PRINCIPLES OF TOXICOLOGY

410 PROPERTIES AND EFFECTS OF NATURAL TOXINS AND VENOMS
17.2 MOLECULAR AND FUNCTIONAL DIVERSITY OF NATURAL TOXINS AND
VENOMS
Every major class of molecules synthesized by living organisms—protein, lipid, carbohydrate,
nucleoside, alkaloid—has been exploited by some species to produce a toxin. Some of the most
important natural toxins that will be discussed in this chapter are listed in Table 17.1.
The most potent toxins are usually proteins, probably because their larger molecular surfaces allow
more bonding contact with the receptors on which they act. Besides this high potency, there is another
possible reason that many toxins are peptides or proteins. Biosynthesis of protein toxins does not
require unusual substrates or catalysts, just a messenger RNA template that specifies the amino acid
sequence of the toxin; the rest of the required biosynthetic machinery (ribosomes, messenger RNA,
transfer RNA, nucleotides, RNA polymerase, etc.) is already present. It is not yet clear how the protein
toxins originated during the course of evolution. However, some snake polypeptide toxins have amino
acid sequences which are very similar to endogenous polypeptides that act as proteolytic enzyme
inhibitors, and it is suspected that these toxins evolved from duplicated (extra) genes for these enzyme
inhibitors.
It is relatively common for chemically similar toxins to be manufactured by creatures that are
taxonomically unrelated. Thus, certain echinoderms (starfish and sea cucumbers) synthesize sterol
glycosides, which are chemically and pharmacologically very similar to the saponins found in some
plants. Anabaseine, an alkaloid toxin occurring in certain marine worms, is almost the same as the
tobacco alkaloid anabasine. This evolutionary convergence at the molecular level is perhaps to be
expected because many toxins are synthesized by enzymes that serve as catalysts for metabolic
pathways which are of general occurrence in living organisms. Plants have long been known to produce
an amazing variety of “secondary” metabolism products containing nitrogen, usually referred to as
alkaloids. Many of these metabolites serve as a defense against herbivores. Animals and protozoans
also produce such compounds, and some of these will be discussed below.
TABLE 17.1 Mouse Lethality of Skeletal Natural Toxins (modified from Middlebrook, 1989)
Toxin Molecular Weight MLD a µg/kg Mouse
Relative Number of
Molecules Causing
Death b
Botulinum 150,000 0.0003 1
Tetanus 150,000 0.001 4
Diphtheria 60,000 0.03 3 × 10 2
Ricin 60,000 3 3 × 10 4
α-Latrotoxin 130,000 10 5 × 10 4
Pseudomonas exotoxin A 60,000 5 5 × 10 4
β-Bungarotoxin 20,000 14 4 × 10 5
Conotoxin M 1,500 5 2 × 10 6
Cholera 84,000 250 2 × 10 6
Batrachotoxin 538 2 3 × 10 6
α-Bungarotoxin 8,500 300 3 × 10 6
Tetrodotoxin 319 8 2 × 10 7
Saxitoxin 354 9 2 × 10 7
Tubocurarine 334 500 1 × 10 9
Diisopropylfluorophosphate 184 1,000 4 × 10 9
Sodium cyanide 49 10,000 1 × 10 11
a MLD, minimum lethal dose.
b Relative to botulinum toxin.