DOCSLIB.ORG

How Human Neuroblastoma Cells Make Morphine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
How Human Neuroblastoma Cells Make Morphine How human neuroblastoma cells make morphine Chotima Boettcher*, Monika Fellermeier, Christian Boettcher, Birgit Dra¨ ger, and Meinhart H. Zenk Biocenter, Martin Luther University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany Contributed by Meinhart H. Zenk, April 20, 2005 Recently, our laboratory demonstrated that human neuroblastoma morphine found in mammalian cells. In brief, heavy isotope-labeled cells (SH-SY5Y) are capable of synthesizing morphine, the major precursors (e.g., with 13C, 2H, and 18O labels) are administered to active metabolite of opium poppy. Now our experiments are human cell cultures and incubated for a certain period. Subse- further substantiated by extending the biochemical studies to the quently, the desired products are isolated, and their structure, 13 entire morphine pathway in this human cell line. L-[1,2,3- C3]- and isotope content, and labeling pattern, which has to be nonrandom, 2 ring-2؅,5؅,6؅- H3]dopa showed high isotopic enrichment and incor- are elucidated by spectroscopic methods. The method of choice is] poration in both the isoquinoline and the benzyl moiety of the ion-selective tandem MS (MS͞MS), because it provides the highest 2 endogenous morphine. [2,2- H2]Dopamine, however, was exclu- sensitivity and specificity. Regarding the interpretation of the sively incorporated only into the isoquinoline moiety. Neither the obtained quantitative incorporation data, the physicochemical 13 trioxygenated (R,S)-[1,3- C2]norcoclaurine, the precursor of mor- characteristics of the applied substrates have to be taken into 2 phine in the poppy plant, nor (R)-[1,3,4- H3]norlaudanosoline consideration, because they influence cell permeability and trans- showed incorporation into endogenous morphine. However, (S)- port. Also, tracer dilution plays a role if the applied substrate is 2 [1,3,4- H3]norlaudanosoline furnished a good isotopic enrichment present endogenously or in the cell culture medium. and the loss of a single deuterium atom at the C-9 position of the The human cell lines SH-SY5Y and DAN-G have been identified morphine molecule, indicating that the change of configuration as suitable systems, because they both produce benzylisoquinoline from (S)- to (R)-reticuline occurs via the intermediacy of 1,2- alkaloids (1) and can be cultured for a sufficient period, on average dehydroreticuline. Additional feeding experiments with potential up to 7 days. In previous studies, by using the least invasive isotopic morphinan precursors demonstrated substantial incorporation of precursor of morphine, 18O, nonrandom, position-specific incor- [7-2H]salutaridinol, but not 7-[7-2H]episalutaridinol, and [7-2H,N- poration of two atoms of 18O into one molecule of morphine 2 2 C H3]oripavine, and [6- H]codeine into morphine. Human mor- produced by the living, metabolizing neuroblastoma cells (at a phine biosynthesis involves at least 19 chemical steps. For the most concentration of 10 nM) could be demonstrated in our laboratory. part, it is a reflection of the biosynthesis in opium poppy; however, Moreover, the potential precursor alkaloids norlaudanosoline (tet- there is a fundamental difference in the formation of the key rahydropapaveroline) and (S)-reticuline, which were also produced intermediate (S)-reticuline: it proceeds via the tetraoxygenated by these cells, were shown to be labeled with two atoms of 18O (1). 