DOCSLIB.ORG

Fermentation Strategies for Production of Pharmaceutical Terpenoids in Engineered Yeast

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Fermentation Strategies for Production of Pharmaceutical Terpenoids in Engineered Yeast pharmaceuticals Review Fermentation Strategies for Production of Pharmaceutical Terpenoids in Engineered Yeast Erdem Carsanba 1,2, Manuela Pintado 2 and Carla Oliveira 2,* 1 Amyris BioProducts Portugal, Unipessoal, Lda. Rua Diogo Botelho 1327, 4169-005 Porto, Portugal; [email protected] 2 CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, 4169-005 Porto, Portugal; [email protected] * Correspondence: [email protected] Abstract: Terpenoids, also known as isoprenoids, are a broad and diverse class of plant natural prod- ucts with significant industrial and pharmaceutical importance. Many of these natural products have antitumor, anti-inflammatory, antibacterial, antiviral, and antimalarial effects, support transdermal absorption, prevent and treat cardiovascular diseases, and have hypoglycemic activities. Produc- tion of these compounds are generally carried out through extraction from their natural sources or chemical synthesis. However, these processes are generally unsustainable, produce low yield, and result in wasting of substantial resources, most of them limited. Microbial production of terpenoids provides a sustainable and environment-friendly alternative. In recent years, the yeast Saccharomyces cerevisiae has become a suitable cell factory for industrial terpenoid biosynthesis due to developments in omics studies (genomics, transcriptomics, metabolomics, proteomics), and mathematical modeling. Besides that, fermentation development has a significant importance on achieving high titer, yield, and productivity (TYP) of these compounds. Up to now, there have been many studies and reviews Citation: Carsanba, E.; Pintado, M.; reporting metabolic strategies for terpene biosynthesis. However, fermentation strategies have not Oliveira, C. Fermentation Strategies been yet comprehensively discussed in the literature. This review summarizes recent studies of for Production of Pharmaceutical recombinant production of pharmaceutically important terpenoids by engineered yeast, S. cerevisiae, Terpenoids in Engineered Yeast. with special focus on fermentation strategies to increase TYP in order to meet industrial demands to Pharmaceuticals 2021, 14, 295. https:// feed the pharmaceutical market. Factors affecting recombinant terpenoids production are reviewed doi.org/10.3390/ph14040295 (strain design and fermentation parameters) and types of fermentation process (batch, fed-batch, and continuous) are discussed. Academic Editor: Marialuigia Fantacuzzi Keywords: terpenoids; S. cerevisiae; pharmaceutics; fermentation; fed-batch Received: 9 March 2021 Accepted: 24 March 2021 Published: 26 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral Terpenoids, also known as isoprenoids or terpenes, constitute one of the largest chem- with regard to jurisdictional claims in ically and structurally diverse group of natural products with over 80,000 members in published maps and institutional affil- a widespread family (currently stated in the Dictionary of Natural Products database, iations. http://dnp.chemnetbase.com, accessed on 26 March 2021) [1–4]. Although the majority of terpenoids are predominantly present in plants, other organisms such as bacteria, fungi, insects, and animals contain them as well [5]. Their essential biological functions can be counted as the regulation of cell growth and defense in plants (e.g., tocopherol, gibberellin), and intracellular electron transport, glycoproteins biosynthesis and cell membranes forma- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. tion in animals (e.g., cholesterol) [6]. Owing to their structural variety, there exist diverse This article is an open access article terpenoid activities, such as mediating symbiotic or antagonistic interactions between distributed under the terms and organisms to electron transfer, protein prenylation, or contribution to membrane fluidity, conditions of the Creative Commons which make these compounds highly useful to be applied in various industries: food, Attribution (CC BY) license (https:// cosmetics, fine chemistry, pharmacy, agriculture, and biofuel [5]. creativecommons.org/licenses/by/ Terpenoids are formed from several isoprene (2-methylbuta-1,3-diene; IUPAC 1997) 4.0/). (CH2=C(CH3)–CH=CH2) structural units (or building