Complete biosynthesis of cannabinoids and their unnatural analogues in yeast

Nature
Xiaozhou LuoJay D Keasling

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...Continue Reading

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Citations

May 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Elie Dolgin
Jun 6, 2019·Journal of Industrial Microbiology & Biotechnology·John M BillingsleyYi Tang
Jul 2, 2019·Natural Product Reports·Mohammad AlanjaryMarnix H Medema
Jun 20, 2019·G3 : Genes - Genomes - Genetics·Max A B HaaseJef D Boeke
Sep 3, 2019·Natural Product Reports·Martina AdamekNadine Ziemert
Sep 19, 2019·Chemistry, an Asian Journal·Byunghyuck JungInsung S Choi
Dec 12, 2019·FEMS Yeast Research·Bettina Lengger, Michael K Jensen
Feb 7, 2020·International Journal of Molecular Sciences·Conor Jenkins, Benjamin Orsburn
Dec 5, 2019·The Journal of the American Academy of Orthopaedic Surgeons·Lindsay T Kleeman-ForsthuberJason M Jennings
May 5, 2020·Natural Product Reports·Stephanie GalanieJames Lalonde
Mar 17, 2020·Annual Review of Plant Biology·Joseph R Jacobowitz, Jing-Ke Weng
Jun 28, 2019·Briefings in Bioinformatics·Fu ChenQian-Nan Hu
Sep 5, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Falone Sunda, Afolake Arowolo
Dec 17, 2019·Beilstein Journal of Organic Chemistry·Eric J N HelfrichJon Clardy
Jan 31, 2020·Frontiers in Bioengineering and Biotechnology·Xiao-Yu WuBang-Ce Ye
Apr 22, 2020·Nucleic Acids Research·Shaozhen DingQian-Nan Hu
May 28, 2020·Frontiers in Plant Science·Konstantinos A Aliferis, David Bernard-Perron
Aug 11, 2020·Journal of Industrial Microbiology & Biotechnology·Natali OzberPeter J Facchini
Jun 15, 2019·Natural Product Reports·Jia Jia ZhangBradley S Moore
Sep 21, 2019·Current Protocols in Pharmacology·John A Beutler
Jun 27, 2020·Nanomedicine·Emmanuel Shan OnaiviVenkatanarayanan Sharma
Aug 13, 2020·Metabolites·Hongting TangJay D Keasling
Nov 23, 2019·International Journal of Molecular Sciences·Simone LandiSergio Esposito
Aug 8, 2019·Scientific Reports·Matthew T WellingGraham J King
Aug 26, 2020·Nature Chemical Biology·Meaghan A ValliereJames U Bowie
May 10, 2020·Nature Communications·Qiang DingXiulai Chen
Mar 21, 2020·Nature Communications·João P A ReisPedro N Leão
Jul 15, 2020·Nature Biotechnology·Ayaan HossainHoward M Salis
Aug 23, 2020·Applied and Environmental Microbiology·Mitchell G ThompsonJay D Keasling
Oct 13, 2020·Applied Microbiology and Biotechnology·Fabian ThomasOliver Kayser
Nov 5, 2020·Natural Product Reports·Lu TongJun O Liu
Oct 31, 2020·Frontiers in Bioengineering and Biotechnology·Mariam ElgabryShane D Johnson
Jul 23, 2020·Bioinformatics·Dongliang LiuQian-Nan Hu
Dec 18, 2020·Frontiers in Bioengineering and Biotechnology·Ruobing GuanYongjun Wei

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Software Mentioned

Python
Agilent MassHunter Qualitative Analysis
BLAST
Openchrom
Scipy
Basic Local Alignment Search Tool ( BLAST )
MUSCLE
Pandas

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