13 initial isoquinoline alkaloid (S)-norlaudanosoline, whereas the In a separate set of experiments, application of [ring- C6]tyramine, 13 13 2 plant morphine biosynthesis proceeds via the trioxygenated (S)- (S)-[1- C,N- CH3]reticuline, and [N-C H3]thebaine to SH-SY5Y norcoclaurine. Following the plant biosynthetic pathway, (S)-reti- cells yielded specific incorporation into endogenous morphine (1). culine undergoes a change of configuration at C-1 during its With these experiments, we unequivocally proved that human transformation to salutaridinol and thebaine. From thebaine, there neuroblastoma cells are capable of synthesizing morphine. is a bifurcate pathway leading to morphine proceeding via codeine Here, we present additional evidence for endogenous morphine or oripavine, in both plants and mammals. biosynthesis focusing on the elucidation of intermediates of the biosynthetic pathway between the two C6-C2 units derived from endogenous morphine ͉ mammalian morphine ͉ morphine biosynthesis ͉ L-tyrosine and the final product, morphine. The biosynthetic route, SH-SY5Y cells which had been established in the poppy plant (summarized in ref. 6), built the basis for the tracer experiments with human neuro- blastoma and pancreas carcinoma cells (1) by using heavy isotope- he presence of opiate receptors in mammalian tissue has labeled potential precursors. Tstimulated the search for endogenous ligands, leading to the discovery of opioid peptides. Recent studies, however, also Materials and Methods provided evidence for the presence of morphine alkaloids in Chemicals. All solvents were of either reagent grade (used for animals. Trace amounts have been detected in various tissues of synthesis) or chromatographic grade (used for sample preparation mammals and lower animals and have been identified by MS or and analysis) and were purchased from ACROS Organics (Geel, even NMR (summarized in ref. 1). However, the origin of the Belgium). Alkaloids used as standards were obtained either from endogenous morphine has been a matter of controversy, because the department collection or by synthesis. Nitro[13C]methane morphine also was found in hay, lettuce, human milk, and cow’s 2 (99%) and [2,2- H2]dopamine (98%) were purchased from Euriso- milk as well as in commercial rat and rabbit feed (2–4). Even 2 Top (Saint-Aubin, France). [ H3]Methyl iodide, deuterium chloride laboratory contamination with morphine could not be excluded. 2 2 (35% in H2O; wt͞wt), and L-[ring-2Ј,5Ј,6Ј- H3]dopa were from To clarify the origin of morphine in mammalian tissues, classical Sigma-Aldrich. N-methyl-N-trimethylsilyl trifluoroacetamide biochemical studies as used in plants can be performed (5). (MSTFA) was obtained from CS Chromatographie Service Morphine’s biosynthetic pathway in Papaver somniferum was elu- (Langerwehe, Germany). cidated by the administration of isotopically labeled putative pre- BIOCHEMISTRY cursors to intact plants and cell cultures, isolation of the labeled Synthesis of Isotope-Labeled Potential Precursors. The synthesis of products, and subsequent determination of the labeling pattern. 13 13 13 L-[1,2,3- C3]dopa, (R,S)-[1,3- C2]norcoclaurine, (R,S)-[1,3- C2, Based on these experiments, most of the enzymes of the morphine 13 2 6-O- CH3]coclaurine, (R)- and (S)-[1,3,4- H3]norlaudanosoline, biosynthesis were discovered and purified, and subsequently some of the corresponding genes were cloned (summarized in ref. 6). The current picture of the morphine biosynthesis in plants, involving 19 Abbreviations: TMS, trimethylsilyl; MS͞MS, tandem MS; [M]•ϩ, molecular ion. steps, is nearly complete. This knowledge of the morphine biosyn- *To whom correspondence should be addressed. E-mail: chotima.poeaknapo@ thesis in plants and the methodology of its elucidation were now biozentrum.uni-halle.de. applied to investigate the origin and the biosynthetic pathway of © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0503244102 PNAS ͉ June 14, 2005 ͉ vol. 102 ͉ no. 24 ͉ 8495–8500 Downloaded by guest on September 26, 2021 Table 1. Feeding experiments with heavy isotope-labeled precursors to human neuroblastoma (SH-SY5Y) cells Substrate applied to SH-SY5Y cells Isolated labeled morphine from SH-SY5Y cells % isotopic Position Applied m͞z*of Position of labeling in % isotopic Substrate enrichment of labeling concentration, ␮M [M]•ϩ morphine molecule enrichment 13 L-dopa 95 [1,2,3- C3] 20 433 C-9, C-10, C-15, C-16 56 2 2 2 † L-dopa 98 [ring-2Ј,5Ј,6Ј- H3] 20 432 [1,2,8 - H3] 40 2 2 Dopamine 98 [2,2- H2] 20 431 [15,15- H2]22 13 ‡ (R,S)-norcoclaurine 95 [1,3- C2] 