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Molecules (Basel, Switzerland) Dec 2020Terpenes are the primary constituents of essential oils and are responsible for the aroma characteristics of cannabis. Together with the cannabinoids, terpenes... (Review)
Review
Terpenes are the primary constituents of essential oils and are responsible for the aroma characteristics of cannabis. Together with the cannabinoids, terpenes illustrate synergic and/or entourage effect and their interactions have only been speculated in for the last few decades. Hundreds of terpenes are identified that allude to cannabis sensory attributes, contributing largely to the consumer's experiences and market price. They also enhance many therapeutic benefits, especially as aromatherapy. To shed light on the importance of terpenes in the cannabis industry, the purpose of this review is to morphologically describe sources of cannabis terpenes and to explain the biosynthesis and diversity of terpene profiles in different cannabis chemovars.
Topics: Biosynthetic Pathways; Cannabinoids; Cannabis; Oils, Volatile; Phenotype; Terpenes; Volatile Organic Compounds
PubMed: 33302574
DOI: 10.3390/molecules25245792 -
Molecules (Basel, Switzerland) Nov 2019Specialized plant terpenoids have found fortuitous uses in medicine due to their evolutionary and biochemical selection for biological activity in animals. However,... (Review)
Review
Specialized plant terpenoids have found fortuitous uses in medicine due to their evolutionary and biochemical selection for biological activity in animals. However, these highly functionalized natural products are produced through complex biosynthetic pathways for which we have a complete understanding in only a few cases. Here we review some of the most effective and promising plant terpenoids that are currently used in medicine and medical research and provide updates on their biosynthesis, natural occurrence, and mechanism of action in the body. This includes pharmacologically useful plastidic terpenoids such as -menthane monoterpenoids, cannabinoids, paclitaxel (taxol), and ingenol mebutate which are derived from the 2--methyl-d-erythritol-4-phosphate (MEP) pathway, as well as cytosolic terpenoids such as thapsigargin and artemisinin produced through the mevalonate (MVA) pathway. We further provide a review of the MEP and MVA precursor pathways which supply the carbon skeletons for the downstream transformations yielding these medically significant natural products.
Topics: Animals; Biosynthetic Pathways; Cannabinoids; Diterpenes; Erythritol; Herbal Medicine; Humans; Mevalonic Acid; Monoterpenes; Paclitaxel; Sugar Phosphates; Terpenes; Thapsigargin
PubMed: 31683764
DOI: 10.3390/molecules24213961 -
Proceedings of the National Academy of... Apr 2022As a midsized gene family conserved more by lineage than function, the typical plant terpene synthases (TPSs) could be a valuable tool to examine plant evolution. TPSs...
As a midsized gene family conserved more by lineage than function, the typical plant terpene synthases (TPSs) could be a valuable tool to examine plant evolution. TPSs are pivotal in biosynthesis of gibberellins and related phytohormones as well as in formation of the extensive arsenal of specialized plant metabolites mediating ecological interactions whose production is often lineage specific. Yet the origin and early evolution of the TPS family is not well understood. Systematic analysis of an array of transcriptomes and sequenced genomes indicated that the TPS family originated after the divergence of land plants from charophytic algae. Phylogenetic and biochemical analyses support the hypothesis that the ancestral TPS gene encoded a bifunctional class I and II diterpene synthase producing the ent-kaurene required for phytohormone production in all extant lineages of land plants. Moreover, the ancestral TPS gene likely underwent duplication at least twice early in land plant evolution. Together these two gave rise to three TPS lineages leading to the extant TPS-c, TPS-e/f, and the remaining TPS (h/d/a/b/g) subfamilies, with the latter dedicated to secondary rather than primary metabolism while the former two contain those genes involved in ent-kaurene production. Nevertheless, parallel evolution from the ent-kaurene–producing class I and class II diterpene synthases has led to roles for TPS-e/f and -c subfamily members in secondary metabolism as well. These results clarify TPS evolutionary history and provide context for the role of these genes in producing the vast diversity of terpenoid natural products observed today in various land plant lineages.
Topics: Alkyl and Aryl Transferases; Embryophyta; Evolution, Molecular; Gene Duplication; Phylogeny; Plant Growth Regulators; Plant Proteins; Terpenes
PubMed: 35394876
DOI: 10.1073/pnas.2100361119 -
Nature Communications Jan 2020The bicyclo[3.3.1]nonane architecture is a privileged structural motif found in over 1000 natural products with relevance to neurodegenerative disease, bacterial and...
