Natural Terpenoids as Messengers: A multidisciplinary study of their production, biological functions and practical applications

444 Pages·2000·28.157 MB·English

by  Paul Harrewijn, Adriaan M. van Oosten, Paul G. M. Piron (auth.)

Natural Terpenoids as Messengers
The cover represents a pentagram, depicting the relationship between bacteria,
fungi, plants, insects and vertebrates (including humans). This pentagram is used
throughout the book to illustrate messenger functions of terpenoids in the
relationships betweenbiological kingdoms.
Natural Terpenoids as Messengers
A multidisciplinary study of their production,
biological functions and practical applications
by
Paul Harrewijn
Plant Research International,
Wageningen, The Netherlands
Adriaan M. van Oosten
TNO Industrial Technology,
Eindhoven, The Netherlands
and
Paul G.M. Piron
Plant Research International,
Wageningen, The Netherlands
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
Library of Congress Cataloging-in-Publication Data
Harrewijn, P. (paul), 1937-
Natural terpenoids as messengers : a multidisciplinary study oftheir production,
biologica1 functions, and practical applications / by Paul Harrewijn, Adriaan M. van
Oosten, Paul G.M. Piron.
p.cm.
Includes bibliographica1 references and index.
ISBN 978-94-010-3822-5 ISBN 978-94-010-0767-2 (eBook)
DOI 10.1007/978-94-010-0767-2
l. Terpenes--Physiologica1 effect. 2. Second messengers (Biochemistry) 1. Oosten,
Adriaan M. van. II. Piron, Paul G. M. ill. Title.
QP752.T47 H37 2001
572'.5--dc2l
2001023448
ISBN 978-94-010-3822-5
Printed on acid-free paper
AlI Rights Reserved
© 2000 Springer Science+Business Media Dordrecht
OriginalIy published by Kluwer Academic Publishers in 2000
Softcover reprint of the hardcover 1s t edition 2000
No part of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and
retrieval system, without written permis sion from the copyright owner.
Contents
page
Preface ix
1 Introduction 1
2 Productionofterpenesand terpenoids 11
2.1 Biosynthesisofisoprenoids 11
2.1.1 Bacteriaandalgae 12
2.1.2 Fungi 17
2.1.3 Green plants 18
2.1.4 Insects 24
2.1.5 Vertebrates 25
2.1.6 Evolutionofisoprenoid biosynthesis 26
2.2 Productionofterpenoids bydifferentorganisms 30
2.2.1 Monoterpenes 30
2.2.2 Sesquiterpenesandditerpenes 39
2.2.3 Triterpenes, sterols, steroid hormones and 49
carotenoids
2.2.4 Complex terpenoids and isoprenoid structures 54
3 The originandevolutionofterpenoid messengers 59
3.1 Selectionofkeyenzymesinisoprenoid biosynthesis 59
3.1.1 Key enzymes inMAlandMAD routes 60
3.1.2 Thedevelopmentofregulatory mechanisms 69
3.2 Feedbackmechanisms 74
3.2.1 Key enzymeregulation in non-sterologenic cells 74
v
VI Contents
3.2.2 Key enzymeregulation in sterologeniccells 77
3.3 Othertypesoffeedback regulation 81
3.3.1 Internalfactors affectingfeedback mechanisms 81
3.3.2 Externalfactors affectingfeedback mechanisms 83
3.4 Siteofactionofthe regulatory mechanisms 86
3.4.1 Transcriptional and post-transcriptional regulation 86
3.4.2 Oxysterols 91
3.4.3 Non-sterol terpenoids 94
3.5 Interferencewith DNA synthesis: prenylated proteins 96
3.5.1 Themechanismofprenylation 97
3.5.2 PrenylationofRas proteins 102
3.5.3 Inhibitionofproteinprenylation 105
4 Specificpropertiesofterpenoids 109
4.1 Messengersonthecellularlevel 109
4.1.1 Messengers withinacell 110
4.1.2 Messengers withinorganisms 113
4.1.3 Homeostasis ofcellnumbers 129
4.1.4 Effects ofterpenoidsonRas proteins 135
4.1.5 Cancerresearch 141
4.1.6 "Tokillorcure,_...." 153
4.1.7 Terpenoids withdifferenteffects oncancercells 160
4.1.8 Impairmentofmevalonicacid synthesis in tumours 166
4.1.9 Terpenoids with unexpectedeffects 168
4.2 Directtoxiceffects 171
4.2.1 Anti-microbialeffects 171
4.2.2 Toxiceffects oninsects and otheranimals 176
4.2.3 How toovercome autotoxicity 178
5 Functionsofnatural terpenoidsinthe interrelationships 181
betweenorganisms
5.1 Semiochemicals 182
5.1.1 Sexpheromones and other semiochemicals with 183
impacton behaviour
5.1.2 Alarmpheromones anddefensive secretions 191
5.1.3 Repellents anddeterrents: defensive metabolites by 197
plants
5.1.4 Kairomones 216
5.1.5 Synomones 222
Contents vii
5.2 Relationship betweenstructureandfunction 228
5.2.1 Similaritiesbetweenreceptors 228
5.2.2 Therole ofterpenoids intheevolution ofinsect 233
behaviour
5.2.3 Signaltransduction andneurologicaladaptation 243
6 Terpenoidsin practice 253
6.1 Naturalterpenoidsand theirsources 253
6.1.1 Terpenoids in land plants andsimpleisolation 253
procedures
6.1.2 Morecomplex isolationtechniques 264
6.2 Utilizationofterpenoidsin biologyandagriculture 269
6.2.1 Beneficialinsects 270
6.2.2 Insectcontrol 272
6.2.3 Resistance breeding 286
6.2.4 Otherapplications 290
7 Naturalterpenoids to the benefitofhumanhealth 297
7.1 Applications inmedicine 297
7.1.1 Anti-microbials 298
7.1.2 Analgesics 299
7.1.3 Cholesterolemia, vascularproblems, PVD 300
7.1.4 Trachealand bronchialdisorders (COPD) 304
7.1.5 Arthritis, rheumatism, inflammatorydisorders 306
7.1.6 Intestinal disorders 307
7.1.7 Stress-relatedproblems, sedatives 308
7.1.8 Cancertherapies 309
7.2 Cosmetics 329
7.2.1 Sex attractants 329
7.2.2 Dermatologicalpreparations 331
7.3 Terpenoid analoguesandderivatives 333
7.3.1 Applications inagriculture 333
7.3.2 Applications in medicine 335
8 Prospectusand suggestionsfor further research 339