20 431 ND Ͻ0.5 13 13 ‡ (R,S)-coclaurine 99 [1,3- C2,6-O- CH3] 40 431 ND Ͻ0.5 2 ‡ (R)-norlaudanosoline 81 [1,3,4- H3] 20 432 ND Ͻ0.5 2 2 (S)-norlaudanosoline 85 [1,3,4- H3] 20 431 [15,16- H2]15 2 2 (R)-reticuline 99 [N-C H3] 20 432 [N-C H3]25 2 2 (S)-reticuline 98 [N-C H3] 20 432 [N-C H3]23 2 2 ‡ 1,2-dehydroreticulinium ion 96 [N-C H3] 20 432 [N-C H3] Ͻ0.5 Salutaridinol 94 [7-2H] 20 430 [7-2H]† 15 7-Episalutaridinol 95 [7-2H] 20 430 ND Ͻ0.5‡ 2 2 2 2 Oripavine 69 [7- H,N-C H3] 20 433 [7- H,N-C H3]12 Codeine 99 [6-2H] 20 430 [6-2H]† 21 [M]•ϩ, molecular ion; ND, below the limit of detection (0.05 pmol). *TMS-morphine derivative (m͞z 429 [M]•ϩ unlabeled morphine). †Theoretically labeled position. ‡An isotopic enrichment calculated from an amount of labeled morphine at the limit of detection. 2 2 (R)- and (S)-[N-C H3]reticuline, [N-C H3]1,2-dehydroreticulinium high-vacuum evaporator (Bachofer, Reutlingen, Germany) and the ion, [7-2H]salutaridinol, 7-[7-2H]episalutaridinol, [7-2H,N- isolated products were converted to the TMS derivatives by the 2 2 C H3]oripavine, and [6- H]codeine is described in detail in Sup- addition of 20 ␮lofN-methyl-N-TMS-trifluoroacetamide and porting Text, which is published as supporting information on the heating to 70°C for 30 min in an oil bath. The solution was PNAS web site. concentrated to 5 ␮l under a gentle stream of nitrogen gas and centrifuged. One microliter of the supernatant was immediately Enzymes. S-adenosylmethionine synthetase from Escherichia coli analyzed by GC͞MS͞MS. DM 25 pkA8 was kindly provided by George D. Markham (Na- tional Institutes of Health, Bethesda, MD). His-tagged N- Feeding Experiments. We transferred 3 ϫ 105 SH-SY5Y cells to methyltransferase from E.
Load more

Recommended publications
  • Alternative Formats If You Require This Document in an Alternative Format, Please Contact: [email protected]
    University of Bath PHD The extraction and chemistry of the metabolites of Mimosa tenuiflora and Papaver somniferum Ninan, Aleyamma Award date: 1990 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 23. Sep. 2021 THE EXTRACTION AND CHEMISTRY OF THE METABOLITES OF MIMOSA TENUIFLORA AND PAP AVER SOMNIFERUM. submitted by ALEYAMMA NINAN for the degree of Doctor of Philosophy of the University of Bath 1990 Attention is drawn to the fact that the copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without prior consent of the author.
    [Show full text]
  • “Biosynthesis of Morphine in Mammals”
    “Biosynthesis of Morphine in Mammals” D i s s e r t a t i o n zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Naturwissenschaftlichen Fakultät I Biowissenschaften der Martin-Luther-Universität Halle-Wittenberg von Frau Nadja Grobe geb. am 21.08.1981 in Querfurt Gutachter /in 1. 2. 3. Halle (Saale), Table of Contents I INTRODUCTION ........................................................................................................1 II MATERIAL & METHODS ........................................................................................ 10 1 Animal Tissue ....................................................................................................... 10 2 Chemicals and Enzymes ....................................................................................... 10 3 Bacteria and Vectors ............................................................................................ 10 4 Instruments ........................................................................................................... 11 5 Synthesis ................................................................................................................ 12 5.1 Preparation of DOPAL from Epinephrine (according to DUNCAN 1975) ................. 12 5.2 Synthesis of (R)-Norlaudanosoline*HBr ................................................................. 12 5.3 Synthesis of [7D]-Salutaridinol and [7D]-epi-Salutaridinol ..................................... 13 6 Application Experiments .....................................................................................
