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      Non-volatile natural products in plant glandular trichomes: chemistry, biological activities and biosynthesis

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          Abstract

          The investigation methods, chemistry, bioactivities, and biosynthesis of non-volatile natural products involving 489 compounds in plant glandular trichomes are reviewed.

          Abstract

          Covering: 1960s to end of August 2018

          Plant glandular trichomes (GTs) are adaptive structures that are well known as “phytochemical factories” due to their impressive capacity to biosynthesize and store large quantities of specialized natural products. The natural products in GTs are chemically diverse and mostly function as defense chemicals, therefore GTs are frequently regarded as “the first defense line” of plants against biotic and abiotic stresses. More importantly, many GT natural products are commercially desirable, thanks to their significant biological activities, thus attracting extensive interest in their biosynthesis. Consequently, it is well known that plant GTs are not only important reservoirs of biologically active natural products but are also a valuable bank of novel biosynthetic genes and enzymes. The non-volatile or oxygenated natural products in plant GTs, which need longer biosynthetic pathways and more energy from the plants, are of particular interest due to their more extensive biological activities and high commercial value. This review mainly focuses on these non-volatile natural products in plant GTs, including their chemistry, biological activities and biosynthesis. The methods employed for investigating natural products and their biosynthesis in plant GTs are also comprehensively discussed.

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          Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

          Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.
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            Phytocannabinoids: a unified critical inventory.

            Covering up to January 2016Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl- and a β-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents (CBG, CBD, Δ(9)-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermos-TRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB1.
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              Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.

              Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.
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                Author and article information

                Journal
                NPRRDF
                Natural Product Reports
                Nat. Prod. Rep.
                Royal Society of Chemistry (RSC)
                0265-0568
                1460-4752
                April 17 2019
                2019
                : 36
                : 4
                : 626-665
                Affiliations
                [1 ]State Key Laboratory of Phytochemistry and Plant Resources in West China
                [2 ]Kunming Institute of Botany
                [3 ]Chinese Academy of Sciences
                [4 ]Kunming 650201
                [5 ]P. R. China
                [6 ]College of Bioscience and Biotechnology
                [7 ]Shenyang Agricultural University
                [8 ]Shenyang
                Article
                10.1039/C8NP00077H
                30468448
                20d21f3a-a64d-4357-85eb-25ec24fdd44a
                © 2019

                http://rsc.li/journals-terms-of-use

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