DOCSLIB.ORG

Introduction to Enzyme and Coenzyme Chemistry Introduction to Enzyme and Coenzyme Introduction to Chemistry Enzyme and T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Introduction to Enzyme and Coenzyme Chemistry Introduction to Enzyme and Coenzyme Introduction to Chemistry Enzyme and T RED BOX RULES ARE FOR PROOF STAGE ONLY. DELETE BEFORE FINAL PRINTING. Third Edition Bugg Third Edition Introduction to Enzyme and Coenzyme Chemistry Coenzyme and Enzyme to Introduction Introduction to Enzyme and Coenzyme Introduction to Chemistry Enzyme and T. D. H. Bugg, Department of Chemistry, University of Warwick, Warwick, UK Coenzyme Enzymes are giant macromolecules which catalyse biochemical reactions. They are remarkable in many ways. Their three-dimensional structures are highly complex, yet they are formed by spontaneous folding of a linear polypeptide chain. Their catalytic Chemistry properties are far more impressive than synthetic catalysts which operate under more extreme conditions. Each enzyme catalyses a single chemical reaction on a particular chemical substrate with very high enantioselectivity and enantiospecifi city at rates which approach “catalytic perfection”. Living cells are capable of carrying out a huge repertoire of enzyme-catalysed chemical reactions, some of which have T. D. H. Bugg little or no precedent in organic chemistry. The popular textbook Introduction to Enzyme and Coenzyme Chemistry has been thoroughly updated to include information on the most recent advances in our understanding of enzyme action, with additional recent examples from the literature used to illustrate key points. A major new feature is the inclusion of two-colour fi gures, and the addition of over 40 new fi gures of the active sites of enzymes discussed in the text, in order to illustrate the interplay between enzyme structure and function. This new edition provides a concise but comprehensive account from the perspective of organic chemistry, what enzymes are, how they work, and how they catalyse many of the major classes of enzymatic reactions, and will continue to prove Third invaluable to both undergraduate and postgraduate students of organic, bio-organic Edition and medicinal chemistry, chemical biology, biochemistry and biotechnology. P1: JYS JWST182-fm JWST182-Bugg April 25, 2012 8:12 Printer: Yet to come Trim: 246mm × 189mm ii P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm Introduction to Enzyme and Coenzyme Chemistry i P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm ii P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm Introduction to Enzyme and Coenzyme Chemistry Third Edition T. D. H. BUGG Department of Chemistry, University of Warwick, UK A John Wiley & Sons, Ltd., Publication iii P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm This edition first published 2012 © 2012 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identified as the author of this work has been asserted in accordance with the 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. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Bugg, T. D. H. Introduction to enzyme and coenzyme chemistry / T. D. H. Bugg. – 3rd ed. p. cm. Includes bibliographical references and index. ISBN 978-1-119-99595-1 (cloth) – ISBN 978-1-119-99594-4 (pbk.) 1. Enzymes. 2. Coenzymes. I. Title. QP601.B955 2012 612.0151–dc23 2012008853 A catalogue record for this book is available from the British Library. Cloth ISBN: 9781119995951 Paper ISBN: 9781119995944 Typeset in 10/12pt Times by Aptara Inc., New Delhi, India Instructors can access PowerPoint files of the illustrations presented within this text, for teaching, at: http://booksupport.wiley.com. iv P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm Contents Preface ix Representation of Protein Three-Dimensional Structures x 1 From Jack Beans to Designer Genes 1 1.1 Introduction 1 1.2 The discovery of enzymes 1 1.3 The discovery of coenzymes 3 1.4 The commercial importance of enzymes in biosynthesis and biotechnology 3 1.5 The importance of enzymes as targets for drug discovery 6 2 All Enzymes Are Proteins 7 2.1 Introduction 7 2.2 The structures of the L-␣-amino acids 7 2.3 The primary structure of polypeptides 9 2.4 Alignment