    [Show full text]
  • 1. Introduction
    Introduction 1. Introduction 1.1. Alkaloids The term alkaloid is derived from Arabic word al-qali, the plant from which “soda” was first obtained (Kutchan, 1995). Alkaloids are a group of naturally occurring low-molecular weight nitrogenous compounds found in about 20% of plant species. The majority of alkaloids in plants are derived from the amino acids tyrosine, tryptophan and phenylalanine. They are often basic and contain nitrogen in a heterocyclic ring. The classification of alkaloids is based on their carbon-nitrogen skeletons; common alkaloid ring structures include the pyridines, pyrroles, indoles, pyrrolidines, isoquinolines and piperidines (Petterson et al., 1991; Bennett et al., 1994). In nature, plant alkaloids are mainly involved in plant defense against herbivores and pathogens. Many of these compounds have biological activity which makes them suitable for use as stimulants (nicotine, caffeine), pharmaceuticals (vinblastine), narcotics (cocaine, morphine) and poisons (tubocurarine). The discovery of morphine by the German pharmacist Friedrich W. Sertürner in 1806 began the field of plant alkaloid biochemistry. However, the structure of morphine was not determined until 1952 due to its stereochemical complexity. Major technical advances occurred in this field allowing for the elucidation of selected alkaloid biosynthetic pathways. Among these were the introduction of radiolabeled precursors in the 1950s and the establishment in the 1970s of plant cell suspension cultures as an abundant source of enzymes that could be isolated, purified and characterized. Finally, the introduction of molecular techniques has made possible the isolation of genes involved in alkaloid secondary pathways (Croteau et al., 2000; Facchini, 2001). 1.1.1. Benzylisoquinoline alkaloids Isoquinoline alkaloids represent a large and varied group of physiologically active natural products.
    [Show full text]
  • Morphine Julie Brousseau a Thesis Submitted
    Synthesis of Carbocycles Using Coinage Metal Catalysis and Formal Synthesis of (±)-Morphine Julie Brousseau A thesis submitted in partial fulfillment of the requirements for the Doctorate in Philosophy degree in Chemistry Department of Chemistry and Biomolecular Sciences Faculty of Science University of Ottawa © Julie Brousseau, Ottawa, Canada, 2020 ABSTRACT Coinage metals such as copper, silver and gold have captivated mankind with their desirable qualities and social value. Recently, these metals have peaked the interests of scientists, where organic chemists have used them extensively in the homogenous catalysis of organic transformations. In our laboratory, we exploited their � -Lewis acidic properties to activate alkyne to induce intramolecular cyclization of nucleophilic enol ethers. We discovered that modulating the steric and electronic profiles of the ancillary ligand on the cationic metal complexes allowed for the regioselective control of such reactions. During the exploration of the substrate dependency of these transformations, we discovered that unsubstituted alkynes undergo a 6-endo-dig/acetalization/Prins reaction cascade in the presence of a silver salt such as [(BrettPhos)Ag(MeCN)]SbF6, resulting in the formation of highly strained polycycles. We have demonstrated that the formation of these products is initiated by a selective 6-endo-dig cyclization. Further mechanistic studies suggested that the reaction may occur through silver dual catalysis using deuterium-labelling experiments, however, single activation of the starting material would lead to the same product and thus both mechanisms were proposed. The further reactivity of these interesting polycyclic products was also explored. ii OTIPS R2 O OTIPS R1 [(BrettPhos)Ag(MeCN)]SbF6 (10 mol%) DCM, 60°C, 36h R1 9 Examples O R2 23-95% Yields Via O H/[Ag] R1 [Ag] O R2 Total synthesis of natural products is often referred to as an art, as it defines the boundaries of organic chemistry.