The bicyclo[3.3.1]nonane architecture is a privileged structural motif found in over 1000 natural products with relevance to neurodegenerative disease, bacterial and parasitic infection, and cancer among others. Despite disparate biosynthetic machinery, alkaloid, terpene, and polyketide-producing organisms have all evolved pathways to incorporate this carbocyclic ring system. Natural products of mixed polyketide/terpenoid origins (meroterpenes) are a particularly rich and important source of biologically active bicyclo[3.3.1]nonane-containing molecules. Herein we detail a fully synthetic strategy toward this broad family of targets based on an abiotic annulation/rearrangement strategy resulting in a 10-step total synthesis of garsubellin A, an enhancer of choline acetyltransferase and member of the large family of polycyclic polyprenylated acylphloroglucinols. This work solidifies a strategy for making multiple, diverse meroterpene chemotypes in a programmable assembly process involving a minimal number of chemical transformations.
Topics: Biosynthetic Pathways; Monoterpenes; Oxidation-Reduction; Stereoisomerism; Terpenes
PubMed: 31980637
DOI: 10.1038/s41467-020-14354-5 -
Nature Jun 2022All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene. This approach is fundamentally different from the biosynthesis of...
All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene. This approach is fundamentally different from the biosynthesis of short-chain (C-C) terpenes that are formed from polyisoprenyl diphosphates. In this study, two fungal chimeric class I TrTSs, Talaromyces verruculosus talaropentaene synthase (TvTS) and Macrophomina phaseolina macrophomene synthase (MpMS), were characterized. Both enzymes use dimethylallyl diphosphate and isopentenyl diphosphate or hexaprenyl diphosphate as substrates, representing the first examples, to our knowledge, of non-squalene-dependent triterpene biosynthesis. The cyclization mechanisms of TvTS and MpMS and the absolute configurations of their products were investigated in isotopic labelling experiments. Structural analyses of the terpene cyclase domain of TvTS and full-length MpMS provide detailed insights into their catalytic mechanisms. An AlphaFold2-based screening platform was developed to mine a third TrTS, Colletotrichum gloeosporioides colleterpenol synthase (CgCS). Our findings identify a new enzymatic mechanism for the biosynthesis of triterpenes and enhance understanding of terpene biosynthesis in nature.
Topics: Ascomycota; Colletotrichum; Cyclization; Diphosphates; Squalene; Substrate Specificity; Talaromyces; Triterpenes
PubMed: 35650436
DOI: 10.1038/s41586-022-04773-3 -
Current Neuropharmacology 2020Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with... (Review)
Review
Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders. Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa was suggested for their treatment. The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, 'cannabis' is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes. Thus, the "entourage effect" is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here, we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids. Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.
Topics: Animals; Anxiety Disorders; Cannabinoids; Humans; Mood Disorders; Terpenes
PubMed: 31481004
DOI: 10.2174/1570159X17666190903103923 -
Marine Drugs Nov 2021Organic extracts of marine invertebrates, mainly sponges, from seas all over the world are well known for their high in vitro anticancer and antibiotic activities which... (Review)
Review
Organic extracts of marine invertebrates, mainly sponges, from seas all over the world are well known for their high in vitro anticancer and antibiotic activities which make them promising sources of compounds with potential use as pharmaceutical leads. Most of the structures discovered so far have a peculiar structural feature in common: a 1,2-dioxane ring. This is a highly reactive heterocycle that can be considered as an endoperoxide function. Together with other structural features, this group could be responsible for the strong biological activities of the substances present in the extracts. Numerous research programs have focused on their structural elucidation and total synthesis since the seventies. As a consequence, the number of established chiral centres and the similarity between different naturally occurring substances is increasingly higher. Most of these compounds have a terpenoid nature, mainly diterpene and sesterterpene, with several peculiar structural features, such as the loss of one carbon atom. Although there are many reviews dealing with the occurrence of marine peroxides, their activities, or potential pharmaceutical uses, no one has focused on those having a terpene origin and the endoperoxide function. We present here a comprehensive review of these compounds paying special attention to their structural features and their biological activity.