of amino acid sequences 11 2.5 Secondary structures found in proteins 12 2.6 The folded tertiary structure of proteins 15 2.7 Enzyme structure and function 17 2.8 Metallo-enzymes 20 2.9 Membrane-associated enzymes 21 2.10 Glycoproteins 23 3 Enzymes Are Wonderful Catalysts 26 3.1 Introduction 26 3.2 A thermodynamic model of catalysis 28 3.3 Proximity effects 30 3.4 The importance of transition state stabilisation 32 3.5 Acid/base catalysis in enzymatic reactions 36 3.6 Nucleophilic catalysis in enzymatic reactions 40 3.7 The use of strain energy in enzyme catalysis 44 3.8 Desolvation of substrate and active site nucleophiles 45 3.9 Catalytic perfection 46 3.10 The involvement of protein dynamics in enzyme catalysis 47 4 Methods for Studying Enzymatic Reactions 50 4.1 Introduction 50 4.2 Enzyme purification 50 4.3 Enzyme kinetics 52 v P1: JYS JWST182-fm JWST182-Bugg May 22, 2012 10:0 Printer: Yet to come Trim: 244mm × 168mm vi Contents 4.4 The stereochemical course of an enzymatic reaction 59 4.5 The existence of intermediates in enzymatic reactions 64 4.6 Analysis of transition states in enzymatic reactions 68 4.7 Determination of active site catalytic groups 71 5 Hydrolytic and Group Transfer Enzymes 77 5.1 Introduction 77 5.2 The peptidases 79 CASE STUDY: HIV-1 protease 90 5.3 Esterases and lipases 92 5.4 Acyl transfer reactions in biosynthesis (coenzyme A) 93 5.5 Enzymatic phosphoryl transfer reactions 95 5.6 Adenosine 5-triphosphate (ATP) 101 5.7 Enzymatic glycosyl transfer reactions 102 5.8 Methyl group transfer: use of S-adenosyl methionine and tetrahydrofolate coenzymes for one-carbon transfers 107 6 Enzymatic Redox Chemistry 115 6.1 Introduction 115 6.2 Nicotinamide adenine dinucleotide-dependent dehydrogenases 117 6.3 Flavin-dependent dehydrogenases and oxidases 122 6.4 Flavin-dependent mono-oxygenases 128 6.5 CASE STUDY: Glutathione and trypanothione reductases 129 6.6 Deazaflavins and pterins 133 6.7 Iron-sulphur clusters 135 6.8 Metal-dependent mono-oxygenases 136 6.9 ␣-Ketoglutarate-dependent dioxygenases 140 6.10 Non-heme iron-dependent dioxygenases 141 7 Enzymatic Carbon–Carbon Bond Formation 148 7.1 Introduction 148 Carbon–carbon bond formation via carbanion equivalents 149 7.2 Aldolases 149 CASE STUDY: Fructose 1,6-bisphosphate aldolase 150 7.3 Claisen enzymes 153 7.4 Assembly of fatty acids and polyketides 156 7.5 Carboxylases: Use of biotin 158 7.6 Ribulose bisphosphate carboxylase/oxygenase (Rubisco) 161 7.7 Vitamin K-dependent
Load more

Recommended publications
  • Enzyme-Catalyzed C–F Bond Formation and Cleavage
    Tong et al. Bioresour. Bioprocess. (2019) 6:46 https://doi.org/10.1186/s40643-019-0280-6 REVIEW Open Access Enzyme-catalyzed C–F bond formation and cleavage Wei Tong1,2 , Qun Huang1,2, Min Li1,2 and Jian‑bo Wang1,2* Abstract Organofuorines are widely used in a variety of applications, ranging from pharmaceuticals to pesticides and advanced materials. The widespread use of organofuorines also leads to its accumulation in the environment, and two major questions arise: how to synthesize and how to degrade this type of compound efectively? In contrast to a considerable number of easy‑access chemical methods, milder and more efective enzymatic methods remain to be developed. In this review, we present recent progress on enzyme‑catalyzed C–F bond formation and cleav‑ age, focused on describing C–F bond formation enabled by fuorinase and C–F bond cleavage catalyzed by oxidase, reductase, deaminase, and dehalogenase. Keywords: Organofuorines, C–F bonds, Enzyme‑catalyzed, Degradation, Formation Introduction usually require harsh conditions and are not environ- Incorporation of fuorine into organic compounds usu- ment friendly (Dillert et al. 2007; Lin et al. 2012; Sulbaek ally endows organofuorines with unique chemical and Andersen et al. 2005). To solve these problems, devel- physical properties, a strategy that has been successfully opment of mild and green methods is urgently needed. applied in agrochemicals, materials science, and pharma- Biocatalysis has been playing an increasingly more ceutical chemistry (Phelps 2004; Müller et al. 2007; Shah important role in modern chemistry due to its high ef- and Westwell 2007; Hagmann 2008; Nenajdenko et al.
