Pharmacognosy with the Basics of Plant Biochemistry - Kovalyov V. M. 2004

Special Part
Peptides and Proteins
Peptide and Protein Toxins

Toxins (from Greek toxikon — poison) are substances that disrupt biochemical processes, leading to symptoms of intoxication and, in severe cases, the death of the Organism.

Toxins can be of polypeptide, protein, or non-protein nature. By origin, they are divided into three groups: microbial toxins, plant toxins (phytotoxins), and animal toxins (zootoxins).

Bacterial toxins are classified into exotoxins and endotoxins. The former, such as the toxins causing botulism, diphtheria, and tetanus, are simple Proteins secreted into the environment by Bacteria during their growth. This group includes toxins produced by gram-positive microflora. Endotoxins are complex proteins located in the outer layers of The Cell wall of pathogenic gram-negative bacteria. These toxins are released after the bacteria die. Bacterial toxins exhibit the highest toxicity, which is due to their high affinity for biological targets.

The most important characteristic of toxins is their high physiological activity, driven by their ability to disrupt molecular mechanisms in metabolic and other physiological processes even at very low concentrations.

Toxins act specifically on various Organs and Tissues, distinguishing between selective-action toxins and cytotoxic substances. The first group includes, for example, the myotropic crotamine from the rattlesnake (Crotalus atrox). Poisons classified In the second group disrupt the biochemical processes of all Cells. For instance, ricin, a protein from the seeds of the castor oil plant (Ricinus communis), impairs ribosomal Protein Synthesis in various cells. Some cytotoxins can act with considerable Specificity on cells of particular tissues.

Characteristics of Selected Toxins and Poisons

Extremely toxic Peptides are produced by certain species of the genus Amanita, such as the destroying angel (A. virosa), the spring amanita (A. verna), and others. The molecules of these compounds are bicyclic Polypeptides. Fatal poisonings are most frequently caused by the death cap (Amanita phalloides), whose toxins have a cyclic Structure and belong to two groups: amatoxins and phallotoxins.

Amatoxin consists of three amanitins — a, ß, and y. The most toxic of these is a-amanitin, an octapeptide containing a specific amino acid in its structure: L-dihydroisoleucine. The sulfur atom of the Cysteine molecule, linked to a Tryptophan residue, divides the cyclopeptide into two rings. The MECHANISM OF ACTION of amatoxins in humans and animals is associated with the inhibition of DNA-dependent RNA polymerase. The Human Body lacks the Enzymes required for the proteolytic Cleavage of amatoxin, and furthermore, it is not destroyed by heat. The peptide content in the fruiting body of the death cap is 17 mg per 100 g of fresh mushroom mass. Ingesting as little than 50 g of fresh mushrooms can cause irreversible Liver cell damage.

Phallotoxins are also highly toxic, though their absorption from the digestive tract is slow. Among the peptides in this group, phalloidin is the most prominent; it is a heptapeptide featuring a thioether bond between cysteine and tryptophan in its structure. Its toxic properties are attributed to the presence of a specific amino acid, y-hydroxyleucine. Phallotoxins bind to hepatocyte membranes, causing structural disruption.

Certain microscopic Fungi and Algae also produce toxins. For instance, the fungus Penicillium islandicum produces the cyclopeptide cyclochlorotine with a Molecular Weight of 572, which exerts a hepatotoxic effect, causing respiratory failure and hemorrhagic intestinal damage. Blue-green algae of the species Microcystis aeruginosa produce microcystistoxin, a neurotoxic cyclodecapeptide with a molecular weight of approximately 12,000.

Denlatoxins A and B, ligatoxin A, phoratoxin, and viscotoxins A₂ and B — toxic substances found in the European mistletoe (Viscum album) — are all of peptide origin. These single-chain polypeptides have a molecular weight of 4,900–6,000 and contain about 50 amino acid residues per molecule. Viscotoxins have been shown to induce reflex bradycardia, hypotension, and constriction of the Skin and Skeletal Muscle Blood Vessels, resulting in an overall cardiotoxic effect.

A large number of phytotoxins have been isolated from other genera of the mistletoe family (Dendropthora, Phoradendron). Crotin I from the purging croton (Croton tiglium, family Passifloraceae) and momordin from the balsam apple (Momordica charantia, family Cucurbitaceae) are polypeptides with molecular weights of 72,000 and 23,000, respectively. Modeccin from Modeca digitata (family Passifloraceae) and volkensin from Adenia volkensii (family Passifloraceae) are Glycoproteins with molecular weights of approximately 63,000. All four of these aforementioned toxins act as Protein Synthesis Inhibitors.

Snake venoms. Snake venom is the secretion of the specialized venom glands of snakes. Within this complex mixture of organic and inorganic substances, toxic proteins constitute the primary active component. In medicine, venoms derived from snakes of the genera Vipera, Naja, and Gloydius are utilized.

Vipera berus L. — common adder, Vipera lebetina L. — Levant viper, Vipera ursinii L. — meadow viper, family Viperidae (vipers).

Naja oxiana — Central Asian cobra, family Elapidae (elapids).

Gloydius blomhoffii — Mamushi pit viper, Gloydius halys — Siberian pit viper, family Crotalidae (pit vipers).

