Natural Poisons and Venoms Animal Toxins - 1st Edition

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Authors
Prof. Dr. Jan-Peter Hildebrandt
Zoological Institute
Animal Physiology and Biochemistry
University of Greifswald
Loitzer Strasse 26
17489 Greifswald
Germany
[email protected]

Prof. Dr. Eberhard Teuscher

Goethestr. 9
07950 Zeulenroda-Triebes
Germany
[email protected]

Prof. Dr. Ulrike Lindequist

Lise-Meitner-Str. 6a
17491 Greifswald
Germany
[email protected]

ISBN 978-3-11-072854-5
e-ISBN (PDF) 978-3-11-072855-2
e-ISBN (EPUB) 978-3-11-072862-0

Library of Congress Control Number: 2023933035

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© 2023 Walter de Gruyter GmbH, Berlin/Boston

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Preface
Living beings produce pharmacologically active substances to ensure their survival.
In many cases, such substances can harm or kill other living creatures or can trigger
allergies. Thus, some of these compounds may pose danger to human beings as well
as to domestic or wild animals.
Our aim is to acquaint readers, especially physicians, veterinarians, pharmacists,
biologists, chemists, food chemists, biochemists, students of these disciplines, and in-
terested laymen, with poisonous and venomous animals and their complex toxin com-
positions. The other volumes of this book series will focus on toxins produced by
plants, microorganisms, and fungi.
The focus of this volume is on the toxic ingredients of animal poisons and ven-
oms, their chemical structures, their effects and modes of actions in target organisms,
and on the biology of poisonous or venomous animals. We highlight the symptoms of
poisoning or envenoming in humans or animals, cite case reports that are available,
and we try to give hints on poisoning prevention and on potential treatments. How-
ever, the book is not intended as a guide to medical practice. Local physicians should
be contacted in case of poisoning or envenoming!
We try to create an understanding that animal toxins are not primarily threats to
humans and domestic animals, but rather admirable evolutionary adaptations allow-
ing animals to deter potential predators, protect themselves from infectious agents, or
to efficiently obtain prey for their own survival.
This book series is based on the book Biogene Gifte, third edition, published in
2010 by Wissenschaftliche Verlagsgesellschaft Stuttgart in German language. Because
of the enormous increase in knowledge in the field of natural poisons and venoms, to
reach a larger readership, and to fit into the STEM series of the De Gruyter publishing
house, the topic is now covered in five volumes in English language.
After a fundamental chapter on toxins (history, chemistry, biology, first aid, and
general and clinical toxicology) Volumes 1 to 3 are devoted to poisonous plants and
their active substances. Volume 4 summarizes the current knowledge about poisonous
and venomous animals. Volume 5 deals with poisonous mushrooms and microalgae
and their ingredients and selected microbial toxins. The volumes will appear in cer-
tain intervals, so that the highest possible timeliness of the content of each volume is
guaranteed.
Despite the extensive bibliographies at the end of each chapter, the cited litera-
ture represents only a selection. We excuse ourselves for any important papers that
we may have missed during our literature searches. For reasons of space, the citation
format is as short as possible.
We would like to thank everyone who helped us with the preparations of the
books. We would especially like to thank Dipl.-Phys. Karl-Heinz Lichtnow, Greifswald
(Germany), for drawing the chemical structures of venom and poison components and
his great help with computer problems of any kind. Thanks go also to Elvira Lutjanov

https://doi.org/10.1515/9783110728552-202
VI Preface

for her help with the literature search. We would like to thank all image authors and
Getty images for the provision of photos. Our thanks go to De Gruyter publishing house,
especially to Mrs. Karin Sora, for making these books possible, and to Dr. Bettina Noto
for her always pleasant and helpful cooperation in the completion of the volumes and
her careful editing work. We thank Mr. David Jüngst (Integra Software Services) for
smoothly managing the production process of this book.
We are grateful for critical comments, reporting of errors, and suggestions for
improvements!
Greifswald and Triebes, February 2023
Jan-Peter Hildebrandt, Eberhard Teuscher, Ulrike Lindequist
Contents
Preface V

Abbreviations and Icons XI

1 Introduction to Animal Toxins 1

1.1 What Are Toxins? 1
1.2 Organisms as Sources for Toxic Compounds 2
1.3 Structure and Function of Animal Toxins 5
1.4 Evolutionary Origins of Animal Toxins 7
1.5 Toxicokinetics of Animal Toxins 10
1.6 Toxicodynamics of Animal Toxins 13
1.7 Animal Toxins and Human Health 15
1.8 Therapeutic Approaches upon Intoxication in Humans 17

