Metabolic and Molecular Adaptation of Wine Yeasts at Low Temperature Fermentation: Strategies for Their Genetic Improvement
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Structural Basis for Human Sterol Isomerase in Cholesterol Biosynthesis and Multidrug Recognition
ARTICLE https://doi.org/10.1038/s41467-019-10279-w OPEN Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition Tao Long 1, Abdirahman Hassan 1, Bonne M Thompson2, Jeffrey G McDonald1,2, Jiawei Wang3 & Xiaochun Li 1,4 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, 1234567890():,; oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacolo- gically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder. 1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. 4 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. -
A Squalene–Hopene Cyclase in Schizosaccharomyces Japonicus Represents a Eukaryotic Adaptation to Sterol-Limited Anaerobic Environments
A squalene–hopene cyclase in Schizosaccharomyces japonicus represents a eukaryotic adaptation to sterol-limited anaerobic environments Jonna Bouwknegta,1, Sanne J. Wiersmaa,1, Raúl A. Ortiz-Merinoa, Eline S. R. Doornenbala, Petrik Buitenhuisa, Martin Gierab, Christoph Müllerc, and Jack T. Pronka,2 aDepartment of Biotechnology, Delft University of Technology, 2629 HZ Delft, The Netherlands; bCenter for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; and cDepartment of Pharmacy, Center for Drug Research, Ludwig-Maximillians University Munich, 81377 Munich, Germany Edited by Roger Summons, Massachusetts Institute of Technology, Cambridge, MA, and approved July 6, 2021 (received for review March 18, 2021) Biosynthesis of sterols, which are key constituents of canonical and acquisition of a bacterial STC gene by horizontal gene transfer is eukaryotic membranes, requires molecular oxygen. Anaerobic protists considered a key evolutionary adaptation of Neocalllimastigomycetes and deep-branching anaerobic fungi are the only eukaryotes in which to the strictly anaerobic conditions of the gut of large herbivores a mechanism for sterol-independent growth has been elucidated. In (7). The reaction catalyzed by STC resembles oxygen-independent these organisms, tetrahymanol, formed through oxygen-independent conversion of squalene to hopanol and/or other hopanoids by cyclization of squalene by a squalene–tetrahymanol cyclase, acts as a squalene–hopene cyclases (8) (SHC; SI Appendix,Fig.S1), which sterol surrogate. This study confirms an early report [C. J. E. A. Bulder, are found in many bacteria (9, 10). Some bacteria synthesize tet- Antonie Van Leeuwenhoek,37,353–358 (1971)] that Schizosaccharo- rahymanol by ring expansion of hopanol, in a reaction catalyzed by myces japonicus is exceptional among yeasts in growing anaerobi- tetrahymanol synthase (THS) for which the precise mechanism cally on synthetic media lacking sterols and unsaturated fatty acids. -
Generate Metabolic Map Poster
Authors: Zheng Zhao, Delft University of Technology Marcel A. van den Broek, Delft University of Technology S. Aljoscha Wahl, Delft University of Technology Wilbert H. Heijne, DSM Biotechnology Center Roel A. Bovenberg, DSM Biotechnology Center Joseph J. Heijnen, Delft University of Technology An online version of this diagram is available at BioCyc.org. Biosynthetic pathways are positioned in the left of the cytoplasm, degradative pathways on the right, and reactions not assigned to any pathway are in the far right of the cytoplasm. Transporters and membrane proteins are shown on the membrane. Marco A. van den Berg, DSM Biotechnology Center Peter J.T. Verheijen, Delft University of Technology Periplasmic (where appropriate) and extracellular reactions and proteins may also be shown. Pathways are colored according to their cellular function. PchrCyc: Penicillium rubens Wisconsin 54-1255 Cellular Overview