blocks) synthesized from meval- Pharmaceuticals 2021, 14, 295. https://doi.org/10.3390/ph14040295 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 31 Pharmaceuticals 2021, 14, 295 2 of 29 Terpenoids are formed from several isoprene (2-methylbuta-1,3-diene; IUPAC 1997) (CH2=C(CH3)−CH=CH2) structural units (or building blocks) synthesized from mevalo- onatenate (MVA)(MVA) oror 2-C-methyl-d-erythritol2-C-methyl-d-erythritol 4-phosphate4-phosphate (MEP)(MEP) (which(which is is also also known known as as the the non-mevalonate)non-mevalonate) pathway pathway [ 2[2,3].,3]. Through Through the the condensation condensation reactions reactions of of these these units, units, sev- sev- eraleral large large and and more more complex complex compounds compounds are are produced. produced. According According to to the the number number of of C5 C5 isopreneisoprene units, units, terpenoids terpenoids are are mainly mainly classified classified in in hemiterpenoid hemiterpenoid (C5), (C5), monoterpenoid monoterpenoid (C10),(C10), sesquiterpenoid sesquiterpenoid (C15), (C15), diterpenoid diterpenoid (C20), (C20), triterpenoid triterpenoid (C30), (C30), tetraterpenoid tetraterpenoid (C40), (C40), andand polyterpenoid polyterpenoid (C (C >˃40) 40) [2,3,6]. [2,3,6]. Terpenoids Terpenoids are are mostly mostly formed formed through through continuous continuous ad- additiondition of of head head to to tail tail manner of building blocks,blocks, whichwhich areareisoprene isoprene diphosphate diphosphate (IPP) (IPP) andand dimethylallyl dimethylallyl diphosphate diphosphate (DMAPP). (DMAPP). For For instance, instance, the the precursor precursor of of monoterpenoids, monoterpenoids, geranylgeranyl diphosphate diphosphate (GPP), (GPP), is is produced produced by by head head to to tail tail condensation condensation of of these these two two build- build- inging blocks. blocks. Later,Later, additionaddition of of IPP IPP leads leads to to th thee formation formation of offarnesyl farnesyl diphosphate diphosphate (FPP) (FPP) and andgeranylgeranyl geranylgeranyl diphosphate diphosphate (GGPP), (GGPP), which which are are precursors ofof sesquiterpenoidsesquiterpenoid andand diterpenoid.diterpenoid. OnOn the other hand hand,, head head to to head head condensation condensation ofof two two molecules molecules of FPP of FPP and andGGPP, GGPP, respectively, respectively, forms forms squalene squalene and and phytoene, phytoene, the the precursors precursors of oftriterpenoid triterpenoid and and tet- tetraterpenoidraterpenoid [6,7] [6,7 ](Figure (Figure 11).). Furthermore,Furthermore, thesethese precursorsprecursors are are exposed exposed to to oxidation, oxidation, by by cytochromecytochrome P450 P450 oxygenases, oxygenases, and and glycosylation, glycosylation, by by glycosyltransferases glycosyltransferases to to form form various various terpenoids. In addition, prenyltransferases concatenates isoprene-derived precursors to terpenoids. In addition, prenyltransferases concatenates isoprene-derived precursors to fatty acid-derived precursor to synthase complex terpenoids or meroterpenoids, which fatty acid-derived precursor to synthase complex terpenoids or meroterpenoids, which consist of the medically important compounds, cannabinoids [2]. consist of the medically important compounds, cannabinoids [2]. FigureFigure 1. 1.The The condensation condensation reactions reactions of of terpenoid terpenoid biosynthesis: biosynthesis: ( A(A)) Head Head to to tail tail condensation condensationand and (B()B Tail) Tail to to tail tail condensation condensation (Adapted (Adapted from from [7 ]).[7]). FromFrom early early ancient ancient times times upup toto now,now, terpenoidsterpenoids have been playing playing important important roles roles in inmany many medical medical treatments treatments as as pharmaceuticals pharmaceuticals with with diverse diverse biomedical biomedical activities, activities, such such as as antimalarial, anticancer, anti-inflammatory, antibacterial, antiviral, hypoglycemic, pre- venting and treating cardiovascular diseases, and promoting the transdermal absorption. Pharmaceuticals 2021, 14, 295 3 of 29 Besides that, they can have insecticidal, immunomodulatory, antioxidant, antiaging, and neuroprotective effects [2,3,8,9]. They are usually produced from natural resources through extraction or by chemical synthesis, but the obtained yields are generally low due to inherently low level of target compound and the necessity of complex extraction and chemical synthesis methods, which are commercially infeasible [10]. In most cases, the natural production method, extracting terpenoids from original sources (e.g., taxol from yew tree and artemisinin from the plant Artemisia annua) generally fails in terms of quality and supply management due to seasonal and geographical alterations [5]. In addition, plant engineering for terpenoid production is difficult and complex due to tissue specific expression and loss of volatile products by evaporation, and productivity and yields are very low [11]. Due to these limitations, microbial production of terpenoids has received