    [Show full text]
  • Nouchali Bandaranayaka Phd Thesis
    Studies of enzymes relevant to the biotransformation of fluorinated natural products Nouchali Bandaranayaka Supervisor: Prof. David O’Hagan This thesis is submitted in partial fulfilment for the degree of PhD at the University of St Andrews NOVEMBER 2016 ii Declarations 1. Candidate’s declarations: I, Nouchali Bandaranayaka hereby certify that this thesis, which is approximately 50,000 words in length, has been written by me, and that it is the record of work carried out by me, or principally by myself in collaboration with others as acknowledged, and that it has not been submitted in any previous application for a higher degree. I was admitted as a research student in November 2009 and as a candidate for the degree of Doctor of Philosophy in November 2011; the higher study for which this is a record was carried out in the University of St Andrews between 2009 and 2016. Date Signature of candidate 2. Supervisor’s declaration: I hereby certify that the candidate has fulfilled the conditions of the Resolution and Regulations appropriate for the degree of Doctor of Philosophy in the University of St Andrews and that the candidate is qualified to submit this thesis in application for that degree. Date Signature of supervisor 3. Permission for publication: In submitting this thesis to the University of St Andrews I understand that I am giving permission for it to be made available for use in accordance with the regulations of the University Library for the time being in force, subject to any copyright vested in the work not being affected thereby.
    [Show full text]
  • Enzymatic Resolution of Α-Haloacids and Esters and Their Use in The
    Engineering of Candida antarctica lipase B for the kinetic resolution of α-halo esters A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2010 Shu-Ling Tang School of Chemistry Contents Contents 2 Abstract 6 Declaration 7 Copyright statement 8 Acknowledgements 9 Abbreviations 10 1 Introduction 12 1.1 Chirality in nature 12 1.2 Enantiomers of drugs 12 1.2.1 Chiral pool asymmetric synthesis 14 1.2.2 Resolution 15 1.2.3 Auxiliary controlled stereoselectivity 17 1.2.4 Reagent controlled stereoselectivity 18 1.3 Pharmacologically active compounds 19 1.3.1 Retrosynthetic analyses of (S)-Keppra and (R)-Tiopronin 19 1.3.2 (S)-Keppra 19 1.3.3 (R)-Tiopronin 23 1.3.4 Synthesis of other chiral starting materials from 2-bromoalkanoic acid 24 1.3.5 2-Fluoropropionic acid 25 1.4 Chemical synthesis of α-haloacids 26 1.4.1 Chemical synthesis of 2-bromopropionic acid 26 1.4.2 Chemical synthesis of enantiopure 2-bromopropionic acid 27 1.4.3 Chemical synthesis of 2-fluoropropionic acid 28 1.4.4 Chemical synthesis of enantiopure 2-fluoropropionic acid 31 1.5 Biocatalysis 31 1.5.1 Biocatalysts 32 1.5.2 Enzyme classes 32 1.5.3 Hydrolases (EC 3.X.X.X) 33 1.6 Biosynthesis of halogenated compounds 34 2 1.6.1 Haloperoxidases and perhydrolases 34 1.6.2 Flavin dependent halogenases 36 1.6.3 Fluorinase 37 1.7 Kinetic resolution of α-haloacids and ester using lipases 38 1.7.1 Kinetic resolution of α-haloacids 39 1.7.2 Kinetic resolution of α-haloesters 40 1.8 Directed evolution
    [Show full text]
  • Characterization of a SAM-Dependent Fluorinase from a Latent Biosynthetic Pathway for Fluoroacetate and 4-Fluorothreonine Format