Connections between pathways are omitted for legibility. Liang Wu, DSM Biotechnology Center Walter M. van Gulik, Delft University of Technology L-quinate phosphate a sugar a sugar a sugar a sugar multidrug multidrug a dicarboxylate phosphate a proteinogenic 2+ 2+ + met met nicotinate Mg Mg a cation a cation K + L-fucose L-fucose L-quinate L-quinate L-quinate ammonium UDP ammonium ammonium H O pro met amino acid a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar a sugar K oxaloacetate L-carnitine L-carnitine L-carnitine 2 phosphate quinic acid brain-specific hypothetical hypothetical hypothetical hypothetical -
Patent Application Publication (10) Pub. No.: US 2009/0131395 A1 Antonelli Et Al
US 20090131395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0131395 A1 Antonelli et al. (43) Pub. Date: May 21, 2009 (54) BIPHENYLAZETIDINONE CHOLESTEROL Publication Classification ABSORPTION INHIBITORS (51) Int. Cl. (75) Inventors: Stephen Antonelli, Lynn, MA A 6LX 3L/397 (2006.01) (US); Regina Lundrigan, C07D 205/08 (2006.01) Charlestown, MA (US); Eduardo J. A6IP 9/10 (2006.01) Martinez, St. Louis, MO (US); Wayne C. Schairer, Westboro, MA (52) U.S. Cl. .................................... 514/210.02:540/360 (US); John J. Talley, Somerville, MA (US); Timothy C. Barden, Salem, MA (US); Jing Jing Yang, (57) ABSTRACT Boxborough, MA (US); Daniel P. The invention relates to a chemical genus of 4-biphenyl-1- Zimmer, Somerville, MA (US) phenylaZetidin-2-ones useful in the treatment of hypercho Correspondence Address: lesterolemia and other disorders. The compounds have the HESLN ROTHENBERG EARLEY & MEST general formula I: PC S COLUMBIA. CIRCLE ALBANY, NY 12203 (US) (73) Assignee: MICROBIA, INC., Cambridge, MA (US) “O O (21) Appl. No.: 11/913,461 o R2 R4 X (22) PCT Filed: May 5, 2006 R \ / (86). PCT No.: PCT/USO6/17412 S371 (c)(1), (2), (4) Date: May 30, 2008 * / Related U.S. Application Data (60) Provisional application No. 60/677,976, filed on May Pharmaceutical compositions and methods for treating cho 5, 2005. lesterol- and lipid-associated diseases are also disclosed. US 2009/013 1395 A1 May 21, 2009 BPHENYLAZETIONONE CHOLESTEROL autoimmune disorders, (6) an agent used to treat demylena ABSORPTION INHIBITORS tion and its associated disorders, (7) an agent used to treat Alzheimer's disease, (8) a blood modifier, (9) a hormone FIELD OF THE INVENTION replacement agent/composition, (10) a chemotherapeutic 0001. -
A Study of the Function and Physiological Forms of Ergosterol in Saccharomyces Cerevisiae
AN ABSTRACT OF THE THESIS OF BRUCE GORDON ADAMS for the Ph. D. (Name of student) (Degree) Microbiology April 25, 1968 in (Microbial Physiology) presented on (Major) (Date) Title: A STUDY OF THE FUNCTION AND PHYSIOLOGICAL FORMS OF ERGOSTEROL IN SACCHAROMYCES CEREVISIAE Abstract approved: A water - soluble complex containing ergosterol together with a component of yeast has been isolated. The complex can be iso- lated from commercial yeast extract to which ergosterol has been added or directly from whole yeast cells. The complexing agent from yeast extract is also capable of solubilizing cholesterol and a long chain hydrocarbon, hexadecane. The complexing agent has been shown to be a polysaccharide and appears to be composed solely of glucose subunits. The complexing agent does not appear to be glycogen. The binding between the sterol and the polysaccharide appears to be noncovalent. The complex is easily prepared and is stable in aqueous solution; ergosterol in this solution is meta- bolically available to yeast cells to which it is added. Data obtained from acid hydrolysis and extraction of yeast have demonstrated that routine saponification does not recover total sterol from the cells. This suggests the existence of a form of ergosterol resistant to saponification. Time course analyses of sterol synthesis by nonproliferating