    [Show full text]
  • Ancestral Class-Promiscuity As a Driver of Functional Diversity in the BAHD
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.18.385815; this version posted November 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Ancestral class-promiscuity as a driver of functional diversity in the 2 BAHD acyltransferase family in plants 3 Lars H. Kruse1, Austin T. Weigle3, Jesús Martínez-Gómez1,2, Jason D. Chobirko1,5, Jason 4 E. Schaffer6, Alexandra A. Bennett1,7, Chelsea D. Specht1,2, Joseph M. Jez6, Diwakar 5 Shukla4, Gaurav D. Moghe1* 6 Footnotes: 7 1 Plant Biology Section, School of Integrative Plant Sciences, Cornell University, Ithaca, 8 NY, 14853, USA 9 2 L.H. Bailey Hortorium, Cornell University, Ithaca, NY, 14853, USA 10 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, 11 USA 12 4 Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana- 13 Champaign, Urbana, IL, 61801, USA 14 5 Present address: Department of Molecular Biology and Genetics, Cornell University, 15 Ithaca, NY, 14853, USA 16 6 Department of Biology, Washington University in St. Louis, St. Louis, MO, 63130, USA 17 7 Present address: Institute of Analytical Chemistry, Universität für Bodenkultur Wien, 18 Vienna, 1190, Austria 19 20 * Corresponding author: [email protected] 21 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.18.385815; this version posted November 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
    [Show full text]
  • Structure of a Berberine Bridge Enzyme-Like Enzyme with an Active Site Specific to the Plant Family Brassicaceae
    Structure of a Berberine Bridge Enzyme-Like Enzyme with an Active Site Specific to the Plant Family Brassicaceae Daniel, Bastian; Wallner, Silvia; Steiner, Barbara; Oberdorfer, Gustav; Kumar, Prashant; van der Graaff, Eric; Roitsch, Thomas; Sensen, Christoph W; Gruber, Karl; Macheroux, Peter Published in: PLOS ONE DOI: 10.1371/journal.pone.0156892 Publication date: 2016 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Daniel, B., Wallner, S., Steiner, B., Oberdorfer, G., Kumar, P., van der Graaff, E., ... Macheroux, P. (2016). Structure of a Berberine Bridge Enzyme-Like Enzyme with an Active Site Specific to the Plant Family Brassicaceae. PLOS ONE, 11(6), e0156892. https://doi.org/10.1371/journal.pone.0156892 Download date: 08. Apr. 2020 RESEARCH ARTICLE Structure of a Berberine Bridge Enzyme-Like Enzyme with an Active Site Specific to the Plant Family Brassicaceae Bastian Daniel1, Silvia Wallner1, Barbara Steiner1, Gustav Oberdorfer2, Prashant Kumar2, Eric van der Graaff3, Thomas Roitsch3,4, Christoph W. Sensen5, Karl Gruber2, Peter Macheroux1* 1 Institute of Biochemistry, Graz University of Technology, Graz, Austria, 2 Institute of Molecular Biosciences, University of Graz, Graz, Austria, 3 Department of Plant and Environmental Sciences, a11111 University of Copenhagen, Copenhagen, Denmark, 4 Global Change Research Centre, Czech Globe AS CR, v.v.i., Drásov 470, Cz-664 24 Drásov, Czech Republic, 5 Institute of Molecular Biotechnology, Graz University of Technology, Graz, Austria * [email protected] OPEN ACCESS Abstract Citation: Daniel B, Wallner S, Steiner B, Oberdorfer Berberine bridge enzyme-like (BBE-like) proteins form a multigene family (pfam 08031), G, Kumar P, van der Graaff E, et al.