2 Chemistry, Pharmacology, and Toxicology of Animal Toxins 19

2.1 Aliphatic Acids 19
2.2 Polyynes 21
2.2.1 General 21
2.2.2 Polyynes of Sponges (Porifera) 22
2.3 Polyketides 23
2.3.1 General 23
2.3.2 Acanthifolicin 26
2.3.3 Aplysiatoxin 27
2.3.4 Brevetoxins 27
2.3.5 Bryostatins 28
2.3.6 Halichondrins 28
2.3.7 Palytoxin 28
2.3.8 Pederin 30
2.3.9 Okadaic Acid 30
2.3.10 Maitotoxin 30
2.4 Terpenes 33
2.4.1 General 33
2.4.2 Monoterpenes 34
2.4.3 Cantharidin 37
2.4.4 Sesquiterpenes 38
2.4.5 Diterpenes 41
2.4.6 Sesterterpenes 44
2.4.7 Triterpenes 44
2.5 Steroids 48
2.5.1 General 48
VIII Contents

2.5.2 Steroids as Defensive Molecules in Animals 49

2.6 Saponin-Like Triterpenes and Steroid Derivatives 56
2.6.1 General 56
2.6.2 Saponin-Like Steroid Derivatives of Sponges (Porifera) 59
2.6.3 Saponin-Like Steroid Derivatives of Corals (Anthozoa) and Beetles
(Coleoptera) 60
2.6.4 Saponin-Like Steroid Derivatives of Echinoderms (Echinodermata) 61
2.6.5 Saponin-Like Steroid Derivatives of Cartilaginous Fish
(Chondrichthyes) and Bony Fish (Osteichthyes) 66
2.7 Phenylpropanoids 70
2.7.1 General 70
2.7.2 Phenylpropanoids in Arthropod Defense Secretions 70
2.8 Amines 73
2.8.1 Tetramethylammonium 73
2.8.2 Acetylcholine 75
2.8.3 Other Choline Esters 75
2.8.4 Nereistoxin 76
2.8.5 Phenylalkylamines 76
2.8.6 Indole and Imidazole Alkylamines 78
2.9 Alkaloids 81
2.9.1 General 81
2.9.2 Imidazole Alkaloids 85
2.9.3 Zoanthamine Alkaloids 87
2.9.4 Pyrrolizidine Alkaloids 87
2.9.5 Pyridoacridine Alkaloids 89
2.9.6 Piperidine Alkaloids 89
2.9.7 Quinazoline Alkaloids 90
2.9.8 Pyridine Alkaloids 91
2.9.9 Pyrimidine Alkaloids 94
2.9.10 Quinoline Alkaloids 94
2.9.11 Quinolizidine Alkaloids 96
2.9.12 Isoquinoline Alkaloids 97
2.9.13 Indole Alkaloids 98
2.9.14 Purine Alkaloids 100
2.9.15 Terpene Alkaloids 102
2.9.16 Steroid Alkaloids 103
2.9.17 Polyamine Alkaloids 106
2.9.18 Azaphenalene Alkaloids 106
2.10 Cyanogenic Compounds 114
2.11 Glucosinolates 117
2.12 Proteins and Peptides 120
2.12.1 General 120
 Contents IX

2.12.2 Enzymes 124

2.12.2.1 Proteases 125
2.12.2.2 Phospholipases 127
2.12.2.3 Hyaluronidases 128
2.12.2.4 Deoxyribonucleases, Ribonucleases, and Nucleosidases 129
2.12.2.5 Esterases and Apyrases 129
2.12.2.6 Amino Acid Oxidases 130
2.12.3 Cytotoxins 130
2.12.4 Neurotoxins 131
2.12.5 Myotoxins 133
2.12.6 Cardiotoxins 134
2.12.7 Hemotoxins 135
2.12.8 Allergens 138
2.12.9 Lectins 139
2.12.10 Antimicrobial Peptides and Proteins 140

