Format

Send to

Choose Destination
Nature. 2019 Mar;567(7746):123-126. doi: 10.1038/s41586-019-0978-9. Epub 2019 Feb 27.

Complete biosynthesis of cannabinoids and their unnatural analogues in yeast.

Author information

1
California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
2
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
3
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
4
Demetrix, Inc., Emeryville, CA, USA.
5
Berkeley Brewing Science, Inc., Berkeley, CA, USA.
6
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.
7
Department of Bioengineering, University of California, Berkeley, CA, USA.
8
Genomatica, Inc., San Diego, CA, USA.
9
Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China.
10
Department of Chemistry, University of California, Berkeley, CA, USA.
11
Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA.
12
Biotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA, USA.
13
California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. keasling@berkeley.edu.
14
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. keasling@berkeley.edu.
15
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA. keasling@berkeley.edu.
16
Department of Bioengineering, University of California, Berkeley, CA, USA. keasling@berkeley.edu.
17
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark. keasling@berkeley.edu.
18
Center for Synthetic Biochemistry, Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technologies, Shenzhen, China. keasling@berkeley.edu.

Abstract

Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia1. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications2. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments3. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids4, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway5. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid6, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases7,8. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency9. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems.

PMID:
30814733
DOI:
10.1038/s41586-019-0978-9
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center