Tropane Alkaloids: Chemistry, Pharmacology, Biosynthesis and Production

Tropane alkaloids (TA) are valuable secondary plant metabolites which are mostly found in high concentrations in the Solanaceae and Erythroxylaceae families. The TAs, which are characterized by their unique bicyclic tropane ring system, can be divided into three major groups: hyoscyamine and scopolamine, cocaine and calystegines. Although all TAs have the same basic structure, they differ immensely in their biological, chemical and pharmacological properties. Scopolamine, also known as hyoscine, has the largest legitimate market as a pharmacological agent due to its treatment of nausea, vomiting, motion sickness, as well as smooth muscle spasms while cocaine is the 2nd most frequently consumed illicit drug globally. This review provides a comprehensive overview of TAs, highlighting their structural diversity, use in pharmaceutical therapy from both historical and modern perspectives, natural biosynthesis in planta and emerging production possibilities using tissue culture and microbial biosynthesis of these compounds.

[1]  B. Dräger Chemistry and biology of calystegines. , 2004, Natural product reports.

[2]  I. Maldonado-Mendoza,et al.  Establishment of hairy root cultures ofDatura stramonium. Characterization and stability of tropane alkaloid production during long periods of subculturing , 1993, Plant Cell, Tissue and Organ Culture.

[3]  Aled Edwards,et al.  The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor , 2002, Nature Structural Biology.

[4]  E. Agostinelli Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives , 2014, Amino Acids.

[5]  R. Dmochowski,et al.  Multicenter phase III trial studying trospium chloride in patients with overactive bladder. , 2006, Urology.

[6]  Weigeldt Archiv für Psychiatrie und Nervenkrankheiten , 2005, Deutsche Zeitschrift für Nervenheilkunde.

[7]  L. Gyermek Structure-activity relationships among derivatives of dicarboxylic acid esters of tropine. , 2002, Pharmacology & therapeutics.

[8]  T. Kanegae,et al.  Species-Dependent Expression of the Hyoscyamine 6[beta]-Hydroxylase Gene in the Pericycle , 1994, Plant physiology.

[9]  J. Wess,et al.  M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system. , 2003, Receptors & channels.

[10]  G. Grynkiewicz,et al.  Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. , 2008, Pharmacological reports : PR.

[11]  P. Doran,et al.  Influence of inoculum morphology on growth of Atropa belladonna hairy roots and production of tropane alkaloids , 1996, Biotechnology Letters.

[12]  C. Mwamba Status report on domestication and commercialization of non-timber forest products in agroforestry systems. , 1996 .

[13]  E. Leete,et al.  The biosynthesis of the benzoyl moiety of cocaine , 1988 .

[14]  K. Oksman-Caldentey,et al.  Alkaloid production in Duboisia hybrid hairy roots and plants overexpressing the h6h gene , 2003 .

[15]  B. Hause,et al.  Immunolocalisation of two tropinone reductases in potato (Solanum tuberosum L.) root, stolon, and tuber sprouts , 2006, Planta.

[16]  H. Ott,et al.  Konfiguration des Cocains und Derivate der Ecgoninsäure , 1955 .

[17]  G. Grynkiewicz,et al.  Tropane alkaloids in pharmaceutical and phytochemical analysis. , 2001, Acta poloniae pharmaceutica.

[18]  K. Nakajima,et al.  Two Tropinone Reductases with Distinct Stereospecificities from Cultured Roots of Hyoscyamus niger. , 1992, Plant physiology.

[19]  J. Vederas,et al.  Functional characterization of recombinant hyoscyamine 6β-hydroxylase from Atropa belladonna. , 2012, Bioorganic & medicinal chemistry.

[20]  V. Courdavault,et al.  Biosynthesis and Regulation of Alkaloids , 2010 .

[21]  M. Reichelt,et al.  The Last Step in Cocaine Biosynthesis Is Catalyzed by a BAHD Acyltransferase[OPEN] , 2014, Plant Physiology.

[22]  S. Mulé,et al.  Cocaine and metabolites: Relationship between pharmacological activity and inhibitory action on dopamine uptake into striatal synaptosomes , 1977 .

[23]  Yucai He,et al.  Efficient biosynthesis of rare natural product scopolamine using E. coli cells expressing a S14P/K97A mutant of hyoscyamine 6β-hydroxylase AaH6H. , 2015, Journal of biotechnology.

