The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems

Blatt-Janmaat, Kaitlyn; Qu, Yang

doi:10.3390/ijms22052454

Cited by 28 publications

(34 citation statements)

References 88 publications

(172 reference statements)

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“…In general, PT1 and PT4 are similarly regulated during female flower maturation in the same variety but the regulation is temporally different. The superimposition suggests that PT1 instead of PT4 more correlates with CBG content, which is not consistent with the recent findings (Blatt-Janmaat & Qu, 2021). Further analysis of these two enzymes will be more explicitly when there are PT1 or PT4 cannabis mutants available.…”

Section: The Correlation Between Cannabinoid Production and The Transcript Levels Of Corresponding Biosynthetic Genescontrasting

confidence: 76%

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Delineating the genetic regulation of cannabinoid biosynthesis during female flower development in Cannabis sativa

Apicella

Sands

et al. 2021

Preprint

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SUMMARYCannabinoids are predominantly produced in the glandular trichomes on cannabis female flowers. There is little known on how cannabinoid biosynthesis is regulated during female flower development. We aim to understand the rate-limiting step(s) in the cannabinoid biosynthetic pathway.We investigated the transcript levels of cannabinoid biosynthetic genes as well as cannabinoid contents during 7 weeks of female flower development. We demonstrated that the enzymatic steps for producing CBG, which involve genes GPPS, PT and OAC, could be rate limit cannabinoid biosynthesis. Our findings further suggest that cannabinoid synthases, CBDAS and THCAS in a hemp and medical marijuana variety respectively, are not critical for cannabinoid biosynthesis. The cannabinoid biosynthetic genes are generally upregulated during flower maturation, which indicate glandular trichome development.MeJA can potentially increase cannabinoid production. We propose that biweekly application of 100 μM MeJA staring from flower initiation would be efficacious for promoting cannabinoid biosynthesis.Our findings suggest that the step of CBG production could rate limit the terminal cannabinoid biosynthesis. In addition, different cannabis varieties demonstrated discrete transcriptional regulation of cannabinoid biosynthetic genes.

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Section: The Correlation Between Cannabinoid Production and The Transcript Levels Of Corresponding Biosynthetic Genescontrasting

confidence: 76%

“…PT1 was initially found to catalyze CBGA biosynthesis (Page & Boubakir, 2012). Recently PT4 was reported to have higher enzymatic activity (Blatt-Janmaat & Qu, 2021).…”

Section: The Correlation Between Cannabinoid Production and The Transcript Levels Of Corresponding Biosynthetic Genesmentioning

confidence: 99%

Delineating the genetic regulation of cannabinoid biosynthesis during female flower development in Cannabis sativa

Apicella

Sands

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Of primary interest are the eponymous cannabis plant and the production of the euphoric drug tetrahydrocannabinol (THC) and other non‐psychoactive drugs, such as cannabidiol (CBD). The site of phytocannabinoid and terpene accumulation are the glandular trichomes present on the aerial tissue and in the highest density on female flowers (reviewed by Blatt‐Janmaat and Qu, 2021).…”

Section: Chalcone Isomerase Fold; Structure and Evolutionmentioning

confidence: 99%

Elusive partners: a review of the auxiliary proteins guiding metabolic flux in flavonoid biosynthesis