    [Show full text]
  • Dr. Duke's Phytochemical and Ethnobotanical Databases Chemicals Found in Papaver Somniferum
    Dr. Duke's Phytochemical and Ethnobotanical Databases Chemicals found in Papaver somniferum Activities Count Chemical Plant Part Low PPM High PPM StdDev Refernce Citation 0 (+)-LAUDANIDINE Fruit -- 0 (+)-RETICULINE Fruit -- 0 (+)-RETICULINE Latex Exudate -- 0 (-)-ALPHA-NARCOTINE Inflorescence -- 0 (-)-NARCOTOLINE Inflorescence -- 0 (-)-SCOULERINE Latex Exudate -- 0 (-)-SCOULERINE Plant -- 0 10-HYDROXYCODEINE Latex Exudate -- 0 10-NONACOSANOL Latex Exudate Chemical Constituents of Oriental Herbs (3 diff. books) 0 13-OXOCRYPTOPINE Plant -- 0 16-HYDROXYTHEBAINE Plant -- 0 20-HYDROXY- Fruit 36.0 -- TRICOSANYLCYCLOHEXA NE 0 4-HYDROXY-BENZOIC- Pericarp -- ACID 0 4-METHYL-NONACOSANE Fruit 3.2 -- 0 5'-O- Plant -- DEMETHYLNARCOTINE 0 5-HYDROXY-3,7- Latex Exudate -- DIMETHOXYPHENANTHRE NE 0 6- Plant -- ACTEONLYDIHYDROSANG UINARINE 0 6-METHYL-CODEINE Plant Father Nature's Farmacy: The aggregate of all these three-letter citations. 0 6-METHYL-CODEINE Fruit -- 0 ACONITASE Latex Exudate -- 32 AESCULETIN Pericarp -- 3 ALANINE Seed 11780.0 12637.0 0.5273634907250652 -- Activities Count Chemical Plant Part Low PPM High PPM StdDev Refernce Citation 0 ALKALOIDS Latex Exudate 50000.0 250000.0 ANON. 1948-1976. The Wealth of India raw materials. Publications and Information Directorate, CSIR, New Delhi. 11 volumes. 5 ALLOCRYPTOPINE Plant Father Nature's Farmacy: The aggregate of all these three-letter citations. 15 ALPHA-LINOLENIC-ACID Seed 1400.0 5564.0 -0.22115561650586155 -- 2 ALPHA-NARCOTINE Plant Jeffery B. Harborne and H. Baxter, eds. 1983. Phytochemical Dictionary. A Handbook of Bioactive Compounds from Plants. Taylor & Frost, London. 791 pp. 17 APOMORPHINE Plant Father Nature's Farmacy: The aggregate of all these three-letter citations. 0 APOREINE Fruit -- 0 ARABINOSE Fruit ANON.
    [Show full text]
  • Feasibility Study on Opium Licensing in Afghanistan
    FEASIBILITY STUDY ON OPIUM LICENSING IN AFGHANISTAN FOR THE PRODUCTION OF MORPHINE AND OTHER ESSENTIAL MEDICINES ﻣﻄﺎﻟﻌﻪ اﻣﮑﺎﻧﺎت در ﻣﻮرد ﺟﻮاز دهﯽ ﺗﺮﻳﺎک در اﻓﻐﺎﻧﺴﺘﺎن ﺑﺮای ﺗﻮﻟﻴﺪ ﻣﻮرﻓﻴﻦ و ادوﻳﻪ ﺟﺎت ﺿﺮوری دﻳﮕﺮ Initial Findings – September 2005 Kabul, Afghanistan The British Institute of International and Comparative Law Hugo Warner • University of Calgary Peter Facchini - Jill Hagel University of Ghent Brice De Ruyver - Laurens van Puyenbroeck University of Kabul Abdul Aziz Ali Ahmad - Osman Babury Cheragh Ali Cheragh - Mohammad Yasin Mohsini University of Lisbon Vitalino Canas - Nuno Aureliano • Shruti Patel • University of Toronto Benedikt Fischer Todd Culbert - Juergen Rehm • Wageningen University Jules Bos - Suzanne Pegge • Ali Wardak • The Senlis Council Gabrielle Archer - Juan Arjona - Luke Bryant Marc Das Gupta - Furkat Elmirzaev - Guillaume Fournier Jane Francis - Thalia Ioannidou - Ernestien Jensema Manna Kamio Badiella - Jorrit Kamminga - Fabrice Pothier Emmanuel Reinert - David Spivack - Daniel Werb FEASIBILITY STUDY ON OPIUM LICENSING IN AFGHANISTAN FOR THE PRODUCTION OF MORPHINE AND OTHER ESSENTIAL MEDICINES Initial Findings – September 2005 Kabul, Afghanistan Study Commissioned by The Senlis Council Study Edited and coordinated by David Spivack Editorial team: Juan Arjona, Jane Francis, Thalia Ioannidou, Ernestien Jensema, Manna Kamio Badiella, Fabrice Pothier. Published 2005 by MF Publishing Ltd 17 Queen Anne’s Gate, London SW1H 9BU, UK ISBN: 0-9550798-2-9 Printed and bound in Afghanistan by Jehoon; Printing Press Other publications
