate to multiple cannabinoid synthases. The bioactive decarboxylated analog of this compound, cannabigerol (CBG), represents an alternate gateway into the cannabinoid space as a substrate either to non-canonical cannabinoid synthase homologs or to synthetic chemical reactions. Herein, we describe the identification and repurposing of aromatic prenyltransferase (AtaPT), which when coupled with native enzymes of C. sativa can form an Escherichia coli production system for CBGA in cell lysates and CBG in whole cells. Engineering of AtaPT, guided by structural analysis, was performed to enhance its kinetics toward CBGA production for subsequent use in a proof-of-concept lysate system. For the first time, we show a synthetic biology platform for CBG biosynthesis in E. coli cells by employing AtaPT under an optimized microbial system. Our results have therefore set the foundation for sustainable production of well-researched and rarer cannabinoids in an E. coli chassis. Graphical Abstract

Funder

EPSRC/BBSRC

Ep

BBSRC/EPSRC Synthetic Biology Research Centre

University of California, San Francisco

UK Biotechnology and Biological Sciences Research Council

BBSRC

Nih

Publisher

Oxford University Press (OUP)

Subject

Agricultural and Biological Sciences (miscellaneous),Biomedical Engineering,Biomaterials,Bioengineering,Biotechnology

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