3 Venomous and Poisonous Animals 147

3.1 Synergism of Venom Components 147
3.2 Animals Producing Poisons or Venoms and Modes of Their
Actions 147
3.2.1 Sponges (Porifera) 147
3.2.2 Cnidaria 155
3.2.2.1 Anthozoa 155
3.2.2.2 Cubozoa and Scyphozoa 159
3.2.2.3 Hydrozoa 164
3.2.3 Mollusca 170
3.2.3.1 Snails and Slugs (Gastropoda) 170
3.2.3.2 Bivalvia 173
3.2.3.3 Cephalopoda 174
3.2.4 Echinodermata 177
3.2.4.1 Sea Urchins (Echinoidea) 177
3.2.4.2 Sea Stars (Asteroidea) 180
3.2.4.3 Sea Cucumbers (Holothuroidea) 181
3.2.5 Worms 182
3.2.5.1 Flat Worms (Plathelminthes) 182
3.2.5.2 Ribbon Worms (Nemertea) 183
3.2.5.3 Ringed Worms (Annelida) 184
3.2.6 Tunicata 191
3.2.7 Arachnida 192
3.2.7.1 Spiders (Araneae) 193
3.2.7.2 Scorpions (Scorpiones) 201
3.2.7.3 Mites (Acari) 208
X Contents

3.2.8 Myriapoda 213

3.2.8.1 Diplopoda 213
3.2.8.2 Chilopoda 214
3.2.9 Insects (Hexapoda) 217
3.2.9.1 Insects with Stinging or Biting Mouthparts 217
3.2.9.2 Hymenoptera 224
3.2.9.3 Beetles (Coleoptera) 235
3.2.9.4 Stick Insects (Phasmatodea) 242
3.2.9.5 Caterpillars of Butterflies (Lepidoptera) 242
3.2.10 Crustacea 250
3.2.11 Fishes (Pisces) 252
3.2.12 Amphibia 263
3.2.12.1 Frogs and Toads (Anura) 264
3.2.12.2 Salamanders (Urodela) 269
3.2.12.3 Caecilians (Apoda) 271
3.2.13 Reptiles and Birds (Sauropsida) 272
3.2.13.1 Lizards (Squamata) 272
3.2.13.2 Snakes (Serpentes) 275
3.2.13.3 Birds (Aves) 303
3.2.14 Mammals (Mammalia) 308

Poison Information Centers 315

Index 317
Abbreviations and Icons
AA arachidonic acid
ACh acetylcholine
AChE acetylcholine esterase
ADP adenosine diphosphate
AMP antimicrobial peptide
ARF acute renal failure
ATP adenosine triphosphate
BTX bungarotoxin
BW body weight
CNS central nervous system
CoA coenzyme A
CYP cytochrome P
DSP diarrhetic shellfish poisoning
DW dry weight
EDTA ethylenediaminetetraacetic acid
ER endoplasmic reticulum
3FTx three-finger toxin
FW fresh weight
HA hyaluronic acid
HCN hydrogen cyanide
i.m. intramuscular
i.p. intraperitoneal
i.v. intravenous
LD lethal dose
mAChR muscarinic acetylcholine receptor
mRNA messenger ribonucleic acid
nAChR nicotinic acetylcholine receptor
NADP+ nicotinamide adenine dinucleotide phosphate (oxidized form)
NADPH + H+ nicotinamide adenine dinucleotide phosphate (reduced form)
NO nitric oxide
NSP nitrile-specifier protein
OA okadaic acid
PFT pore-forming toxin
PLA phospholipase A
PNS peripheral nervous system
p.o. per os, oral uptake
PSP paralytic shellfish poisoning
ROS reactive oxygen species
s.c. subcutaneous
TRP channel transient receptor potential cation channel
TTX tetrodotoxin
WHO World Health Organization

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XII Abbreviations and Icons

Symptoms and consequences of human exposure to animal toxins

First aid and potential treatment
Case description
Allergy
Effects of animal toxins on other animals
1 Introduction to Animal Toxins