8.1 Searchfor new bioactiveterpenoids 339
8.1.1 Incorporation ofterpenoids intonew methodologies 340
8.1.2 Futureofterpenoids in registrationrequirements 345
8.2 Amultidisciplinaryapproach 348
viii Contents
8.2.1 Bacteria, fungi, plants, insects and humans 348
8.2.2 Terpenoids and model systems 351
Epilogue 357
References 361
General reading 417
Glossary 421
Index 425
Preface
No other group of metabolites shows such diversity, with so many
functions and produced by so many organisms than terpenoids. One cannot
avoid being in contact with these carbon-based compounds. Step into your
car, and you drive on terpenoids: tires are made of rubber and rubber
consists of isoprene units, collected from trees and chemically altered with
sulphur by the industry. Excellent literature on rubber production is
available, and the same holds for many terpenoids which have drawn the
attention ofmankind because oftheir usefulness. Textbooks exist on several
classes of terpenoids, their presence and structure. Detailed studies and
monographs are available on specific terpenoids, e.g. on azadirachtin, a
triterpene produced by the neem tree, Azadirachta indica, which among
otherapplications is used as an insecticide.
Over the years a huge amount of data on terpenoids has been collected
and most ofit is easily accessible, to mention the websites ofthe internet as
an example. So why should we write a book on terpenoids? Those involved
in research on terpenoids inevitably had to specialize and became involved
in a small group of terpenoids in a narrow area of biology or chemistry.
Because natural terpenoids have a role in internal orexternal communication
in all thinkable organisms, a particular terpenoid has been studied by
different groups, unaware of the fact that the same compound has profound
effects in undreamed forms oflife. It happened to ourselves: in the 1980s we
studied semiochemicals ofaphids such as farnesenes, tofind that mevalonate
metabolism of these insects produces an array of terpenoids with unknown
functions in Homoptera. We came into contact with colleagues working in
different disciplines and found that it came as a surprise to many scientists
that the terpenoids they were investigatingin aparticularorganismwere also
present in unrelated organisms, where they appear to have unthought
IX
x Preface
functions. The same terpenoid can have different targets, depending on the
receptor(and the organisms).
To discuss all known natural terpenoids in all disciplines of science and
industry is an impossibletask. Duringourstudies ofinsect-plantrelations we
eventually realized that plants, invertebrates and vertebrates produce the
same isoprenoid structures and that insects could ideally be utilized in a
model system to investigate regulatory functions of terpenoids. Not that the
idea of using the insect as a medium for the study of physiology was new:
No one less than Sir Vincent B. Wigglesworth has stressed that "rich veins
ofgold await the real specialist who cares to utilize the insect as a medium
for the advancement of physiology" in chapter 10 of his collected essays:
Insects and the life of man (1976). Not that the use of terpenoids is new
either: terpenoids have been utilized since ancient times, and old cultures
like in Asiatic countries use essential oils for many purposes, often because
there simply is not a cheap alternative. And alternatives do not always offer
a definite solution. We are not surprised to find that we are coming back to
ways ofthinking, which were general in the first halfofthe 20th century, but
had been abandoned with the development of potent synthetic insecticides,
antibiotics and (at least) the hope for a rapid improvement ofcures for fatal
diseases such ascancer.
As one of us was specialised in mevalonate metabolites, one in insect
plant relations, and one with a medical background became involved in
aphids, we were struck by the role of terpenoids in the interrelationships
between micro-organisms, plants, insects, and vertebrates, in particular
human beings. We began to look at the collected material with other eyes:
when terpenoids are involved, plant defense is often based on a number of
compounds (allomones) aimed at several targets and directed toward
different phases ofthe attack. We became convinced that this principle is of
great value to combat complex pathological disorders in mammals (and
man), such as developing cancers. Combination and multi-stage therapies
(with terpenoids already known to have a function in e.g. plant-insect
relationships) show a great deal of analogy with the strategies utilized by
plants to defend themselves to attackby micro-organisms and herbivores.
When focussing on the relationship between plants, insects and man, as
did the great Wigglesworth, we might be able to explain why so many
functions ofthese compounds were selected early in evolution and why they
are omnipresent in the living world. The present comparative study of
terpenoids is not devoted to mere generalities but outlines the fascinating
ways along which Nature has utilized isoprene units, and how they could
serve to ourown benefit.
We realize that much of the available information cannot be presented
within this compass, but we hope that the book offers a good deal of