    F1000Research 2014, 3:61 Last updated: 16 MAY 2019 RESEARCH ARTICLE Characterization of a SAM-dependent fluorinase from a latent biosynthetic pathway for fluoroacetate and 4-fluorothreonine formation in Nocardia brasiliensis [version 1; peer review: 2 approved] Yaya Wang, Zixin Deng , Xudong Qu Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China First published: 19 Feb 2014, 3:61 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.3-61.v1) Latest published: 19 Feb 2014, 3:61 ( https://doi.org/10.12688/f1000research.3-61.v1) Reviewer Status Abstract Invited Reviewers Fluorination has been widely used in chemical synthesis, but is rare in 1 2 nature. The only known biological fluorination scope is represented by the fl pathway from Streptomyces cattleya that produces fluoroacetate (FAc) and version 1 4-fluorothreonine (4-FT). Here we report the identification of a novel published report report pathway for FAc and 4-FT biosynthesis from the actinomycetoma-causing 19 Feb 2014 pathogen Nocardia brasiliensis ATCC 700358. The new pathway shares overall conservation with the fl pathway in S. cattleya. Biochemical characterization of the conserved domains revealed a novel fluorinase 1 Changsheng Zhang, Chinese Academy of NobA that can biosynthesize 5’-fluoro-5’-deoxyadenosine (5’-FDA) from Sciences, Guangzhou, China inorganic fluoride and S-adenosyl-l-methionine (SAM). The NobA shows Cormac Murphy, University College Dublin, similar halide specificity and characteristics to the fluorination enzyme FlA 2 Dublin, Ireland of the fl pathway. Kinetic parameters for fluoride (Km 4153 μM, kcat 0.073 -1 -1 min ) and SAM (Km 416 μM, kcat 0.139 min ) have been determined, Any reports and responses or comments on the revealing that NobA is slightly (2.3 fold) slower than FlA.
    [Show full text]
  • Generated by SRI International Pathway Tools Version 25.0, Authors S
    Authors: Pallavi Subhraveti Ron Caspi Peter Midford Peter D Karp 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. Ingrid Keseler Periplasmic (where appropriate) and extracellular reactions and proteins may also be shown. Pathways are colored according to their cellular function. Gcf_000190595Cyc: Cellulophaga lytica DSM 7489 Cellular Overview Connections between pathways are omitted for legibility. Anamika Kothari phosphate molybdate RS04350 RS08315 phosphate molybdate Macromolecule Modification tRNA-uridine 2-thiolation inosine 5'- Nucleoside and Nucleotide Degradation ditrans,octacis- a peptidoglycan with ditrans,octacis- a [bis(guanylyl an N-terminal- a [protein] and selenation (bacteria) phosphate guanosine ditrans,octacis- (4R)-4-hydroxy- an L-asparaginyl- an L-cysteinyl- Aminoacyl-tRNA Charging tRNA charging nucleotides undecaprenyldiphospho- (L-alanyl-γ-D-glutamyl- undecaprenyldiphospho- undecaprenyldiphospho- molybdopterin) cys L-methionyl-L- C-terminal glu degradation 2-oxoglutarate [tRNA Asn ] [tRNA Cys ] degradation III N-acetyl-(N-acetyl-β-D- L-lysyl-D-alanyl-D- N-acetyl-(N- N-acetyl-(N- cofactor cysteinyl-[protein] L-glutamate cys glucosaminyl)muramoyl- alanine) pentapeptide acetylglucosaminyl) acetylglucosaminyl) chaperone]- Phe IMP bifunctional phe a tRNA L-alanyl-γ-D-glutamyl-L-
    [Show full text]
  • Poster Abstracts