1.1 What Are Toxins?

Toxins are molecules which are synthesized by living organisms and used to parasit-
ize or to predate on other creatures or to avoid being attacked by predators or para-
sites. Poisonous animals make use of one or several toxic compounds that they
secrete onto the body surface (skin, feathers, fur) or accumulate internally in body
tissues to repel, to harm or to kill predators or to avoid being colonized by microor-
ganisms. In some cases, parent animals provide protection to their young by impreg-
nating eggs or newborns with poisonous substances.
Venoms are generally mixtures of several substances produced in specialized
glands and applied to target organisms by special applicators like stings or fangs.
They may be used by animals as means to efficiently obtain prey or as chemical weap-
ons for defense against attackers. In predatory animals, venoms are used to immedi-
ately immobilize or kill prey which requires that they cause rapid onsets of their
paralyzing effects. Thus, venoms used by predators mostly target neuronal or muscle
cell systems with the aim of interrupting signal transmission from motor neurons to
muscle cells and impairing voluntary motor functions in the target organism.
The scientific field studying the generation, the application, the molecular interac-
tions with endogenous targets, the metabolism and excretion or elimination of natu-
ral poisons, venoms or related molecules is called ‘toxinology’. It is a subdiscipline of
‘toxicology’.
The extent to which toxins harm their target organisms depend on
– the kind of toxin,
– the amount of toxin,
– the pathway of application to or introduction into the target organism, e.g.,
– topical – superficial application to parts of the body surface
– per os or peroral (p.o.) – through the mouth
– intraperitoneal (i.p.) – injection through the peritoneum into the body cavity
– intramuscular (i.m.) – injection into the body wall muscle
– intravenous (i.v.) – injection into the blood stream
– subcutaneous (s.c.) – injection under the skin into the subcutis
– whether the toxin is acutely or chronically applied,
– the sensitivity of the target organism against the toxin,
– the metabolism of the toxin within the target organism, or
– the rate of elimination of the toxin from the target organism.

This illustrates that the toxin character of a given substance is relative and depends
on many variables. This has been recognized very early in history, e.g., by Famoso
Doctor Paracelsus (Philippus Theophrastus Aureolus Bombastus von Hohenheim,

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2 1 Introduction to Animal Toxins

1493–1541) who is famous for his proverbial phrase: ‘Alle Ding’ sind Gift und nichts
ohn’ Gift; allein die Dosis macht, das ein Ding’ kein Gift ist’ (everything is a poison and
nothing is no poison; just the dose is relevant for its toxicity).
Also, the administration route may be relevant whether a substance acts as a
toxin or not: A protein toxin that may be highly toxic when injected into an animal
may be completely harmless if ingested because it is denatured by the acidic environ-
ment in the stomach and readily digested by proteases in the intestines.
The scientific discipline dealing with questions on the uptake rates, metabolism,
and elimination of toxins in or from target organisms is called ‘toxicokinetics’. The
mechanism of action of a toxin within a target organism is studied in ‘toxicodynam-
ics’. The term ‘toxicography’ describes studies of complex effects of toxins on target
organisms and the reasoning about potential antidotes or therapies.
In this book, we focus on biogenic substances used by animals which are directed
against other animals or humans. However, antimicrobial compounds that are gener-
ated and used by animals to combat potential pathogenic microorganisms will also be
considered.

1.2 Organisms as Sources for Toxic Compounds

Animals that are able to produce their own toxins display ‘primary toxicity’. ‘Secondary
toxicity’, however, is a feature of animals which are not able to originally generate their
own toxins but acquire their toxins or at least precursors of such toxins from food organ-
isms or from commensal or symbiontic microorganisms. Evolutionary adaptations in ani-
mal species with secondary toxicity to tolerate their own toxins in the body are common.
An interesting example is the impregnation of tissues of inner organs in Indo-Pacific
puffer fish (Tetraodontidae) of the genus Takifugu with tetrodotoxin (see Section 2.9.7), a
toxin that is originally produced by bacteria (Aeromonas, Vibrio) [10, 13]. Tetrodotoxin is
a highly effective blocker of voltage-gated sodium channels in animals and inhibits the
generation of action potentials in neurons and skeletal muscle cells resulting in paralysis.
Mutations in one of the subunits of the voltage-gated sodium channel in Takifugu which
resulted in the exchange of just a few amino acids in this protein rendered the channel
tetrodotoxin-resistant in these fishes [14]. Another example of evolutionary development
of resistance against specific alkaloid toxins of food organisms are the poison frogs of
Central and South America (see Section 3.2.12). In these animals, mutations in the NaV1.4
voltage-gated sodium channel that are conserved among the different species of frogs in
the genus Dendrobates are associated with alkaloid toxin resistance [18]. Being resistant
against these toxins but making the own body toxic for other organisms protects these
animals from becoming victims of predators. Caterpillars of the monarch butterfly (Da-
naus plexippus) (see Section 3.2.9) tolerate high concentrations of cardenolides in their
bodies because the α-subunit of the Na+/K+-ATPase carries a mutation (N122H, asparagine
to histidine at amino acid position 122) which renders the enzyme insensitive to such
 1.2 Organisms as Sources for Toxic Compounds 3