Load more

Recommended publications
  • Retention Indices for Frequently Reported Compounds of Plant Essential Oils
    Retention Indices for Frequently Reported Compounds of Plant Essential Oils V. I. Babushok,a) P. J. Linstrom, and I. G. Zenkevichb) National Institute of Standards and Technology, Gaithersburg, Maryland 20899, USA (Received 1 August 2011; accepted 27 September 2011; published online 29 November 2011) Gas chromatographic retention indices were evaluated for 505 frequently reported plant essential oil components using a large retention index database. Retention data are presented for three types of commonly used stationary phases: dimethyl silicone (nonpolar), dimethyl sili- cone with 5% phenyl groups (slightly polar), and polyethylene glycol (polar) stationary phases. The evaluations are based on the treatment of multiple measurements with the number of data records ranging from about 5 to 800 per compound. Data analysis was limited to temperature programmed conditions. The data reported include the average and median values of retention index with standard deviations and confidence intervals. VC 2011 by the U.S. Secretary of Commerce on behalf of the United States. All rights reserved. [doi:10.1063/1.3653552] Key words: essential oils; gas chromatography; Kova´ts indices; linear indices; retention indices; identification; flavor; olfaction. CONTENTS 1. Introduction The practical applications of plant essential oils are very 1. Introduction................................ 1 diverse. They are used for the production of food, drugs, per- fumes, aromatherapy, and many other applications.1–4 The 2. Retention Indices ........................... 2 need for identification of essential oil components ranges 3. Retention Data Presentation and Discussion . 2 from product quality control to basic research. The identifi- 4. Summary.................................. 45 cation of unknown compounds remains a complex problem, in spite of great progress made in analytical techniques over 5.
    [Show full text]
  • Phase I Pharmacokinetic Trial of Perillyl Alcohol (NSC 641066) in Patients with Refractory Solid Malignancies1
    Vol. 6, 3071–3080, August 2000 Clinical Cancer Research 3071 Phase I Pharmacokinetic Trial of Perillyl Alcohol (NSC 641066) in Patients with Refractory Solid Malignancies1 Gary R. Hudes,2 Christine E. Szarka, mononuclear cells obtained from patients treated at the Andrea Adams, Sulabha Ranganathan, highest dose level. The metabolites PA and DHPA did not ras Robert A. McCauley, Louis M. Weiner, change expression or isoprenylation of p21 in MCF-7 breast or DU145 prostate carcinoma cells at concentra- Corey J. Langer, Samuel Litwin, Gwen Yeslow, tions that exceeded those achieved in patient plasma after Theresa Halberr, Mingxin Qian, and POH treatment. We conclude that POH at 1600–2100 James M. Gallo mg/m2 p.o. three times daily is well tolerated on a 14-day Departments of Medical Oncology [G. R. H., C. E. S., S. R., R. A. M., on/14-day off dosing schedule. Inhibition of p21ras func- L. M. W., C. J. L., G. Y., T. H.], Pharmacology [A. A., M. Q., tion in humans is not likely to occur after POH adminis- J. M. G.], and Biostatistics [S. L.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 tration at safe doses of the present oral formulation. ABSTRACT INTRODUCTION Perillyl alcohol (POH) is a monoterpene with anti- The monoterpenes are a diverse class of isoprenoid carcinogenic and antitumor activity in murine tumor molecules derived from the anabolism of acetate by the models. Putative mechanisms of action include activation mevalonic acid branch biosynthetic pathways of plants. d- of the transforming growth factor ␤ pathway and/or in- Limonene, a major component of orange peel oil and the hibition of p21ras signaling, leading to differentiation or prototype monoterpene in carcinogenesis studies, is formed apoptosis.