    [Show full text]
  • 102 4. Biosynthesis of Natural Products Derived from Shikimic Acid
    102 4. Biosynthesis of Natural Products Derived from Shikimic Acid 4.1. Phenyl-Propanoid Natural Products (C6-C3) The biosynthesis of the aromatic amino acids occurs through the shikimic acid pathway, which is found in plants and microorganisms (but not in animals). We (humans) require these amino acids in our diet, since we are unable to produce them. For this reason, molecules that can inhibit enzymes on the shikimate pathway are potentially useful as antibiotics or herbicides, since they should not be toxic for humans. COO COO NH R = H Phenylalanine 3 R = OH Tyrosine R NH3 N Tryptophan H The aromatic amino acids also serve as starting materials for the biosynthesis of many interesting natural products. Here we will focus on the so-called phenyl-propanoide (C6-C3) natural products, e.g.: OH OH OH HO O HO OH HO O Chalcone OH O a Flavone OH O OH O a Flavonone OH OH Ar RO O O O HO O O OH O OR OH Anthocyanine OH O a Flavonol Podophyllotoxin MeO OMe OMe OH COOH Cinnamyl alcohol HO O O Cinnamic acid OH (Zimtsäure) Umbellierfone OH a Coumarin) MeO OH O COOH HO Polymerization OH Wood OH HO OH O OH MeO OMe Shikimic acid O HO 4.2. Shikimic acid biosynthesis The shikimic acid pathway starts in carbohydrate metabolism. Given the great social and industrial significance of this pathway, the enzymes have been intensively investigated. Here we will focus on the mechanisms of action of several key enzymes in the pathway. The following Scheme shows the pathway to shikimic acid: 103 COO- COO- Phosphoenolpyruvate HO COO- 2- O O3P-O 2- O3P-O DHQ-Synthase
    [Show full text]
  • Redalyc.Identification of Isoquinoline Alkaloids from Berberis Microphylla
    Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas ISSN: 0717-7917 [email protected] Universidad de Santiago de Chile Chile MANOSALVA, Loreto; MUTIS, Ana; DÍAZ, Juan; URZÚA, Alejandro; FAJARDO, Víctor; QUIROZ, Andrés Identification of isoquinoline alkaloids from Berberis microphylla by HPLC ESI-MS/MS Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, vol. 13, núm. 4, 2014, pp. 324-335 Universidad de Santiago de Chile Santiago, Chile Available in: http://www.redalyc.org/articulo.oa?id=85631435002 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative © 2014 Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas 13 (4): 324 - 335 ISSN 0717 7917 www.blacpma.usach.cl Artículo Original | Original Article In memorian Professor Luis Astudillo, Universidad de Talca, Chile Identification of isoquinoline alkaloids from Berberis microphylla by HPLC ESI-MS/MS [Identificación de alcaloides isoquinolínicos en Berberis microphylla G. Forst mediante CLAE IES-MS/MS] Loreto MANOSALVA1, Ana MUTIS2, Juan DÍAZ3, Alejandro URZÚA4, Víctor FAJARDO5 & Andrés QUIROZ2 1Doctorado en Ciencias de Recursos Naturales; 2Laboratorio de Ecología Química, Departamento de Ciencias Químicas y Recursos Naturales; 3Laboratory of Mass Spectrometry, Scientific and Technological Bioresource Nucleus (Bioren), Universidad de La Frontera, Temuco, Chile 4Laboratory of Chemical Ecology, Department of Environmental Sciences, Faculty of Chemistry and Biology, Universidad de Santiago de Chile 5Chile Laboratorio de Productos Naturales, Universidad de Magallanes, Punta Arenas, Chile Contactos | Contacts: Andrés QUIROZ - E-mail address: [email protected] Abstract: Berberis microphylla (G.