cell suspensions reveal an inverse relationship between the amounts of base labile and acid labile forms of sterol. These data give strong presumptive evi- dence for dual forms of ergosterol which are interconvertible according to the respiratory state of the cell. Experiments dealing with the effect of respiratory inhibitors on sterol synthesis in nonprofilerating cell suspensions suggest that the synthesis and physiological form of ergosterol is inti- mately related to the integrity of the respiratory apparatus and that the DNA encoding for the synthesis and regulation of ergo- sterol is located in the mitochondria. -
Inhibition of Ergosterol Biosynthesis by Etaconazole in Ustilago Maydis
Inhibition of Ergosterol Biosynthesis by Etaconazole in Ustilago maydis Edith Ebert, John Gaudin, Wolfgang Muecke, Klaus Ramsteiner, and Christian Vogel Agricultural Division, CIBA-GEIGY Limited, CH-4002 Basel, Switzerland Hermann Führer Central Research Laboratories, CIBA-GEIGY Limited, CH-4002 Basel, Switzerland Z. Naturforsch. 38 c, 2 8 -3 4 (1983); received July 22, 1982 Fungal Lipids, Ergosterol, Inhibition, Etaconazole, Fungicide The triazole fungicide etaconazole (CGA64 251) interferes with the ergosterol biosynthesis in Ustilago maydis by inhibiting the C-14 demethylation of the sterol nucleus. During the late log growth phase of U. maydis a novel endogenous sterol metabolite (14x-methyl-ergosta-8,24(28)- dien-3/?,6a-diol) was discovered and analyzed, which accumulates under the influence of the fungicide. The structure of this metabolite points to a hydroxylation-dehydration mechanism for the introduction of the double bond at C-5 during the ergosterol biosynthesis. Introduction investigated, as well as the accumulation of the various sterol intermediates of ergosterol biosyn In the past decade a series of substances have thesis studied after an inhibition time of only a few been discovered that inhibit the biosynthesis of hours. It was of interest for us to follow up the ergosterol. Some of them have been developed as appearance and accumulation of the various sterol fungicides and introduced to practical application. intermediates of ergosterol biosynthesis throughout They include various structural classes, such as the entire growth phase of the fungus under the piperazines (triforine), pyridines (S-1358), pyrimi influence of etaconazole. dines (fenarimol, triarimol), triazoles (triadimefon), and others [1]. More recently, further analogues of one of these classes of compounds, namely the M ethods triazoles, have been developed as plant protection /. -
A Phosphorylated Transcription Factor Regulates Sterol Biosynthesis in Fusarium Graminearum
ARTICLE https://doi.org/10.1038/s41467-019-09145-6 OPEN A phosphorylated transcription factor regulates sterol biosynthesis in Fusarium graminearum Zunyong Liu1,2, Yunqing Jian1,2, Yun Chen 1,2, H. Corby Kistler 3, Ping He4, Zhonghua Ma 1,2 & Yanni Yin1,2 Sterol biosynthesis is controlled by transcription factor SREBP in many eukaryotes. Here, we show that SREBP orthologs are not involved in the regulation of sterol biosynthesis in Fusarium graminearum, a fungal pathogen of cereal crops worldwide. Instead, sterol produc- 1234567890():,; tion is controlled in this organism by a different transcription factor, FgSR, that forms a homodimer and binds to a 16-bp cis-element of its target gene promoters containing two conserved CGAA repeat sequences. FgSR is phosphorylated by the MAP kinase FgHog1, and the phosphorylated FgSR interacts with the chromatin remodeling complex SWI/SNF at the target genes, leading to enhanced transcription. Interestingly, FgSR orthologs exist only in Sordariomycetes and Leotiomycetes fungi. Additionally, FgSR controls virulence mainly via modulating deoxynivalenol biosynthesis and responses to phytoalexin. 1 State Key Laboratory of Rice Biology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. 2 Institute of Biotechnology, Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. 3 United States Department of Agriculture, Agricultural Research Service, 1551 Lindig Street, St. Paul, MN 55108, USA. 4 Department of Biochemistry -
