PRINCIPLES OF TOXICOLOGY - Biology East Borneo

410 PROPERTIES AND EFFECTS OF NATURAL TOXINS AND VENOMS17.2 MOLECULAR AND FUNCTIONAL DIVERSITY OF NATURAL TOXINS ANDVENOMSEvery 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 mostimportant 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 allowmore bonding contact with the receptors on which they act. Besides this high potency, there is anotherpossible reason that many toxins are peptides or proteins. Biosynthesis of protein toxins does notrequire unusual substrates or catalysts, just a messenger RNA template that specifies the amino acidsequence 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 proteintoxins originated during the course of evolution. However, some snake polypeptide toxins have aminoacid sequences which are very similar to endogenous polypeptides that act as proteolytic enzymeinhibitors, and it is suspected that these toxins evolved from duplicated (extra) genes for these enzymeinhibitors.It is relatively common for chemically similar toxins to be manufactured by creatures that aretaxonomically unrelated. Thus, certain echinoderms (starfish and sea cucumbers) synthesize sterolglycosides, which are chemically and pharmacologically very similar to the saponins found in someplants. Anabaseine, an alkaloid toxin occurring in certain marine worms, is almost the same as thetobacco alkaloid anabasine. This evolutionary convergence at the molecular level is perhaps to beexpected because many toxins are synthesized by enzymes that serve as catalysts for metabolicpathways which are of general occurrence in living organisms. Plants have long been known to producean amazing variety of “secondary” metabolism products containing nitrogen, usually referred to asalkaloids. Many of these metabolites serve as a defense against herbivores. Animals and protozoansalso 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 MouseRelative Number ofMolecules CausingDeath bBotulinum 150,000 0.0003 1Tetanus 150,000 0.001 4Diphtheria 60,000 0.03 3 × 10 2Ricin 60,000 3 3 × 10 4α-Latrotoxin 130,000 10 5 × 10 4Pseudomonas exotoxin A 60,000 5 5 × 10 4β-Bungarotoxin 20,000 14 4 × 10 5Conotoxin M 1,500 5 2 × 10 6Cholera 84,000 250 2 × 10 6Batrachotoxin 538 2 3 × 10 6α-Bungarotoxin 8,500 300 3 × 10 6Tetrodotoxin 319 8 2 × 10 7Saxitoxin 354 9 2 × 10 7Tubocurarine 334 500 1 × 10 9Diisopropylfluorophosphate 184 1,000 4 × 10 9Sodium cyanide 49 10,000 1 × 10 11a MLD, minimum lethal dose.b Relative to botulinum toxin.