    [Show full text]
  • Interpreting Sources and Endocrine Active Components of Trace Organic Contaminant Mixtures in Minnesota Lakes
    INTERPRETING SOURCES AND ENDOCRINE ACTIVE COMPONENTS OF TRACE ORGANIC CONTAMINANT MIXTURES IN MINNESOTA LAKES by Meaghan E. Guyader © Copyright by Meaghan E. Guyader, 2018 All Rights Reserved A thesis submitted to the Faculty and the Board of Trustees of the Colorado School of Mines in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Civil and Environmental Engineering). Golden, Colorado Date _____________________________ Signed: _____________________________ Meaghan E. Guyader Signed: _____________________________ Dr. Christopher P. Higgins Thesis Advisor Golden, Colorado Date _____________________________ Signed: _____________________________ Dr. Terri S. Hogue Professor and Department Head Department of Civil and Environmental Engineering ii ABSTRACT On-site wastewater treatment systems (OWTSs) are a suspected source of widespread trace organic contaminant (TOrC) occurrence in Minnesota lakes. TOrCs are a diverse set of synthetic and natural chemicals regularly used as cleaning agents, personal care products, medicinal substances, herbicides and pesticides, and foods or flavorings. Wastewater streams are known to concentrate TOrC discharges to the environment, particularly accumulating these chemicals at outfalls from centralized wastewater treatment plants. Fish inhabiting these effluent dominated environments are also known to display intersex qualities. Concurrent evidence of this phenomenon, known as endocrine disruption, in Minnesota lake fish drives hypotheses that OWTSs, the primary form of wastewater treatment in shoreline residences, may contribute to TOrC occurrence and the endocrine activity in these water bodies. The causative agents specific to fish in this region remain poorly understood. The objective of this dissertation was to investigate OWTSs as sources of TOrCs in Minnesota lakes, and TOrCs as potential causative agents for endocrine disruption in resident fish.
    [Show full text]
  • Possible Fungistatic Implications of Betulin Presence in Betulaceae Plants and Their Hymenochaetaceae Parasitic Fungi Izabela Jasicka-Misiak*, Jacek Lipok, Izabela A
    Possible Fungistatic Implications of Betulin Presence in Betulaceae Plants and their Hymenochaetaceae Parasitic Fungi Izabela Jasicka-Misiak*, Jacek Lipok, Izabela A. S´wider, and Paweł Kafarski Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland. Fax: +4 87 74 52 71 15. E-mail: [email protected] * Author for correspondence and reprint requests Z. Naturforsch. 65 c, 201 – 206 (2010); received September 23/October 26, 2009 Betulin and its derivatives (especially betulinic acid) are known to possess very interesting prospects for their application in medicine, cosmetics and as bioactive agents in pharmaceu- tical industry. Usually betulin is obtained by extraction from the outer layer of a birch bark. In this work we describe a simple method of betulin isolation from bark of various species of Betulaceae trees and parasitic Hymenochaetaceae fungi associated with these trees. The composition of the extracts was studied by GC-MS, whereas the structures of the isolated compounds were confi rmed by FTIR and 1H NMR. Additionally, the signifi cant fungistatic activity of betulin towards some fi lamentous fungi was determined. This activity was found to be strongly dependent on the formulation of this triterpene. A betulin-trimyristin emul- sion, in which nutmeg fat acts as emulsifi er and lipophilic carrier, inhibited the fungal growth even in micromolar concentrations – its EC50 values were established in the range of 15 up to 50 μM depending on the sensitivity of the fungal strain. Considering the lack of fungistatic effect of betulin applied alone, the application of ultrasonic emulsifi cation with the natural plant fat trimyristin appeared to be a new method of antifungal bioassay of water-insoluble substances, such as betulin.