    ENGINEERING BACTERIAL NITROREDUCTASES FOR ANTICANCER GENE THERAPY AND TARGETED CELL ABLATION Abigail Sharrock, School of Biological Sciences, Victoria University of Wellington, NZ [email protected] Elsie Williams, Department of Chemistry, Emory University, USA Kelsi Hall, School of Biological Sciences, Victoria University of Wellington, NZ Jeff Mumm, Wilmer Eye Institute, Johns Hopkins University, USA David Ackerley, School of Biological Sciences, Victoria University of Wellington, NZ Key Words: nitroreductase, prodrug, directed evolution, gene therapy, cell ablation Bacterial nitroreductases are members of a diverse family of oxidoreductase enzymes that can catalyse the bioreductive activation of nitroaromatic compounds, including anti-cancer and antibiotic prodrugs. Nitroreductases have diverse applications in medicine and research, including anti-cancer gene therapy and targeted ablation of nitroreductase-expressing cells in transgenic zebrafish to model degenerative diseases. Research in these fields to date has focused almost exclusively on the canonical nitroreductase NfsB from Escherichia coli (NfsB_Ec), which is a relatively inefficient choice for most applications. By exploring alternative nitroreductase candidates from a variety of bacterial species, in concert with enzyme engineering to fine-tune specific activities, we have generated improved prodrug-activating enzymes. The nitroreductase NfsB from Vibrio vulnificus (NfsB_Vv) has been central to our efforts, and following solution of its crystal structure, was selected as a scaffold for directed evolution via site-saturation mutagenesis. By applying library screening strategies that involved rounds of both positive and negative selection, several mutants that displayed improved activity with a promising next-generation cancer prodrug were identified. In parallel work, an engineered NfsB_Vv variant from the same library was found to be substantially improved in activation of the antibiotic prodrug metronidazole, which is widely used for targeted cell ablation in transgenic zebrafish.
    [Show full text]
  • Enzymatic Defluorination of Fluorinated Compounds
    Seong et al. Appl Biol Chem (2019) 62:62 https://doi.org/10.1186/s13765-019-0469-6 INVITED REVIEW Open Access Enzymatic defuorination of fuorinated compounds Hyeon Jeong Seong†, Seong Woo Kwon†, Dong‑Cheol Seo, Jin‑Hyo Kim* and Yu‑Sin Jang* Abstract Fluorine‑containing compounds are widely used because they have properties required in textiles and coatings for electronic, automotive, and outdoor products. However, fuorinated compounds do not easily break down in nature, which has resulted in their accumulation in the environment as well as the human body. Recently, the enzymatic defuorination of fuorine‑containing compounds has gained increasing attention. Here, we review the enzymatic defuorination reactions of fuorinated compounds. Furthermore, we review the enzyme engineering strategies for cleaving C–F bonds, which have the highest dissociation energy found in organic compounds. Keywords: C–F bond, Defuorination, Fluorine, Perfuorinated compound Introduction and the corresponding enzymes, have not been well Because perfuorinated compounds (PFCs) repel both elucidated. water and oil, they are used as durable repellent treat- On the other hand, fuorinated compounds such as ments for textiles such as outdoor clothes and for home fuoroacetate and 5′-fuoro-5′-deoxyadenosine have been products such as carpets [1]. In addition, PFCs are widely identifed as natural products in nature [10, 11], dem- used in the production of fuoropolymers such as polyte- onstrating the existence of a biosynthesis pathway for trafuoroethylene (trade name, Tefon), which is widely fuorinated compounds in organisms [12]. A representa- used in coatings for electronic, automotive, and outdoor tive pathway of this type is the C–F bond forming reac- products [2].