steroid glycosides which, in turn, harm other organisms trying to feed on these caterpil-
lars or the adult butterflies [7, 9].
Some animals store their toxins in specialized gland reservoirs and mobilize these
compounds only to the external space. This is the case in many snakes where the toxins
are contained in specialized salivary glands in the upper jaws [3, 8] and released
through ducts connected to teeth that work as injection needles. Honeybees, e.g., Apis
mellifera, carry their toxins in venom glands and associated storage compartments
while all other tissues of such animals are entirely free of any toxic material. Such a
separation of toxin compartments from other tissues in the body (sequestration) avoids
being poisoned by the own toxins.
Differences in toxin profiles between individuals of the same species are common
features in animals [17]. Temporal or regional differences in toxin content of animals
have been observed in primarily as well as in secondarily toxic animals. Toxin pro-
files may also change during ontogenic development so that juveniles may express
toxin compositions that differ in quality or quantity from those expressed in adults
[12]. Venoms of honeybee workers vary between summer and winter and are differ-
ent from that of queens [1]. Juveniles of rattlesnakes (see Section 3.2.13) may express
different compositions of toxins than adult animals from the same geographical re-
gion. On the other hand, adult rattle snakes from different locations may produce ven-
oms with different toxin compositions [6]. Similar findings have been made for the
venom compositions of regional populations of the monocled cobra, Naja kaouthia
[15]. Some of these differences are based on genetic differences (local adaptation) be-
tween subpopulations [5]. The marine box jellyfishes from Northern Australia (Chiro-
nex fleckeri) (see Section 3.2.2) show geographical differences in venom composition
as well but it remains unclear whether these differences are due to genetic or envi-
ronmental factors [16].
Especially secondarily toxic animals differ in their toxin composition depending
on environmental factors. In some cases, the differences result from interaction of in-
dividuals with different types of toxin-producing microorganisms; in other cases,
toxin profiles depend on the choice of food organisms. Secondary toxicity may fade
away if animals are reared without access to toxin-producing microorganisms. This is
the case with crust anemones (Palythoa sp., Cnidaria) in the Pacific Ocean which
carry the highly toxic palytoxin (see Section 2.3.7) only when toxin-producing dinofla-
gellates, Ostreopsis sp., are present in the surrounding water [2].
The tissue distribution of toxins in animals that impregnate their tissues with
toxic compounds to deter predators is more generalized. Certain tissues in such ani-
mals, however, may contain higher toxin concentrations than others as in the case of
the Takifugu-puffer fish whose skin and inner organs may be highly toxic while skele-
tal muscle tissue contains only low amounts of tetrodotoxin [10]. In fact, thin slices of
puffer fish muscle tissue (fugu) are considered a delicacy by traditional Japanese
gourmets (see Section 3.2.11).
4 1 Introduction to Animal Toxins

Generally, we differentiate actively toxic animals or ‘venomous animals’ from

passively toxic animals which are also called ‘poisonous animals’. Venomous animals
produce highly effective toxins in specialized glands that generally comprise secretory
cells and storage compartments. The entire complement or portions of the stored
venom may be conditionally applied to other organisms using specialized tools like
stings or biting mouthparts. This may occur in attempts to apply disabling or deadly
venom to prey or to defend oneself against an attack by a predator. Examples of ven-
omous animals are spiders and snakes. Poisonous animals, however, use their toxic
compounds to impregnate the external body surface or tissues of the integument or
of internal organs and become toxic as a whole. This may help to deter potential pred-
ators from preying on such animals because the poisonous tissue has bad taste or
smell, may exert inflammatory effects on the predator’s mucous membranes, or may
harm the internal organs of a predator after consuming tissue of a poisonous animal
[4]. Examples of poisonous animals are the above-mentioned puffer fish Takifugu or
the slow loris of the genus Nycticebus (see Section 3.2.14) who impregnate their fur
with toxic salivary compounds.
Some researchers add to these two a third category of animal toxins, the so-called
‘toxungens’ [11]. These are animal-borne toxic substances which are delivered to the
body surface of a target organism without creating a wound. This is illustrated by the
defensive action of a spitting cobra (Naja sp.) which can project venom from its fangs to
a target that is up to 2 m away. The venom stream is directed toward the eyes of an
attacker (Photo 1.1). When hit, the venom is absorbed by the moist surfaces around the
eyes of the target animal and may readily unfold its cytotoxic or neurotoxic actions.