    [Show full text]
  • Download Product Insert (PDF)
    Product Information Betulin Item No. 11041 CH2 CAS Registry No.: 473-98-3 H3C β Formal Name: lup-20(29)-ene-3 ,28-diol H Synonyms: NSC 4644, Trochol OH H MF: C30H50O2 CH CH FW: 442.7 3 3 Purity: ≥98% H CH3 Stability: ≥2 years at -20°C Supplied as: A crystalline solid OH H Laboratory Procedures For long term storage, we suggest that betulin be stored as supplied at -20°C. It should be stable for at least two years. Betulin is supplied as a crystalline solid. A stock solution may be made by dissolving the betulin in the solvent of choice. Betulin is soluble in dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of betulin in DMF is approximately 2.5 mg/ml. Betulin is sparingly soluble in aqueous solutions. To enhance aqueous solubility, dilute the organic solvent solution into aqueous buffers or isotonic saline. If performing biological experiments, ensure the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. We do not recommend storing the aqueous solution for more than one day. Sterol regulatory element binding protein 2 (SREBP-2) regulates cholesterol synthesis by activating the transcription of genes for HMG-CoA reductase and other enzymes of the cholesterol synthetic pathway.1,2 When cellular sterol levels are high, SREBP is bound by SCAP and Insig to ER membranes as a glycosylated precursor protein. Upon cholesterol depletion, the protein is cleaved to its active form and translocated into the nucleus to stimulate transcription of genes involved in the uptake and synthesis of cholesterol.3 Betulin, the precursor of betulinic acid, is a pentacyclic triterpene found in the bark of birch trees.
    [Show full text]
  • Redalyc.Degradation of Citronellol, Citronellal and Citronellyl Acetate By
    Electronic Journal of Biotechnology E-ISSN: 0717-3458 [email protected] Pontificia Universidad Católica de Valparaíso Chile Tozoni, Daniela; Zacaria, Jucimar; Vanderlinde, Regina; Longaray Delamare, Ana Paula; Echeverrigaray, Sergio Degradation of citronellol, citronellal and citronellyl acetate by Pseudomonas mendocina IBPse 105 Electronic Journal of Biotechnology, vol. 13, núm. 2, marzo, 2010, pp. 1-7 Pontificia Universidad Católica de Valparaíso Valparaíso, Chile Available in: http://www.redalyc.org/articulo.oa?id=173313806002 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 Electronic Journal of Biotechnology ISSN: 0717-3458 Vol.13 No.2, Issue of March 15, 2010 © 2010 by Pontificia Universidad Católica de Valparaíso -- Chile Received April 24, 2009 / Accepted November 6, 2009 DOI: 10.2225/vol13-issue2-fulltext-8 RESEARCH ARTICLE Degradation of citronellol, citronellal and citronellyl acetate by Pseudomonas mendocina IBPse 105 Daniela Tozoni Instituto de Biotecnologia Universidade de Caxias do Sul R. Francisco G. Vargas 1130 Caxias do Sul, RS, Brazil Jucimar Zacaria Instituto de Biotecnologia Universidade de Caxias do Sul R. Francisco G. Vargas 1130 Caxias do Sul, RS, Brazil Regina Vanderlinde Instituto de Biotecnologia Universidade de Caxias do Sul R. Francisco G. Vargas 1130 Caxias do Sul, RS, Brazil Ana Paula Longaray Delamare Universidade de Caxias do Sul R. Francisco G. Vargas 1130 Caxias do Sul, RS, Brazil Sergio Echeverrigaray* Universidade de Caxias do Sul R. Francisco G. Vargas 1130 Caxias do Sul, RS, Brazil E-mail: [email protected] Financial support: COREDES/FAPERGS, and D.
    [Show full text]
  • ISOLATION of GERANIOL from RHODINOL by USING PDC REAGENT Nahso3 and Nabh4
    The 2nd International Conference on Chemical Sciences Proceeding ISSN NO. 1410-8313 Yogyakarta, October 14-16th, 2010 ISOLATION OF GERANIOL FROM RHODINOL BY USING PDC REAGENT NaHSO3 AND NaBH4 Zaina Mukhia Bintan, Priatmoko1,*), and Hardono Sastrohamidjojo*) 1 Department of Chemistry, Universitas Gadjah Mada, Yogyakarta, Indonesia * Corresponding author, tel/fax : +62274545188 ABSTRACT Isolation geraniol from the rhodinol have been coducted by using PDC (pyridinium dichromate) reagent, NaHSO3 and NaBH4. The prosses consits of four steps : first step was rhodinol to get the high grade (it are compare between citronella oil from sample A, sample B and sample C, second step was the oxidation of rhodinol by using PDC, third step was separation of citral from citronellol by using sodium bisulfit, and the last step was reduction of citral to geraiol by using NaBH4 in etanol. The higher grade rhodinol was isolated from citronella oil of sample with purity 29.03%. The rhodinol wich used in this research was product of the third fraction redistillation of distillate the second fraction citronella oil, with grade of rhodinol was 90.55%. The oxidation of rhodinol by using PDC, could selectively oxidize geraniol become citral, whereas nothing change with citronellol. The product of oxidation was mixture of citral and citronellol, yellow liquid with fragnance odor, weight : 0.8 g. The geraniol can be obtained from reduction geraniol by using NaBH4 in ethanol. Product of reduction was colourless liquid, with fragnance odor, weight : 0.4 g. The product was analyzed by using GC and infrared spectrometer. Keywords: geraniol, citral, pyridinium dichromate INTRODUCTION Schmidts (1979 have also made the reagent to oxidase alcohol (primary, secondary and so he essential oil is a natural product that on) become the carbonyl compound.