    [Show full text]
  • Metabolic Engineering of Escherichia Coli for Natural Product Biosynthesis
    Trends in Biotechnology Special Issue: Metabolic Engineering Review Metabolic Engineering of Escherichia coli for Natural Product Biosynthesis Dongsoo Yang,1,4 Seon Young Park,1,4 Yae Seul Park,1 Hyunmin Eun,1 and Sang Yup Lee1,2,3,∗ Natural products are widely employed in our daily lives as food additives, Highlights pharmaceuticals, nutraceuticals, and cosmetic ingredients, among others. E. coli has emerged as a prominent host However, their supply has often been limited because of low-yield extraction for natural product biosynthesis. from natural resources such as plants. To overcome this problem, metabolically Escherichia coli Improved enzymes with higher activity, engineered has emerged as a cell factory for natural product altered substrate specificity, and product biosynthesis because of many advantages including the availability of well- selectivity can be obtained by structure- established tools and strategies for metabolic engineering and high cell density based or computer simulation-based culture, in addition to its high growth rate. We review state-of-the-art metabolic protein engineering. E. coli engineering strategies for enhanced production of natural products in , Balancing the expression levels of genes together with representative examples. Future challenges and prospects of or pathway modules is effective in natural product biosynthesis by engineered E. coli are also discussed. increasing the metabolic flux towards target compounds. E. coli as a Cell Factory for Natural Product Biosynthesis System-wide analysis of metabolic Natural products have been widely used in food and medicine in human history. Many of these networks, omics analysis, adaptive natural products have been developed as pharmaceuticals or employed as structural backbones laboratory evolution, and biosensor- based screening can further increase for the development of new drugs [1], and also as food and cosmetic ingredients.
    [Show full text]
  • Diversity of the Mountain Flora of Central Asia with Emphasis on Alkaloid-Producing Plants
    diversity Review Diversity of the Mountain Flora of Central Asia with Emphasis on Alkaloid-Producing Plants Karimjan Tayjanov 1, Nilufar Z. Mamadalieva 1,* and Michael Wink 2 1 Institute of the Chemistry of Plant Substances, Academy of Sciences, Mirzo Ulugbek str. 77, 100170 Tashkent, Uzbekistan; [email protected] 2 Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; [email protected] * Correspondence: [email protected]; Tel.: +9-987-126-25913 Academic Editor: Ipek Kurtboke Received: 22 November 2016; Accepted: 13 February 2017; Published: 17 February 2017 Abstract: The mountains of Central Asia with 70 large and small mountain ranges represent species-rich plant biodiversity hotspots. Major mountains include Saur, Tarbagatai, Dzungarian Alatau, Tien Shan, Pamir-Alai and Kopet Dag. Because a range of altitudinal belts exists, the region is characterized by high biological diversity at ecosystem, species and population levels. In addition, the contact between Asian and Mediterranean flora in Central Asia has created unique plant communities. More than 8100 plant species have been recorded for the territory of Central Asia; about 5000–6000 of them grow in the mountains. The aim of this review is to summarize all the available data from 1930 to date on alkaloid-containing plants of the Central Asian mountains. In Saur 301 of a total of 661 species, in Tarbagatai 487 out of 1195, in Dzungarian Alatau 699 out of 1080, in Tien Shan 1177 out of 3251, in Pamir-Alai 1165 out of 3422 and in Kopet Dag 438 out of 1942 species produce alkaloids. The review also tabulates the individual alkaloids which were detected in the plants from the Central Asian mountains.
    [Show full text]