Converting Sugars into Cannabinoids—The State-of-the-Art of Heterologous Production in Microorganisms
Abstract
:1. Introduction
2. Biosynthesis of Phytocannabinoids
3. Metabolic Engineering towards Phytocannabinoids Biosynthesis in Microorganisms
3.1. Design of a Suitable Host
3.2. From Sugar to Cannabinoids
3.3. Patent Prospection
3.4. Culture Medium, Production System, and Broth Composition
3.5. Metabolic Engineering In Silico
4. Conceptual Downstream Analysis
4.1. Process Flowchart
4.2. Process Description
5. Further Analysis and Improvements
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Enzyme | Abbreviation | Accession No. | EC No. | References |
---|---|---|---|---|
Acyl activating enzyme 1 | AAE | AFD33345.1 | 6.2.1.1 | [81] |
Olivetol synthase (tetraketide synthase 3) | OLS (TKS) | AB164375 | 2.3.1.206 | [82] |
Olivetolic cyclase | OAC | AFN42527.1 | 4.4.1.26 | [60] |
Geranylpyrophosphate:olivetolate geranyltransferase | GOT (CsPT4-T) | US10975379B2 a | 2.5.1.102 | [13] |
Tetrahydrocannabinolic acid synthase | THCAS | AB057805 | 1.21.3.7 | [83] |
Cannabidiolic acid synthase | CBDAS | AB292682 | 1.21.3.8 | [84] |
Cannabichromenic acid synthase | CBCAS | WO2015196275A1 b | 1.3.3- | [85,86] |
Patent Number | Title | Resume | Country | Applicants | Granted | Citations | Year (Publication) |
---|---|---|---|---|---|---|---|
US9546362B2 | Genes and proteins for alkanoyl-coa synthesis | Proposition of genetic engineering of plant, yeast, or bacterial cells with a cassette comprising 13 where homologous, isolated, and/or purified sequences of Cannabis sativa for the production of cannabinoids using carboxylic acids as substrate | Canada | University of Saskatchewan and Natural Resources Council | Yes | 18 | 2014 |
EP3067058A1 | Biological composition based on engineered Lactobacillus paracasei subsp. paracasei f19 for the biosynthesis of cannabinoids | Discloses the use of the strain Lactobacillus paracasei subsp. paracasei f19 as a suitable host for Cannabis sativa gene incorporation | Italy | Farmagens Health Care SRL | No | 8 | 2016 |
US10801049B2 | Production of cannabinoids in microorganisms from a carbon sugar precursor | Claims the application of the insertion of the pgi, zwf, and gItA genes and the mutation of the fadD gene to the synthesis of the hexanoyl-CoA precursor from simple sugar sources | USA | Syntiva Therapeutics Inc. | Yes | 0 | 2019 |
US10392635B2 | Production of Tetrahydrocannabinolic Acid in Yeast | Insertion of a mutant aromatic prenyltransferase in yeast models, resulting in a higher yield of geranyl pyrophosphate, an important precursor of the cannabinoids | USA | Librede Inc. | Yes | 1 | 2019 |
US10837031B2 | Recombinant production systems for prenylated polyketides of the cannabinoid family | Proposes the recombinant production of cannabinoids in yeasts and filamentous fungi through the production of cannabinoid precursors when grown in the presence of exogenous prenol and isoprenol | USA | Baymedica Inc. | Yes | 3 | 2019 |
US2020370073A1 | Biosynthetic cannabinoid production methods | Proposes the commercial-scale production and processing of biosynthetic cannabinoids produced by growing genetically modified microalgae in a photo-bioreactor and the posterior recovery of the cannabinoid via extraction and distillation | USA | Insectergy LLC | No | 0 | 2020 |
US2020340026A1 | Neurotransmitters and Methods of Making the Same | Discloses the modification of microalgae for the expression of Cannabis sativa-encoding genes | USA | Purissima Inc. | No | 0 | 2020 |