[24]  S. Fornalé,et al.  Alkaloid production in Duboisia hybrid hairy root cultures overexpressing the pmt gene. , 2002, Phytochemistry.

[25]  R. Sangwan,et al.  Molecular cloning and catalytic characterization of a recombinant tropine biosynthetic tropinone reductase from Withania coagulans leaf. , 2013, Gene.

[26]  A. Niemann Ueber eine neue organische Base in den Cocablättern , 1860 .

[27]  Yuanshe Huang,et al.  Functional characterisation of a tropine-forming reductase gene from Brugmansia arborea, a woody plant species producing tropane alkaloids. , 2016, Phytochemistry.

[28]  R. Hiltunen,et al.  Enhancement of scopolamine production in Hyoscyamus muticus L. hairy root cultures by genetic engineering , 1999, Planta.

[29]  E. Basch,et al.  An Evidence-Based Systematic Review of Belladonna by the Natural Standard Research Collaboration , 2004, Journal of herbal pharmacotherapy.

[30]  Jianbo Xiao,et al.  Enhancing the production of tropane alkaloids in transgenic Anisodus acutangulus hairy root cultures by over-expressing tropinone reductase I and hyoscyamine-6β-hydroxylase. , 2012, Molecular bioSystems.

[31]  W. Brandt,et al.  Evolution of putrescine N‐methyltransferase from spermidine synthase demanded alterations in substrate binding , 2009, FEBS letters.

[32]  C. Schlagmann,et al.  Zur Behandlung der Parkinson-Krankheit , 1986, Klinische Wochenschrift.

[33]  T. Hemscheidt,et al.  Biosynthesis of 6β-Hydroxytropine (I) in Datura stramonium: Nonregiospecific Incorporation of (1,2-13C2)Acetate. , 1992 .

[34]  Christopher J Langmead,et al.  Muscarinic acetylcholine receptors as CNS drug targets. , 2008, Pharmacology & therapeutics.

[35]  Milen I Georgiev,et al.  Genetically transformed roots: from plant disease to biotechnological resource. , 2012, Trends in biotechnology.

[36]  Yasuyuki Yamada,et al.  The formation of 3α‐ and 3β‐acetoxytropanes byDatura stramonium transformed root cultures involves two acetyl‐CoA‐dependent acyltransferases , 1991 .

[37]  O. Kayser,et al.  Scopolamine: a journey from the field to clinics , 2016, Phytochemistry Reviews.

[38]  J. Lombard,et al.  Receptor‐Mediated Events in the Microcirculation , 2011 .

[39]  Yasuyuki Yamada,et al.  Alkaloid production in cultured roots of three species of Duboisia , 1985 .

[40]  S. Kamalraj,et al.  Novel Microbial Sources of Tropane Alkaloids: First Report of Production by Endophytic Fungi Isolated from Datura metel L. , 2018, Current Microbiology.

[41]  M. Overgaard,et al.  Tropisetron (Navoban) in the prevention of chemotherapy-induced nausea and vomiting — the Nordic experience , 1994, Supportive Care in Cancer.

[42]  P. Zhu,et al.  Molecular Cloning, Expression and Characterization of Hyoscyamine 6β-Hydroxylase from Hairy Roots of Anisodus tanguticus , 2005, Planta medica.

[43]  W. J. Griffin,et al.  Chemotaxonomy and geographical distribution of tropane alkaloids. , 2000, Phytochemistry.

[44]  V. De Luca,et al.  Making iridoids/secoiridoids and monoterpenoid indole alkaloids: progress on pathway elucidation. , 2014, Current opinion in plant biology.

[45]  Erik Nordling,et al.  Short-chain dehydrogenases/reductases (SDR): the 2002 update. , 2003, Chemico-biological interactions.

[46]  W. J. Griffin,et al.  Cultivation of a Duboisia Hybrid. Part A. Nutritional Requirements and Effects of Growth Regulators on Alkaloid Content , 1980 .

[47]  B. Dräger,et al.  Calystegines in Calystegia sepium derive from the tropane alkaloid pathway. , 2001, Phytochemistry.

[48]  P. Covello,et al.  Functional genomic analysis of alkaloid biosynthesis in Hyoscyamus niger reveals a cytochrome P450 involved in littorine rearrangement. , 2006, Chemistry & biology.

[49]  Xiao-yun Wang,et al.  Functional identification of hyoscyamine 6β-hydroxylase from Anisodus acutangulus and overproduction of scopolamine in genetically-engineered Escherichia coli , 2011, Biotechnology Letters.