Topics: Animals; Aquatic Organisms; Peroxides; Porifera; Structure-Activity Relationship; Terpenes
PubMed: 34940660
DOI: 10.3390/md19120661 -
Molecules (Basel, Switzerland) Mar 2017Solanesol is a non-cyclic terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants. Solanesol plays an important role in the... (Review)
Review
Solanesol is a non-cyclic terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants. Solanesol plays an important role in the interactions between plants and environmental factors such as pathogen infections and moderate-to-high temperatures. Additionally, it is a key intermediate for the pharmaceutical synthesis of ubiquinone-based drugs such as coenzyme Q10 and vitamin K2, and anti-cancer agent synergizers such as N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl) ethylenediamine (SDB). In plants, solanesol is formed by the 2--methyl-d-erythritol 4-phosphate (MEP) pathway within plastids. Solanesol's biosynthetic pathway involves the generation of C5 precursors, followed by the generation of direct precursors, and then the biosynthesis and modification of terpenoids; the first two stages of this pathway are well understood. Based on the current understanding of solanesol biosynthesis, we here review the key enzymes involved, including 1-deoxy-d-xylulose 5-phosphate synthase (DXS), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), isopentenyl diphosphate isomerase (IPI), geranyl geranyl diphosphate synthase (GGPPS), and solanesyl diphosphate synthase (SPS), as well as their biological functions. Notably, studies on microbial heterologous expression and overexpression of key enzymatic genes in tobacco solanesol biosynthesis are of significant importance for medical uses of tobacco.
Topics: Metabolic Networks and Pathways; Molecular Structure; Plant Proteins; Plastids; Solanaceae; Terpenes
PubMed: 28333111
DOI: 10.3390/molecules22040510 -
Natural Product Reports Oct 2014Fungi (Ascomycota and Basidiomycota) are prolific producers of structurally diverse terpenoid compounds. Classes of terpenoids identified in fungi include the sesqui-,... (Review)
Review
Fungi (Ascomycota and Basidiomycota) are prolific producers of structurally diverse terpenoid compounds. Classes of terpenoids identified in fungi include the sesqui-, di- and triterpenoids. Biosynthetic pathways and enzymes to terpenoids from each of these classes have been described. These typically involve the scaffold generating terpene synthases and cyclases, and scaffold tailoring enzymes such as e.g. cytochrome P450 monoxygenases, NAD(P)+ and flavin dependent oxidoreductases, and various group transferases that generate the final bioactive structures. The biosynthesis of several sesquiterpenoid mycotoxins and bioactive diterpenoids has been well-studied in Ascomycota (e.g. filamentous fungi). Little is known about the terpenoid biosynthetic pathways in Basidiomycota (e.g. mushroom forming fungi), although they produce a huge diversity of terpenoid natural products. Specifically, many trans-humulyl cation derived sesquiterpenoid natural products with potent bioactivities have been isolated. Biosynthetic gene clusters responsible for the production of trans-humulyl cation derived protoilludanes, and other sesquiterpenoids, can be rapidly identified by genome sequencing and bioinformatic methods. Genome mining combined with heterologous biosynthetic pathway refactoring has the potential to facilitate discovery and production of pharmaceutically relevant fungal terpenoids.
Topics: Alkyl and Aryl Transferases; Biological Products; Fungi; Molecular Structure; Terpenes
PubMed: 25171145
DOI: 10.1039/c4np00075g -
Journal of Natural Medicines Jun 2021The teleocidin B family members are terpene indole compounds isolated from Streptomyces bacteria, and they strongly activate protein kinase C (PKC). Their unique... (Review)
Review
The teleocidin B family members are terpene indole compounds isolated from Streptomyces bacteria, and they strongly activate protein kinase C (PKC). Their unique structures have attracted many researchers in the natural product chemistry and pharmacology fields, and numerous isolation and bioactivity studies have been conducted. The accumulated information has facilitated the identification of the enzymatic reactions in teleocidin biosynthesis, and new developments in structural biology have strongly aided efforts to clarify the finer points of these reactions. This review describes the recent biochemical and structural biological studies to reveal their reaction mechanisms, with a primary focus on the terpene cyclization triggered by the C-N bond formation by P450 oxygenase (TleB), the prenyltransferase (TleC), and the methyltransferase (TleD). This new knowledge will benefit future engineering studies to create unnatural PKC activators.
Topics: Bacterial Proteins; Cytochrome P-450 Enzyme System; Dimethylallyltranstransferase; Indoles; Lyngbya Toxins; Methyltransferases; Molecular Structure; Multigene Family; Streptomyces; Terpenes
PubMed: 33675456
DOI: 10.1007/s11418-021-01504-2