Steroids and Nortriterpenoids from Lichens'
Journ . Haltori Bot. Lab. No. 63 : 351- 355 (Dec. 1987) STEROIDS AND NORTRITERPENOIDS FROM LICHENS' R. TABACCHI\ G. TSOUPRAS2 AND S. HUNECK3 ABSTRACT. The following lichens have been analysed for steroids and nortriterpenoids by GCI MS : Evernia mesomorpha, Lecanora stenotropa, Leptogium saturninum, Nephroma he/veticum, Par melia omphalodes, Ramalina terebrata, Rhizoplaea ehrysoleuea, Umbilicaria deellssata, and Usnea antare/iea. Fourteen steroids and three nortriterpenoids have been found. I NTRODUCTION Only relatively few lichens were analysed for steroids, triterpenoids and simple aliphatic compounds, contrary to the numerous phenolic compounds. Reasons for this are a) the low concentration of these metabolites which ranges in the case of steroids about 0.01 ~;.; , b) the small amount of plant material available, and c) that these metabolites are mostly complex mixtures. The following steroids and nortriterpenoids with known structure have been iso lated from lichens: cholestan-3,B-ol, cholesterol, brassicasterol, fecosterol, episterol, lichesterol, ergost-5-en-3,B-ol, ergosterol, ergosterol peroxide, 24-ethyIcholestan-3,B-ol, cIionasterol, sitosterol, 24-ethyIcholest-7-en-3,B-ol, 24-methyIcholestan-3,B-ol, cam pesterol, 24-methyIcholest-7-en-3,B-ol (Culberson et al. 1977), peroxyergosteryl di varicatinate (Bruun & Motzfeldt 1974), 24-methyIcholesta-5, 22-dien-3,B-ol (Safe et at. 1975), lanosterol (Nicollier et al. 1979), 21 a H-30-nor-hopan-3, 22-dione (Nicollier et al. 1979), and 21a H-30-nor-hopan-22-one (Hveding-Bergseth et al. 1979). We investigated the "steroid" fraction of 9 lichens by gas liquid chromatography mass spectrometry (GC-MS) and report here on the results. -
Actin Cytoskeletal Inhibitor 19,20-Epoxycytochalasin Q
www.nature.com/scientificreports OPEN Actin cytoskeletal inhibitor 19,20‑epoxycytochalasin Q sensitizes yeast cells lacking ERG6 through actin‑targeting and secondarily through disruption of lipid homeostasis Kwanrutai Watchaputi1, Pichayada Somboon2, Nipatthra Phromma‑in1, Khanok Ratanakhanokchai1 & Nitnipa Soontorngun1* Repetitive uses of antifungals result in a worldwide crisis of drug resistance; therefore, natural fungicides with minimal side‑efects are currently sought after. This study aimed to investigate antifungal property of 19, 20‑epoxycytochalasin Q (ECQ), derived from medicinal mushroom Xylaria sp. BCC 1067 of tropical forests. In a model yeast Saccharomyces cerevisiae, ECQ is more toxic in the erg6∆ strain, which has previously been shown to allow higher uptake of many hydrophilic toxins. We selected one pathway to study the efects of ECQ at very high levels on transcription: the ergosterol biosynthesis pathway, which is unlikely to be the primary target of ECQ. Ergosterol serves many functions that cholesterol does in human cells. ECQ’s transcriptional efects were correlated with altered sterol and triacylglycerol levels. In the ECQ‑treated Δerg6 strain, which presumably takes up far more ECQ than the wild‑type strain, there was cell rupture. Increased actin aggregation and lipid droplets assembly were also found in the erg6∆ mutant. Thereby, ECQ is suggested to sensitize yeast cells lacking ERG6 through actin‑targeting and consequently but not primarily led to disruption of lipid homeostasis. Investigation of cytochalasins may provide valuable insight with potential biopharmaceutical applications in treatments of fungal infection, cancer or metabolic disorder. Te incidence of the COVID-19 pandemic provides a valuable lesson and increases our awareness on danger- ous virus as well as other bugs, including microbes. -