Ph. 1.1: Naja pallida spitting venom from its fangs toward an attacker (Source: Guido Westhoff 2007, with
permission).
 1.3 Structure and Function of Animal Toxins 5

References

[1] Danneels EL et al. (2015) Toxins 7(11): 4468

[2] Deeds JR et al. (2011) PLoS ONE 6(4): e18235
[3] Fry BG et al. (2003) Rapid Commun Mass Spectrom 17(18): 2047
[4] Garson MJ (2010) Marine natural products as antifeedants. In: Liu H-W, Mander L (eds.)
Comprehensive Natural Products II. Elsevier, Oxford, p. 503
[5] Gren ECK et al. (2017) Geographic variation of venom composition and neurotoxicity in the
rattlesnakes Crotalus oreganus and C. helleri: Assessing the potential roles of selection and neutral
evolutionary processes in shaping venom variation. In: Dreslik MJ, Hayes WK, Beaupre SJ, Mackessy
SP (eds.) The Biology of Rattlesnakes II. ECO Herpetological Publishing and Distribution, Rodeo,
New Mexico, p. 228
[6] Holding ML et al. (2021) Proc Natl Acad Sci U S A 118(17): e2015579118
[7] Holzinger F et al. (1992) FEBS Lett 314(3): 477
[8] Kardong KV (2002) J Toxicol: Toxin Rev 21(1–2): 1
[9] Mebs D et al. (2000) Chemoecology 10(4): 201
[10] Melnikova DI, Magarlamov TY (2022) Toxins 14(8): 576
[11] Nelsen DR et al. (2014) Biol Rev 89(2): 450
[12] Schonour RB et al. (2020) Toxins 12(10): 659
[13] Simidu U et al. (1987) Appl Environ Microbiol 53(7): 1714
[14] Soong TW, Venkatesh B (2006) Trends Genet 22(11): 621
[15] Tan KY et al. (2017) PeerJ 5: e3142
[16] Winter KL et al. (2010) Toxicol Lett 192(3): 419
[17] Yu C et al. (2020) Int J Biol Macromol 165(Pt B): 2994
[18] Yuan ML, Wang IJ (2018) PLoS ONE 13(3): e0194265

1.3 Structure and Function of Animal Toxins

Proteins and peptides are constituents of most animal poisons or venoms and may
function as cytotoxins, as blockers of ion channels, as inhibitors of transmitter recep-
tors, as enzymes, or as enzyme inhibitors. These compounds need to be injected into
target organisms because oral application would result in loss of function due to pro-
tein denaturation (loss of tertiary and quaternary structure) and enzymatic digestion
of the toxic molecules in the gastrointestinal tract of the target organism.
Proteins are macromolecules composed of one or more chains of amino acid
residues bound to each other by the peptide bond (Fig. 1.1). Small proteins up to 100
amino acid residues are called ‘peptides’, longer ones or those composed of several
amino acid strands are called ‘proteins’ in the narrow sense. There are generally 20
different amino acids that are used by organisms to build proteins. The amino acid
sequence within a given protein is dictated by the nucleotide sequence of the respec-
tive gene. The chemical nature of the amino acid side chains at specific locations in
the protein determines the way of local protein folding into specific 3D structures
called ‘protein domains’. The combination of specific domains in the overall struc-
ture determines protein function. An example is the highly specific interaction of a
6 1 Introduction to Animal Toxins

HO H
O O H N+ P
OHH
P C N P P C N P H
O
H H

Fig. 1.1: The peptide bond (left) between two consecutive amino acids in a protein. Cleavage of the
peptide bond (middle) via hydrolysis (red) is mediated by ‘proteinases’ (or shorter ‘proteases’) yielding
two independent peptide strands (P) of which one has a new C-terminus (C) and the other a new N-
terminus (N).