    [Show full text]
  • Chemoenzymatic Enantioselective Synthesis
    TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS SARJA - SER. D OSA - TOM. 815 MEDICA - ODONTOLOGICA CHEMOENZYMATIC ENANTIOSELECTIVE SYNTHESIS OF b-AMINO ACID DERIVATIVES USING LIPASES by Xiang-Guo Li TURUN YLIOPISTO Turku 2008 Department of Pharmacology, Drug Development and Therapeutics/ Laboratory of Synthetic Drug Chemistry University of Turku Turku, Finland. Supervisor and custos: Professor Liisa T. Kanerva, Ph.D. Laboratory of Synthetic Drug Chemistry University of Turku Turku, Finland. Reviewers: Professor Ulf Hanefeld, Ph.D. Delft University of Technology Delft, The Netherlands and Professor Reko Leino, Ph.D. Åbo Academi University Turku, Finland Opponent: Professor Per Berglund, Ph.D. Royal Institute of Technology (KTH) Stockholm, Sweden ISBN 978-951-29-3671-7 (PRINT) ISBN 978-951-29-3672-4 (PDF) ISSN 0355-9483 Painosalama Oy – Turku, Finland 2008 CONTENTS Abstract Tiivistelmä (Abstract in Finnish) HAbbreviations HList of original papers H1 Introduction............................................................................................................................ H1 H2 Review of the literature .......................................................................................................... H3 H2.1 Kinetic resolution ........................................................................................................... H3 H2.2 Lipase catalysis .............................................................................................................. H5 H2.2.1 Lipases ...............................................................................................................
    [Show full text]
  • Organic & Biomolecular Chemistry
    Please do not adjust margins Organic & Biomolecular Chemistry Paper An enzymatic Finkelstein reaction: Fluorinase catalyses direct halogen exchange Received 00th January 20xx, Accepted 00th January 20xx Phillip T. Lowe,a Steven L. Cobbb and David O'Hagan*a DOI: 10.1039/x0xx00000x www.rsc.org/ The fluorinase enzyme from Streptomyces cattleya is shown to catalyse a direct displacement of bromide and iodide by fluoride ion from 5’-bromodeoxyadenosine (5’-BrDA) and 5’-iododeoxyadenosine (5’-IDA) respectively, to form 5’-fluorodeoxyadenosine (5’-FDA) in the absence of L-methionine (L-Met) or S-adenosyl- L-methionine (SAM). 5’-BrDA is the most efficient substrate for this enzyme catalysed Finkelstein reaction. Introduction 5’-chloro-5’-deoxy adenosine (5’-ClDA) 1 by L-Met to generate SAM Fluorine containing compounds have a remarkable record in tuning 2.15 When this reaction is conducted in the presence of fluoride ion, the properties of medicinal,1,2 agricultural3,4 and materials5 the resultant SAM 2 is then converted to 5’-FDA 3, to achieve a two- chemistry products. As such, in recent years the development of step transhalogenation from 5’-ClDA 1 to 5’-FDA 3. The substrate methodology to incorporate fluorine into biologically and flexibility of this ‘two-step’ fluorination process extends to 2’-deoxy commercially relevant compounds under mild conditions has analogues16 of 5’-ClDA 1 as well as C-2 decoration of the adenosine intensified. The naturally occurring fluorinase enzyme (5’-fluoro-5’- base of 5’-ClDA 1 with an acetylene, or terminally functionalised deoxy-adenosine synthase), originally isolated from Streptomyces acetylene moieties.17-23 In this manner, fluorinase-mediated trans- cattleya where it is involved in the C-F bond forming step in halogenation reactions have become established as a strategy for the fluoroacetate and 4-fluorothreonine biosynthesis, offers a rare synthesis of fluorinated bioactive compounds under experimentally opportunity to introduce fluorine enzymatically.