    [Show full text]
  • The Phytochemistry of Cherokee Aromatic Medicinal Plants
    medicines Review The Phytochemistry of Cherokee Aromatic Medicinal Plants William N. Setzer 1,2 1 Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA; [email protected]; Tel.: +1-256-824-6519 2 Aromatic Plant Research Center, 230 N 1200 E, Suite 102, Lehi, UT 84043, USA Received: 25 October 2018; Accepted: 8 November 2018; Published: 12 November 2018 Abstract: Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers in North America. Methods: The aim of this review was to examine the Cherokee ethnobotanical literature and the published phytochemical investigations on Cherokee medicinal plants and to correlate phytochemical constituents with traditional uses and biological activities. Results: Several Cherokee medicinal plants are still in use today as herbal medicines, including, for example, yarrow (Achillea millefolium), black cohosh (Cimicifuga racemosa), American ginseng (Panax quinquefolius), and blue skullcap (Scutellaria lateriflora). This review presents a summary of the traditional uses, phytochemical constituents, and biological activities of Cherokee aromatic and medicinal plants. Conclusions: The list is not complete, however, as there is still much work needed in phytochemical investigation and pharmacological evaluation of many traditional herbal medicines. Keywords: Cherokee; Native American; traditional herbal medicine; chemical constituents; pharmacology 1. Introduction Natural products have been an important source of medicinal agents throughout history and modern medicine continues to rely on traditional knowledge for treatment of human maladies [1]. Traditional medicines such as Traditional Chinese Medicine [2], Ayurvedic [3], and medicinal plants from Latin America [4] have proven to be rich resources of biologically active compounds and potential new drugs.
    [Show full text]
  • The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside
    Published online: 2019-03-11 Reviews The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside Author Armin Scheffler Affiliation ABSTRACT Niefern-Öschelbronn, Germany, With central European approval in January 2016 for a betulin- oleogel (Episalvan), used to accelerate wound closure in par- Key words tial thickness wounds, the herbal active ingredient triterpene ‑ wound healing, split thickness skin graft, burn wounds, dry extract (betulin), from birch bark, was introduced into Betula pendula Betula pubescens Betulaceae, , ,betulin therapy for the first time. Clinical evidence of accelerated wound healing was provided in a new study design by means received October 30, 2018 of intraindividual comparison of split-thickness skin graft do- revised January 28, 2019 nor wounds and burn wounds. Clinical results of a phase II accepted January 29, 2019 study evidencing accelerated wound healing in the rare dis- Bibliography ease epidermolysis bullosa are also available, and a pivotal DOI https://doi.org/10.1055/a-0850-0224 multi-centre phase III study is currently being conducted. Published online March 11, 2019 | Planta Med 2019; 85: 524– The mode of action affects all three phases of wound healing 527 © Georg Thieme Verlag KG Stuttgart · New York | (inflammation, migration, and differentiation), and it has ISSN 0032‑0943 been possible, in some cases, to shed light on this down to the molecular level. After temporary stimulation of the in- Correspondence flammatory phase, the keratinocytes migrate more rapidly to Dr. Armin Scheffler the wound closure and, finally, epidermal differentiation is Bussardweg 15/1, 75223 Niefern-Öschelbronn, Germany stimulated. With this project, we have shown that scientifi- Phone: + 4972333580, Fax: + 497233974138 cally founded new developments in phytotherapy are possible [email protected] in Europe.