[50]  M. Satake,et al.  Alkaloid production by hairy root cultures in Atropa belladonna , 1986, Plant Cell Reports.

[51]  Min Chen,et al.  Promoting scopolamine biosynthesis in transgenic Atropa belladonna plants with pmt and h6h overexpression under field conditions. , 2016, Plant physiology and biochemistry : PPB.

[52]  Kan Wang Agrobacterium Protocols , 2015, Methods in Molecular Biology.

[53]  T. Naudé CHAPTER 70 – Datura spp. and other related plants , 2007 .

[54]  P. Facchini,et al.  Alkaloid biosynthesis: metabolism and trafficking. , 2008, Annual review of plant biology.

[55]  J. D’Auria Acyltransferases in plants: a good time to be BAHD. , 2006, Current opinion in plant biology.

[56]  J. Pearn,et al.  The history of hyoscine. , 1982, Histoire des sciences medicales.

[57]  A. Elbein,et al.  Biological activities of the nortropane alkaloid, calystegine B2, and analogs: structure-function relationships. , 1996, Journal of natural products.

[58]  Yasuyuki Yamada,et al.  Biosynthesis of nicotine and scopolamine in a root culture of Duboisia leichhardtii. , 1990 .

[59]  T. Hemscheidt,et al.  Biosynthesis of 6.beta.-hydroxytropine in Datura stramonium: nonregiospecific incorporation of [1,2-13C2]acetate , 1992 .

[60]  Yasuyuki Yamada,et al.  Two‐step epoxidation of hyoscyamine to scopolamine is catalyzed by bifunctional hyoscyamine 6β‐hydroxylase , 1993, FEBS letters.

[61]  K. Nakajima,et al.  Two tropinone reductases, that catalyze opposite stereospecific reductions in tropane alkaloid biosynthesis, are localized in plant root with different cell-specific patterns. , 1999, Plant & cell physiology.

[62]  K. Rice,et al.  Amphetamine‐type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin , 2001, Synapse.

[63]  W. Brandt,et al.  Putrescine N-methyltransferase--the start for alkaloids. , 2009, Phytochemistry.

[64]  Min Chen,et al.  Enhancing the scopolamine production in transgenic plants of Atropa belladonna by overexpressing pmt and h6h genes. , 2011, Physiologia plantarum.

[65]  Satpal Singh,et al.  Biochemical and structural characterization of recombinant hyoscyamine 6β-hydroxylase from Datura metel L. , 2010, Plant physiology and biochemistry : PPB.

[66]  J. D’Auria,et al.  Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis , 2016, Molecules.

[67]  P. Sowiński,et al.  Production of tropane alkaloids in Hyoscyamus niger (black henbane) hairy roots grown in bubble-column and spray bioreactors , 2013, Biotechnology Letters.

[68]  N. Walton,et al.  Studies on the biosynthesis of tropane alkaloids in Datura stramonium L. transformed root cultures , 2004, Planta.

[69]  A. Hourvitz,et al.  Adverse reaction to atropine and the treatment of organophosphate intoxication. , 2002, The Israel Medical Association journal : IMAJ.

[70]  A. Giulietti,et al.  Scopolamine, anisodamine and hyoscyamine production by Brugmansia candida hairy root cultures in bioreactors , 2010 .

[71]  M. Avram,et al.  The Essence of Analgesia and Analgesics , 2012 .

[72]  B. Dräger Identification and quantification of calystegines, polyhydroxyl nortropane alkaloids , 1995 .

[73]  J. Vederas,et al.  Isolation, expression and biochemical characterization of recombinant hyoscyamine-6β-hydroxylase from Brugmansia sanguinea - tuning the scopolamine production. , 2018, MedChemComm.

[74]  O. Kayser,et al.  Influence of Light, Temperature, and Macronutrients on Growth and Scopolamine Biosynthesis in Duboisia species , 2017, Planta Medica.

[75]  Zhongming Chen,et al.  BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1 , 2019, Psychiatry Research.

[76]  P. Covello,et al.  Genetically engineered hairy root cultures of Hyoscyamus senecionis and H. muticus: ploidy as a promising parameter in the metabolic engineering of tropane alkaloids , 2017, Plant Cell Reports.

[77]  D. O'Hagan,et al.  The biosynthesis of tropic acid: the (R)-D-phenyllactyl moiety is processed by the mutase involved in hyoscyamine biosynthesis in Datura stramonium , 1995 .

