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The Chemistry of Fungi James R. Hanson Department of Chemistry, University of Sussex, Brighton, UK ISBN: 978-0-85404-136-7 A catalogue record for this book is available from the British Library r James R. Hanson, 2008 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Preface The diverse structures, biosyntheses and biological activities of fungal meta- bolites have attracted chemists for many years. This book is an introduction to the chemistry of fungal metabolites. The aim is to illustrate, within the context of fungal metabolites, the historical progression from chemical to spectroscopic methods of structure elucidation, the development in biosynthetic studies from establishing sequences and mechanisms to chemical enzymology and genetics and the increasing understanding of the biological roles of natural products. Fungi occupy an important place in the natural world. As non-photosynthetic organisms they obtain their nutrients from the degradation of organic material. They use many of their secondary metabolites to secure a place in a competitive natural environment and to protect themselves from predation. Fungi are ubiquitous and their activities affect many aspects of our daily lives, whether it be as sources of pharmaceuticals and food or as spoilage or- ganisms and the causes of diseases in plants and man. The chemistry of the fungi involved in these activities has been the subject of considerable study, particularly over the last 50 years. Although their ramifications can be large, as in the spread of plant diseases, the quantities of metabolites that could be isolated precluded much chemical work until the advent of spectroscopic methods. Whereas many natural products derived from plants were isolated before the 1960s on a scale that permitted extensive chemical degradation this was rarely the case for fungal metabolites. However, whenever it was possible, interesting chemistry was discovered. This book begins with an historical introduction followed by a description of the general chemical features that contribute to the growth of fungi. There are many thousands of fungal metabolites whose structures are known and it is not the purpose of the book to list them all. There are databases that fulfil this role. The aim is to describe some of the more important metabolites classified ac- cording to their biosynthetic origin. Biosynthesis provides a unifying feature underlying the diverse structures of fungal metabolites. Therefore, the next chapters begin with a general outline of the relevant biosynthetic pathway The Chemistry of Fungi By James R. Hanson r James R. Hanson, 2008 v vi Preface before presenting a detailed description of particular metabolites. Investi- gations into these biosyntheses have utilized many subtle isotopic labelling experiments. Compounds that are fungal pigments and those that are dis- tinctive metabolites of the more conspicuous Basidiomycetes are treated sep- arately. Many fungal metabolites are involved in the interactions of fungi with plants and others are toxic to man. Some of these are described in the sub- sequent chapters. Fungi can transform chemicals in ways that can complement conventional reactions. The use of fungi as reagents forms the subject of the final chapter. This book owes a great deal to Brian Turner’s Fungal Metabolites, volumes which cover the literature to 1982, although I have attempted to present more of the chemistry and biological activity than was described in those volumes. A great deal has been discovered since they were published. Reviews on various aspects of microbiological chemistry that have appeared in Natural Product Reports and elsewhere are cited in the bibliography. Finally, I wish to thank Dr Brian Cross and Dr John Grove who first introduced me to microbiological chemistry at The Frythe, Professor Tom Simpson FRS who read the manuscript and Dr Merlin Fox of the Royal Society of Chemistry for his help in the production of the book. James R. Hanson University of Sussex Contents Chapter 1 Fungi and the Development of Microbiological Chemistry 1.1 Introduction 1 1.2 Structure of Fungi 2 1.3 Classification of Fungi 4 1.4 The Fungal Cell Wall 5 1.5 History of Fungal Metabolites 6 1.5.1 Fungal Metabolites in the Nineteenth Century 7 1.5.2 Fungal Metabolites 1900–1940 8 1.5.3 Fungi in the Antibiotic Era, 1940–1960 10 1.5.4 Study of Fungal Plant Diseases 1940–1965 12 1.5.5 Impact of Spectroscopic Methods on Structure Elucidation 13 1.5.6 Fungal Metabolites 1965–2005 13 1.5.7 History of Biosynthetic