In homeopathy, venoms from pit vipers of the genus Bothrops are used, most notably the jararaca (Bothrops jararaca L.) and the cascabel rattlesnake (Crotalus durissus cascavella L.), family Crotalidae. From the family Elapidae, venom is collected from the spectacled cobra (Naja naja L., South Asia) and the coral snake (Elaps corallinus L.), which inhabits the forests of eastern Brazil.

Representatives of the genus Vipera are predominantly distributed in Europe, whereas elapids and pit vipers are mainly found in Asia.

Venom extraction is performed once a month. The highest yield of secretion is observed in April and October, while it decreases in May and July. Freshly harvested venom is a viscous, transparent, colorless or yellowish liquid. The specific gravity of cobra venom is 1.046, and that of blunt-nosed vipers and adders ranges from 1.030 to 1.032. The reaction of cobra venom is neutral, whereas that of adders and pit vipers is acidic. Exposure of venom to Water, ether, chloroform, potassium permanganate, UV radiation, or X-rays leads to a loss of toxicity. However, freezing and drying preserve The properties of the secretion.

Snake venom is a complex mixture of enzymes, proteins, Amino Acids, mineral components, pigments, and other substances. Its toxicity is primarily driven by proteins, while highly active enzymes amplify the damaging effects.

Based on their toxic profile, snake venoms are divided into two groups: those with hemorrhagic action and those with neurotropic action. Hemorrhagic venoms are typical of vipers and rattlesnakes, containing specific toxic proteins such as viperotoxin and crototoxin, respectively. Their action manifests as the destruction of red Blood Cells and capillaries, initial thrombus formation followed by impaired blood-clotting function, and subsequent Hemorrhage. Cobra venom contains the protein cobrotoxin and exhibits a neurotropic mode of action. Envenomation disrupts Nerve Impulse transmission and leads to paralysis of the respiratory center and skeletal Muscles. Additionally, all venoms contain enzymes such as phospholipase A2, hyaluronidase, L-Amino Acid Oxidase, phosphodiesterase, and 5'-nucleotidase; viper and pit viper venoms also contain proteases, while cobra venom contains acetylcholinesterase and alkaline phosphatase.

Snake venoms are utilized for the Diagnosis and Treatment of various diseases, serving as the base for injectable formulations and ointments. Injectable preparations such as vipraxin and cobrotoxin, which possess analgesic, antispasmodic, and anticonvulsant properties, are used to treat neuralgia, neuritis, radiculitis, cardiovascular and Nervous system disorders, and Epilepsy. Viperalgin, a stabilized solution of viper venom, has found application in treating atherosclerosis, Hypertension, neuroses, epilepsy, and thrombophlebitis, as well as for pain relief. Epilarctin (epileptoside), a standardized rattlesnake venom preparation, is used for nervous system disorders, migraines, and chorea. Ointments containing snake venoms, such as vipratox (vipracutan), viprosal, viprazid, and vypletox, are recommended for Lumbago, myositis, rheumatism, and neuralgia. Furthermore, snake venoms are used to produce antivenoms. Individual venom components, such as L-amino acid oxidase, phospholipase A₂, phosphodiesterase, and endonuclease, are used to manufacture chemical Reagents for diagnosing blood disorders, nervous system conditions, and systemic diseases.

Bee venom — Apitoxinum. It is produced by the venom glands of bees. A bee has two venom glands in its abdomen connected to the sting and a venom reservoir. When a bee drives its sting into the skin, venom from the reservoir flows through the sting channel into the wound. Detachment of the sting results in the bee's death.

Venom is obtained by irritating bees with ether or an electric current. A single bee yields approximately 0.085 mg of venom.

Bee venom is a colorless, viscous liquid with a honey-like odor and a bitter, burning taste. The reaction of the venom is acidic, and its specific gravity is 1.1313. It is soluble in water, and less soluble in formic acid and 60% ethanol. Its properties remain stable under METABOLISM/18.html">The Influence of acids, Temperature fluctuations, alkalis, certain bacteria, and enzymes. In a dry state, it can be stored for several years. Its composition includes polypeptides (melittin, apamin, minimin); enzymes (phospholipase A₂, hyaluronidase); lipoids; acids (formic, hydrochloric, orthophosphoric); and amino acids (Alanine, valine, leucine, isoleucine, Threonine, Lysine, phenylalanine, Arginine, aspartic acid, tryptophan, Proline, Tyrosine, cystine, Methionine, Histidine). Melittin exhibits general toxicity, local irritant effects, direct hemolytic and ganglion-blocking activity, and increases glucocorticoid secretion.

In small doses, bee venom has anti-inflammatory and antispasmodic effects, dilates blood vessels, slows down blood clotting, and lowers Cholesterol levels.

It is administered via direct stinging (apitherapy); by rubbing into the skin over the affected area (ointments such as Virapin, Apizartron, and Forapin); using Electrophoresis (Apifor tablets); and through injections (Apizartron, Venapiolin, Virapin).

Bee venom preparations and apitherapy are used in the treatment of rheumatism, polyarthritis, myositis, radiculitis, neuralgia, Bronchial Asthma, migraine, trophic ulcers, hypertension, thyrotoxicosis, eye diseases, etc.