[78]  K. Oksman-Caldentey,et al.  Somaclonal Variation of Scopolamine Content in Protoplast-Derived Cell Culture Clones of Hyoscyamus muticus , 1986 .

[79]  Y. Yamada,et al.  Hyoscyamine 6beta-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, in alkaloid-producing root cultures. , 1986, Plant physiology.

[80]  M. Behmanesh,et al.  Chromium-induced tropane alkaloid production and H6H gene expression in Atropa belladonna L. (Solanaceae) in vitro-propagated plantlets. , 2012, Plant physiology and biochemistry : PPB.

[81]  F. Gaedcke Ueber das Erythroxylin, dargestellt aus den Blättern des in Südamerika cultivirten Strauches Erythroxylon Coca Lam , 1855 .

[82]  S. Mizusaki,et al.  N-methylputrescine oxidase from tobacco roots , 1972 .

[83]  Y. Yamada,et al.  Expression of Atropa belladonna putrescine N-methyltransferase gene in root pericycle. , 1999, Plant & cell physiology.

[84]  Yasuyuki Yamada,et al.  Production of tropane alkaloids in genetically engineered root cultures , 1993 .

[85]  Y. Yamada,et al.  Purification and characterization of hyoscyamine 6 beta-hydroxylase from root cultures of Hyoscyamus niger L. Hydroxylase and epoxidase activities in the enzyme preparation. , 1987, European journal of biochemistry.

[86]  T. Kaila,et al.  Pharmacokinetics of scopolamine during caesarean section: relationship between serum concentration and effect , 1989, Acta anaesthesiologica Scandinavica.

[87]  J. Rétey,et al.  The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme , 1998, FEBS letters.

[88]  Yasuyuki Yamada,et al.  Purification and characterization of hyoscyamine 6 beta-hydroxylase from root cultures of Hyoscyamus niger L. Hydroxylase and epoxidase activities in the enzyme preparation. , 1987, European journal of biochemistry.

[89]  J. Barnes Medicinal natural products , 2010 .

[90]  K. Oksman-Caldentey,et al.  Engineering tropane biosynthetic pathway in Hyoscyamus niger hairy root cultures. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  Cornelius S. Barry,et al.  A Root-Expressed l-Phenylalanine:4-Hydroxyphenylpyruvate Aminotransferase Is Required for Tropane Alkaloid Biosynthesis in Atropa belladonna[C][W] , 2014, Plant Cell.

[92]  W. Kirch,et al.  Pharmacokinetics and Pharmacodynamics in Clinical Use of Scopolamine , 2005, Therapeutic drug monitoring.

[93]  Cornelius S. Barry,et al.  Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization , 2018, Nature Communications.

[94]  Eukaryotic microalgae as hosts for light-driven heterologous isoprenoid production , 2018, Planta.

[95]  M. Teuber,et al.  Putrescine N-methyltransferases—a structure–function analysis , 2007, Plant Molecular Biology.

[96]  P. Covello,et al.  An atypical pattern of accumulation of scopolamine and other tropane alkaloids and expression of alkaloid pathway genes in Hyoscyamus senecionis. , 2013, Plant physiology and biochemistry : PPB.

[97]  A. Aharoni,et al.  Transcriptome and Metabolic Profiling Provides Insights into Betalain Biosynthesis and Evolution in Mirabilis jalapa. , 2018, Molecular plant.

[98]  T. Hoye,et al.  N-methylputrescine oxidation during cocaine biosynthesis: study of prochiral methylene hydrogen discrimination using the remote isotope method. , 2000, Organic letters.

[99]  W. Fischer,et al.  Inhibition of human intestinal α-glucosidases by calystegines. , 2013, Journal of agricultural and food chemistry.

[100]  Walter Sneader,et al.  Drug Discovery (The History) , 2005 .

[101]  Min Chen,et al.  A Phenylpyruvic Acid Reductase Is Required for Biosynthesis of Tropane Alkaloids. , 2018, Organic letters.

[102]  A. Giulietti,et al.  Expression of Brugmansia candida Hyoscyamine 6beta-Hydroxylase gene in Saccharomyces cerevisiae and its potential use as biocatalyst , 2008, Microbial cell factories.

[103]  Y. Yamada,et al.  Jasmonate induction of putrescine N-methyltransferase genes in the root of Nicotiana sylvestris. , 2000, Plant & cell physiology.

[104]  P. Barnes,et al.  The pharmacological properties of tiotropium. , 2000, Chest.