    [Show full text]
  • Generated by SRI International Pathway Tools Version 25.0, Authors S
    Authors: Pallavi Subhraveti Ron Caspi Peter Midford Peter D Karp 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. Ingrid Keseler Periplasmic (where appropriate) and extracellular reactions and proteins may also be shown. Pathways are colored according to their cellular function. Gcf_000299235Cyc: Leptospirillum ferriphilum ML-04 Cellular Overview Connections between pathways are omitted for legibility. Anamika Kothari phosphate phosphate phosphate phosphate ammonium ammonium ammonium predicted ABC transporter RS12230 RS11960 RS10935 RS01775 RS01785 RS04585 of phosphate phosphate phosphate phosphate ammonium ammonium ammonium phosphate Macromolecule Modification Inorganic Nutrient Metabolism tRNA-uridine 2-thiolation UDP-N-acetyl- undecaprenyl- a carboxy- a nascent a peptidoglycan an [amino-group β 34 a nucleoside cob(II)yrinate a,c- Cofactor, Carrier, and Vitamin Biosynthesis selenate reduction α-D-glucosamine diphospho-N- adenylated- peptidoglycan a uracil in DNA D-glycero- -D- a cytidine lys dimer (meso- met carrier protein]- [2Fe-2S] iron-sulfur thioredoxin flavin biosynthesis I (bacteria and plants) lipoate biosynthesis lipoate salvage I benzimidazolyl adenosylcobamide lipoate biosynthesis pyridoxal 5'-phosphate biosynthesis I folate transformations III (E. coli) Fatty Acid and
    [Show full text]
  • Natural Production of Fluorinated Compounds and Biotechnological Prospects of the Fluorinase Enzyme
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repositório Científico do Instituto Politécnico do Porto Natural production of fluorinated compounds and biotechnological prospects of the fluorinase enzyme a b,c Maria F. Carvalho and Rui S. Oliveira aCIIMAR – Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Porto, Portugal; bCentre for Functional Ecology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal; cDepartment of Environmental Health, Research Centre on Health and Environment, School of Allied Health Sciences, Polytechnic Institute of Porto, Porto, Portugal ABSTRACT Fluorinated compounds are finding increasing uses in several applications. They are employed in almost all areas of modern society. These compounds are all produced by chemical synthesis and their abundance highly contrasts with fluorinated molecules of natural origin. To date, only some plants and a handful of actinomycetes species are known to produce a small number of fluori- nated compounds that include fluoroacetate (FA), some x-fluorinated fatty acids, nucleocidin, 4-fluorothreonine (4-FT), and the more recently identified (2R3S4S)-5-fluoro-2,3,4-trihydroxypenta- noic acid. This largely differs from other naturally produced halogenated compounds, which totals more than 5000. The mechanisms underlying biological fluorination have been uncovered after discovering the first actinomycete species, Streptomyces cattleya, that is capable of produc- ing FA and 4-FT, and a fluorinase has been identified as the enzyme responsible for the forma- tion of the C–F bond. The discovery of this enzyme has opened new perspectives for the biotechnological production of fluorinated compounds and many advancements have been achieved in its application mainly as a biocatalyst for the synthesis of [18F]-labeled radiotracers for medical imaging.
    [Show full text]
  • A Localised Tolerance in the Substrate Specificity of the Fluorinase Enables ‘Last Step’ [18F]-Fluorination of a RGD Peptide Under Ambient Aqueous Conditions
    A localised tolerance in the substrate specificity of the fluorinase enables ‘last step’ [18F]-fluorination of a RGD peptide under ambient aqueous conditions Stephen Thompsona, Qingzhi Zhanga, Mayca Onegab, Stephen McMahona, Ian Flemingc, Sharon Ashworth,b James H. Naismitha, Jan Passchierb, David O’Hagana*. aSchool of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK. bImanova, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London,W12 0NN, UK cAberdeen Biomedical Imaging Centre, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. dImperial College London, Departent of Medicine, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom) ǂAuthors contributed equally. Abstract: A strategy for last step [18F]-fluorination of bioconjugated peptides is reported that exploits an ‘Achilles heel’ in the substrate specificity of the fluorinase enzyme. An acetylene functionality at C-2 of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyses a transhalogenation of 5’-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5’-fluorodeoxy-2-ethynyladenosine [18F]-FDEA. Extending a polyethelene glycol linker from the terminus of the acetylene allows bio- conjugation cargo to be presented to the enzyme for [18F]-labeling. The method benefits from using an 18 18 aqueous (H2 O) solution of [ F]-fluoride, generated by the cyclotron and has the modular capacity
    [Show full text]