Studies with Fungi 15 Chapter 2 The Chemistry of Growing Fungi 2.1 The Culture Medium 18 2.2 Laboratory Fermentation 20 2.3 Isolation of Fungal Metabolites 21 2.4 The Stages in a Fermentation 23 2.5 Utilization of the Constituents of the Medium 25 2.6 Fungi Growing in the Wild 28 2.7 Biosynthetic Experiments 29 Chapter 3 Fungal Metabolites Derived from Amino Acids 3.1 Introduction 32 3.2 Penicillins 33 The Chemistry of Fungi By James R. Hanson r James R. Hanson, 2008 vii viii Contents 3.3 Cephalosporins 36 3.4 Biosynthesis of b-Lactams 37 3.5 Metabolites Containing a Diketopiperazine Ring 39 3.5.1 Mycelianamide 40 3.5.2 Gliotoxin 40 3.6 The Cyclopenin-Viridicatin Group of Metabolites 42 3.7 Tryptophan-derived Metabolites 42 3.8 Glutamic Acid Derivatives 44 3.9 Fungal Peptides 45 Chapter 4 Polyketides from Fungi 4.1 Introduction 47 4.2 Polyketide Biosynthesis 48 4.3 Triketides 50 4.4 Tetraketides 51 4.4.1 6-Methylsalicylic Acid 51 4.4.2 Patulin and Penicillic Acid 52 4.4.3 Gladiolic Acid and its Relatives 55 4.4.4 Tetraketide Tropolones 56 4.4.5 Mycophenolic Acid 57 4.5 Pentaketides 58 4.5.1 Citrinin 58 4.5.2 Terrein 60 4.6 Hepta- and Octaketides 61 4.6.1 Griseofulvin 61 4.6.2 Cladosporin (Asperentin) 64 4.7 Polyketide Lactones 65 4.8 Statins 66 4.9 Cytochalasins 68 4.10 Fatty Acids from Fungi 68 4.11 Polyacetylenes from the Higher Fungi 70 Chapter 5 Terpenoid Fungal Metabolites 5.1 Introduction 73 5.2 Biosynthesis of Fungal Terpenoids 73 5.3 Monoterpenoids 76 5.4 Sesquiterpenoids 76 5.4.1 Cyclonerodiol 77 5.4.2 Helicobasidin 78 5.4.3 Trichothecenes 78 5.4.4 PR-Toxin 81 5.4.5 Botryanes 81 Contents ix 5.4.6 Culmorin and Helminthosporal 84 5.4.7 Sesquiterpenoids of the Basidiomycetes 85 5.5 Diterpenoid Fungal Metabolites 93 5.5.1 Virescenosides 94 5.5.2 Rosanes 94 5.5.3 Gibberellins and Kaurenolides 97 5.5.4 Aphidicolin 101 5.5.5 Pleuromutilin 102 5.5.6 Fusicoccins and Cotylenins 102 5.6 Sesterterpenoids 104 5.7 Fungal Triterpenoids and Steroids 105 5.7.1 Ergosterol 106 5.7.2 Fusidane Steroidal Antibiotics 107 5.7.3 Viridin, Wortmannin and their Relatives 111 5.7.4 Triterpenoids of the Basidiomycetes 113 5.8 Meroterpenoids 116 Chapter 6 Fungal Metabolites Derived from the Citric Acid Cycle 6.1 Introduction 120 6.2 Citric Acid and Related Acids 120 6.3 Fungal Tetronic Acids 122 6.4 Canadensolide and Avenaciolide 123 6.5 Nonadrides 124 6.6 Squalestatins 126 Chapter 7 Pigments and Odours of Fungi 7.1 Introduction 127 7.2 Polyketide Fungal Pigments 128 7.2.1 Fumigatin 128 7.2.2 Auroglaucin and Flavoglaucin 129 7.2.3 Hydroxyanthraquinone Pigments 129 7.2.4 Xanthone and Naphthopyrone Pigments 130 7.2.5 Extended and Dimeric Quinones 131 7.3 Fungal Pigments Derived from the Shikimate Pathway 132 7.3.1 Terphenyls 132 7.3.2 Pulvinic Acids 133 7.4 Some Pigments Containing Nitrogen 135 7.5 Terpenoid Pigments 138 7.5.1 Fungal Carotenoids 138 7.6 Lichen Substances 140 7.7 Odours of Fungi 142 7.7.1 Organoleptic Components of Mushrooms 142 7.7.2 Volatile Fungal Metabolites Containing Sulfur 144 x Contents Chapter 8 The Chemistry of Some Fungal Diseases of Plants 8.1 Introduction 147 8.2 General Chemistry of Plant–Fungal Interactions 148 8.3 Chemistry of some Leaf-spot Diseases 149 8.3.1 Botrytis cinerea 149 8.3.2 Alternaria Leaf-spot Diseases 151 8.3.3 Cercospora Leaf-spot Diseases 153 8.3.4 Diseases Caused by Colletotrichum Species 154 8.4 Fungal Diseases of the Gramineae 155 8.5 Root-infecting Fungi 157 8.6 Some Fungal Diseases of Trees 159 8.6.1 Dutch Elm Disease 159 8.6.2 Eutypa Dieback 160 8.6.3 Armillaria mellea 161 8.6.4 Phytophthora cinnamomi 162 8.6.5 Silver-leaf Disease 162 8.6.6 Nectria galligena Canker 162 8.6.7 Canker Diseases of Cypress 163 8.7 Trichoderma Species as Anti-fungal Agents 163 8.8 Fungal Diseases of Plants and Global Warming 164 Chapter 9 Mycotoxins 9.1 Introduction 165 9.2 Ergotism 165 9.3 Trichothecenes as Mycotoxins 166 9.4 Other Fusarium Toxins 168 9.5 Aflatoxins 169 9.6 Mycotoxins of Penicillium Species 171 9.7 Poisonous Mushrooms 173 Chapter 10 Fungi as Reagents 10.1 Introduction 177 10.2 Xenobiotic Transformations 177 10.2.1 Microbial Hydrolysis 178 10.2.2 Microbial Redox Reactions 179 10.2.3 Microbiological Hydroxylation 180 10.3 Biosynthetically-patterned Biotransformations 183 Contents xi Epilogue 188 Further Reading and Bibliography 190 Glossary 204 Subject Index 209 CHAPTER 1 Fungi and the Development of Microbiological Chemistry 1.1 Introduction Fungi are widespread, non-photosynthetic microorganisms that play a vital role in the environment, particularly in the biodegradation of organic material.