Discovering a Novel Antifungal Target in Downstream Sterol Biosynthesis Using a Squalene Synthase Functional Motif
University of Kentucky UKnowledge Theses and Dissertations--Molecular and Cellular Biochemistry Molecular and Cellular Biochemistry 2017 DISCOVERING A NOVEL ANTIFUNGAL TARGET IN DOWNSTREAM STEROL BIOSYNTHESIS USING A SQUALENE SYNTHASE FUNCTIONAL MOTIF Kristin Brooke Linscott University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-7145-4884 Digital Object Identifier: https://doi.org/10.13023/ETD.2017.290 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Linscott, Kristin Brooke, "DISCOVERING A NOVEL ANTIFUNGAL TARGET IN DOWNSTREAM STEROL BIOSYNTHESIS USING A SQUALENE SYNTHASE FUNCTIONAL MOTIF" (2017). Theses and Dissertations-- Molecular and Cellular Biochemistry. 33. https://uknowledge.uky.edu/biochem_etds/33 This Doctoral Dissertation is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Molecular and Cellular Biochemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. -
Principles of Human Nutrition 00 05/03/2003 10:52 Page Ii 00 05/03/2003 10:52 Page Iii
00 05/03/2003 10:52 Page i Principles of Human Nutrition 00 05/03/2003 10:52 Page ii 00 05/03/2003 10:52 Page iii Principles of Human Nutrition Second edition Martin Eastwood Edinburgh, UK 00 05/03/2003 10:52 Page iv © 2003 by Blackwell Science Ltd, First edition published 1997 by Chapman & Hall a Blackwell Publishing Company This edition first published 2003 by Blackwell Science Ltd Editorial Offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK Library of Congress Tel: 01865 776868 Cataloging-in-Publication Data Blackwell Publishing, Inc., 350 Main Street, Malden, is available MA 02148-5018, USA Tel: +1 781 388 8250 0-632-05811-0 Iowa State Press, a Blackwell Publishing Company, 2121 State Avenue, Ames, Iowa 50014-8300, USA A catalogue record for this title is available from the Tel: +1 515 292 0140 British Library Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton South, Set in Times and produced by Gray Publishing, Victoria 3053, Australia Tunbridge Wells, Kent Tel: +61 (0)3 9347 0300 Printed and bound in Great Britain by Blackwell Wissenschafts Verlag, Kurfürstendamm 57, Ashford Colour Press, Gosport, Hants 10707 Berlin, Germany Tel: +49 (0)30 32 79 060 For further information on The right of the Author to be identified as the Author Blackwell Publishing, visit our website: of this Work has been asserted in accordance with the www.blackwellpublishing.com Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. -
Relationship Between Acyl-Lipid and Sterol Metabolisms in Diatoms Eric Maréchal, Josselin Lupette
Relationship between acyl-lipid and sterol metabolisms in diatoms Eric Maréchal, Josselin Lupette To cite this version: Eric Maréchal, Josselin Lupette. Relationship between acyl-lipid and sterol metabolisms in diatoms. Biochimie, Elsevier, 2020, 169, pp.3-11. 10.1016/j.biochi.2019.07.005. hal-02185071 HAL Id: hal-02185071 https://hal.archives-ouvertes.fr/hal-02185071 Submitted on 24 Sep 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. Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0 International License *Manuscript - Maréchal & Lupette revision Click here to view linked References Short title: 1 2 3 Acyl-lipid and sterol metabolisms in diatoms 4 5 Title: 6 7 Relationship between acyl-lipid and sterol metabolisms in diatoms 8 9 10 Authors: 11 12 Eric Maréchal1, Josselin Lupette2,* 13 14 15 16 17 Affiliations: 18 19 1Laboratoire de Physiologie Cellulaire et Végétale, CNRS, CEA, INRA, Université Grenoble 20 21 Alpes, Institut de Recherche Interdisciplinaire de Grenoble, CEA Grenoble, 17 avenue des 22 23 Martyrs, 38000, Grenoble, France. 24 25 2 MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, 26 27 USA.