    [Show full text]
  • Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: a Route to New Bioactive Compounds
    Review Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds Joana L. C. Sousa 1,2,*, Carmen S. R. Freire 2, Armando J. D. Silvestre 2 and Artur M. S. Silva 1,* 1 QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal 2 CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; [email protected] (C.S.R.F.); [email protected] (A.J.D.S.) * Correspondence: [email protected] (J.L.C.S.); [email protected] (A.M.S.S.); Tel.: +351-234-370-714 (A.M.S.S.) Received: 29 December 2018; Accepted: 17 January 2019; Published: 19 January 2019 Abstract: Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23- hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others. Keywords: triterpenes; betulinic acid; betulin; betulonic acid; 23-hydroxybetulinic acid; synthesis; functionalization; derivatization 1.
    [Show full text]
  • Monoterpene Emission of Quercus Suber L. Highly Infested By
    Monoterpene emission of Quercus suber L. highly infested by Cerambyx welensii Küster Israel Sánchez-Osorio, Gloria López-Pantoja, Raúl Tapias, Evangelina Pareja-Sánchez, Luis Domínguez To cite this version: Israel Sánchez-Osorio, Gloria López-Pantoja, Raúl Tapias, Evangelina Pareja-Sánchez, Luis Domínguez. Monoterpene emission of Quercus suber L. highly infested by Cerambyx welensii Küster. Annals of Forest Science, Springer Nature (since 2011)/EDP Science (until 2010), 2019, 76 (4), pp.98. 10.1007/s13595-019-0879-y. hal-02970736 HAL Id: hal-02970736 https://hal.archives-ouvertes.fr/hal-02970736 Submitted on 19 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Annals of Forest Science (2019) 76: 98 https://doi.org/10.1007/s13595-019-0879-y RESEARCH PAPER Monoterpene emission of Quercus suber L. highly infested by Cerambyx welensii Küster Israel Sánchez-Osorio1 & Gloria López-Pantoja1 & Raúl Tapias1 & Evangelina Pareja-Sánchez2 & Luis Domínguez 1 Received: 25 February 2019 /Accepted: 27 August 2019 /Published online: 18 October 2019 # INRA and Springer-Verlag France SAS, part of Springer Nature 2019 Abstract & Key message Cork oaks highly infested by Cerambyx welensii emit an amount of limonene at dusk, when C.
    [Show full text]
  • Tryptophan | C11H12N2O2 - Pubchem
    07.01.2021 Tryptophan | C11H12N2O2 - PubChem COVID-19 is an emerging, rapidly evolving situation. Get the latest public health information from CDC: https://www.coronavirus.gov. Get the latest research from NIH: https://www.nih.gov/coronavirus. COMPOUND SUMMARY Tryptophan PubChem CID 6305 Structure 2D 3D Crystal Find Similar Structures Chemical Safety Laboratory Chemical Safety Summary (LCSS) Datasheet Molecular Formula C11H12N2O2 L-tryptophan 73-22-3 tryptophan Synonyms L-Tryptophane (S)-Tryptophan More... Molecular Weight 204.22 g/mol Modify Create Dates 2021-01-02 2004-09-16 Tryptophan is the least plentiful of all 22 amino acids and an essential amino acid in humans (provided by food), Tryptophan is found in most proteins and a precursor of serotonin. Tryptophan is converted to 5-hydroxy-tryptophan (5-HTP), converted in turn to serotonin, a neurotransmitter essential in regulating appetite, sleep, mood, and pain. Tryptophan is a natural sedative and present in dairy products, meats, brown rice, fish, and soybeans. (NCI04) NCI Thesaurus (NCIt) Source: NCI Thesaurus (NCIt) Record Name: Tryptophan URL: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C29603 Description: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities. License Note: Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. License URL: https://www.cancer.gov/policies/copyright-reuse L-tryptophan is the L-enantiomer of tryptophan. It has a role as an antidepressant, a nutraceutical, a micronutrient, a plant metabolite, a human metabolite, a Saccharomyces cerevisiae metabolite, an Escherichia coli metabolite and a mouse metabolite.
    [Show full text]