scorpion peptide, charybdotoxin (see Section 3.2.7), with homotetrameric, voltage-

gated potassium channels in plasma membranes of neurons in the central nervous
system. The toxin blocks this channel and elongates action potentials resulting in
neuronal overexcitation in the brain [3–5].
Most animal toxins, however, are secondary metabolites generated via diverse
metabolic pathways. Just to mention a few examples, formic acid is used by ants to
deter attackers or to hinder microbes from overgrowing the ant brood. Amino com-
pounds are used for the same purpose by cnidarians, molluscs, and echinoderms.
Polyethers may be present in mussels or in corals. This class of molecules encom-
passes some of the most toxic substances in nature. Badly smelling molecules like
mercaptans and sulfides are used by ants and martens to deter predators. Macrocy-
clic ketones are constituents of coral toxins. Benzoic acid, benzoquinones, and cya-
nides are used by beetles and diplopods to defend themselves against attackers.
Terpenes are used for the same purpose by mites, bees, ants, butterflies and beetles,
and N-heterocyclic compounds by fire ants or spiders. Plant-borne polycyclic hydro-
carbons, especially steroids, are used by toads or salamanders or alkaloids like coc-
cinellin by ladybirds to avert predators. Bacterial toxins as tetrodotoxin (TTX) in
puffer fish or batrachotoxin (BTX) in frogs [2] and birds [1] render these animals
inedible for carnivores.

References

[1] Bartram S, Boland W (2001) Chem Bio Chem 2(11): 809

[2] Daly JW et al. (2005) J Nat Prod 68(10): 1556
[3] Miller C (1995) Neuron 15(1): 5
[4] Novoseletsky VN et al. (2016) Acta Naturae 8(2): 35
[5] Thompson J, Begenisich T (2000) Biophys J 78(5): 2382
 1.4 Evolutionary Origins of Animal Toxins 7

1.4 Evolutionary Origins of Animal Toxins

Although the toxin character of proteins, peptides, or secondary metabolites produced

by animals is well known in many cases, researchers often do not know the exact mech-
anisms of action of these substances in potential target organisms. This is mostly due to
the fact that the functional domains of such molecules that actually make a molecule a
toxin are hidden among a lot of other chemical groups within the respective molecule
that do not have any significance in this context. This is a consequence of biological
evolution that does not evolve specific toxins in a targeted manner but, instead, gener-
ates genetic diversity by accumulation of mutations in the DNA which result in the pro-
duction of variants of already existing molecules that originally may have served
entirely other functions than being toxins [3]. Processes like gene duplication [15], ge-
netic recombination like exon shuffling [14], and diversification may contribute to such
diversity within a given organism [4]. These processes may accidentally result in some
molecules that turn out to have toxic properties against certain target organisms. Only
in cases in which the interaction of a toxic animal and such a target organism is biologi-
cally relevant and gives a selective advantage to the toxin producer, the pathway of
toxin synthesis and all additional traits necessary for the toxin producer to deal with
this compound will be stabilized and inherited through subsequent generations. Other-
wise, the trait will be lost over several generations because it does not provide the car-
riers of this trait with a selective advantage, i.e., production of more offspring per
generation in trait carriers compared with the noncarriers.
Evolutionary genesis of a toxic compound may occur directly (by mutation of
genes that code for the toxic proteins or peptides) or indirectly (by mutations in the
genes of enzymes involved in generation of intermediate or secondary metabolic
products with toxin properties) [7]. This evolutionary process is illustrated by the fact
that many snake venoms contain protein toxins that are structural homologs of phos-
pholipase A2 [2], an enzyme that is important in all animal cells as a component of an
essential signal transduction pathway. The toxic character of the secreted neurotoxic
phospholipase A2 in animal venoms is related to its enzymatic activity [13] but lies at
least to the same degree in its ability of leaving the producing cell which was not an
original feature of the signal transduction molecule or bind to target molecules that
were not the original ones of the signal transduction molecule [11]. This example
shows that the toxin character of a given protein molecule may not only evolve by
changing its primary sequence but may be related to evolutionary changes in other
molecules that result in previously impossible molecular interactions, changes in cel-
lular trafficking or alterations in localization of a given molecule. This way, a harm-
less molecule may become a toxin without any changes in the molecule itself.
When this rationale of generating molecular diversity and selection of the most suit-
able variants would strictly apply to all animal toxins, we would expect that each individ-
ual of a given animal species expresses just one highly efficient toxin that optimally
fulfills a specific function in the respective target organism. However, nature is not that