US2020325508A1 | Genes and proteins for aromatic polyketide synthesis | Expression or over-expression of the enzyme that catalyzes the synthesis of aromatic polyketides (e.g., olivetolic acid) which may result in increased production of cannabinoid compounds | Canada | University of Saskatchewan and Natural Resources Council | No | 0 | 2020 |
US2020291434A1 | Metabolic engineering of E. coli for the biosynthesis of cannabinoid products | Insertion of an overexpressed, bifunctional enzyme ispDF responsible for the synthesis of isoprene, terpenoids, and cannabinoids | Canada | Inmed Pharmaceuticals Inc. | No | 0 | 2020 |
US2020224231A1 | Production of cannabinoids in yeast using a fatty acid feedstock | Modification of the peroxisomal β-oxidation in yeasts to provide an affordable and sustainable production of cannabinoids using vegetable oil or animal fat | USA | Levadura Biotechnology Inc. | No | 0 | 2020 |
US10975379B2 | Microorganisms and methods for producing cannabinoids, and cannabinoid derivatives | Proposes the recombinant expression of a geranyl pyrophosphate: olivetolic acid geranyltransferase (GOT) to produce cannabinoids molecules, precursors, or its derivatives | USA | University of California | Yes | 0 | 2020 |
US2020165644A1 | Production of cannabinoids in yeast | Heterologous synthesis of cannabinoids using 5% of fatty acids in genetically modified yeasts containing one or more genes responsible for the production of GPP producing; two or more olivetolic acid-producing genes; one or more cannabinoid precursor or cannabinoid producing genes; and one or more Hexanoyl-CoA producing genes | USA | Biomedican Inc. | No | 0 | 2020 |
US2020165641A1 | Bidirectional multi-enzymatic scaffolds for biosynthesizing of cannabinoids | Metabolic engineering of yeasts and bacteria using a complex system of 15 enzyme-encoding sequences for the production of a wide range of cannabinoids using glucose as carbon source via hexanoyl-CoA, malonyl-CoA, or mevalonate pathways | USA | Khona Pharms LLC | No | 0 | 2020 |
US2020080115A1 | Cannabinoid Production by Synthetic In Vivo Means | Transformation of yeast cells with three or more vectors comprising for the enhanced GPP production, production of OTA and GOT activity | USA | Biotic Sciences LLC | No | 0 | 2020 |
US2020071732A1 | Production of Cannabinoids in Yeast | Genetic engineering of yeast cells with the inclusion of the GPP pathway genes, allowing a superior yield of cannabinoids and use of glucose as carbon source | USA | Librede Inc. | No | 0 | 2020 |
US10954534B2 | Production of Cannabigerolic Acid in Yeast | Claims the heterologous expression of cannabigerolic acid in yeasts and bacteria through the insertion of Cannabis sativa acyl-activating enzyme, mutant prenyltransferase, olivetolic synthase, olivetolic acid cyclase, and aromatic prenyltransferase | USA | Librede Inc. | Yes | 0 | 2020 |
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Favero, G.R.; de Melo Pereira, G.V.; de Carvalho, J.C.; de Carvalho Neto, D.P.; Soccol, C.R. Converting Sugars into Cannabinoids—The State-of-the-Art of Heterologous Production in Microorganisms. Fermentation 2022, 8, 84. https://doi.org/10.3390/fermentation8020084
Favero GR, de Melo Pereira GV, de Carvalho JC, de Carvalho Neto DP, Soccol CR. Converting Sugars into Cannabinoids—The State-of-the-Art of Heterologous Production in Microorganisms. Fermentation. 2022; 8(2):84. https://doi.org/10.3390/fermentation8020084
Chicago/Turabian StyleFavero, Gabriel Rodrigues, Gilberto Vinícius de Melo Pereira, Júlio Cesar de Carvalho, Dão Pedro de Carvalho Neto, and Carlos Ricardo Soccol. 2022. "Converting Sugars into Cannabinoids—The State-of-the-Art of Heterologous Production in Microorganisms" Fermentation 8, no. 2: 84. https://doi.org/10.3390/fermentation8020084