Dastmalchi

2021

The Plant Journal

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SUMMARY Flavonoids are specialized metabolites widely distributed across the plant kingdom. They are involved in the growth and survival of plants, conferring the ability to filter ultra‐violet rays, conduct symbiotic partnerships, and respond to stress. While many branches of flavonoid biosynthesis have been resolved, recent discoveries suggest missing auxiliary components. These overlooked elements can guide metabolic flux, enhance production, mediate stereoselectivity, transport intermediates, and exert regulatory functions. This review describes several families of auxiliary proteins from across the plant kingdom, including examples from specialized metabolism. In flavonoid biosynthesis, we discuss the example of chalcone isomerase‐like (CHIL) proteins and their non‐catalytic role. CHILs mediate the cyclization of tetraketides, forming the chalcone scaffold by interacting with chalcone synthase (CHS). Loss of CHIL activity leads to derailment of the CHS‐catalyzed reaction and a loss of pigmentation in fruits and flowers. Similarly, members of the pathogenesis‐related 10 (PR10) protein family have been found to differentially bind flavonoid intermediates, guiding the composition of anthocyanins. This role comes within a larger body of PR10 involvement in specialized metabolism, from outright catalysis (e.g., (S)‐norcoclaurine synthesis) to controlling stereochemistry (e.g., enhancing cis‐trans cyclization in catnip). Both CHILs and PR10s hail from larger families of ligand‐binding proteins with a spectrum of activity, complicating the characterization of their enigmatic roles. Strategies for the discovery of auxiliary proteins are discussed, as well as mechanistic models for their function. Targeting such unanticipated components will be crucial in manipulating plants or engineering microbial systems for natural product synthesis.

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“…Studies of the cannabinoid receptors have shown that endocannabinoids attenuate and suppress the perception of pain ( 8 , 9 ). Naturally, cannabinoids are produced from cannabis plants, with more than 100 cannabinoids identified ( 10 ). The main cannabinoids produced are tetrahydrocannabinol (THC) and cannabidiol (CBD), but in contrast to the highly psychoactive THC, CBD has virtually no psychoactive properties ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…Naturally, cannabinoids are produced from cannabis plants, with more than 100 cannabinoids identified ( 10 ). The main cannabinoids produced are tetrahydrocannabinol (THC) and cannabidiol (CBD), but in contrast to the highly psychoactive THC, CBD has virtually no psychoactive properties ( 10 , 11 ). In people, there is evidence that CBD may be a useful treatment for various chronic pain conditions ( 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

A Case Report of Subcutaneously Injected Liposomal Cannabidiol Formulation Used as a Compassion Therapy for Pain Management in a Dog

et al. 2022

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A 14-year-old intact mixed breed dog (26 kg) was submitted for a novel cannabidiol (CBD) analgesic treatment. The dog was cachectic and had a testicular neoplasia, hip and elbow osteoarthritis and severe cervical pain. Analgesic treatment included canine osteoarthritic supplement, robencoxib and gabapentin. An additional liposomal CBD injectable formulation at 5 mg/kg was administered subcutaneously between the shoulder blades. The dog was monitored using an activity monitoring collar (PetPace), owner wellbeing questionnaire (Canine Brief Pain Inventory; CBPI), pain interactive visual analog scale (iVAS), blood work and CBD plasma concentrations. A week from the injection and up to 3 weeks afterwards the dog had improved CBPI and iVAS pain scores, and increased collar activity scores. CBD was quantified in plasma for 28 days. Due to disease progression, further difficulty to rise and walk, and relapse to pain after 3 weeks, the owners requested a second liposomal CBD injection, which was performed 4 weeks following the first injection using 3 mg/kg dose. Two days later, the dog was found dead in the yard under direct sun, while environmental temperature was 37°C. Major findings on necropsy revealed evidence of heat stroke and severe cervical disc protrusion with spinal hematoma, none related to liposomal CBD. In conclusion, subcutaneous liposomal CBD produced quantifiable CBD plasma concentrations for 28 days and may be an effective additional treatment as part of multimodal pain management in dogs.

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The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems

Cited by 28 publications

References 88 publications

Delineating the genetic regulation of cannabinoid biosynthesis during female flower development in Cannabis sativa

Delineating the genetic regulation of cannabinoid biosynthesis during female flower development in Cannabis sativa

Elusive partners: a review of the auxiliary proteins guiding metabolic flux in flavonoid biosynthesis

A Case Report of Subcutaneously Injected Liposomal Cannabidiol Formulation Used as a Compassion Therapy for Pain Management in a Dog

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