Bungarotoxin

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Bungarotoxins are toxins found in the venom of snakes and kraits. Bites from these animals can result in severe symptoms including bleeding or hemorrhage, paralysis and tissue damage that can result in amputation. The paralytic effects of venom are particularly dangerous as they can impair breathing. [1] These symptoms are the result of bungarotoxin presence in the venom. In actuality, venom contains several distinct bungarotoxins, each varying in which receptors they act on and how powerful they are.

Contents

History

Bungarotoxins are a group of closely related neurotoxic proteins of the three-finger toxin superfamily found in the venom of kraits including Bungarus multicinctus (the many-banded krait). [2] These toxins alter neurotransmission to yield powerful paralytic effects on skeletal muscle. [3] Venom of the many-banded krait began to be studied by Chuan-Chiung Chang and Chen-Yuan Lee of the National Taiwan University in the 1950s; [4] however, it was not until 1963 that its components were separated and isolated. [5] They discovered that this venom consisted of a mixture of individual toxins that act at different sites and receptors to modulate neurotransmission. [6] Through electrophoresis the venom was found to be composed of five distinct toxins, one of which remains unnamed. [3]

The four characterized toxins are:

Snake bites

Research involving bungarotoxins has been significant in improving our understanding of neurotransmission. Additionally, snake and krait bites and envenomation cause significant morbidity; understanding the mechanism by which bungarotoxins work can improve treatment options in such situations. According to the World Health Organization, approximately 5.4 million people are bitten by snakes each year with 2.7 million people becoming envenomed. [7] Majority of these cases occur in Africa, Asia and Latin America and outcomes can be debilitating if not treated immediately. Symptoms of envenomation include shortness of breath, weakness or paralysis, difficulty swallowing and skin damage at the bite site. [7] Symptoms can be worse or progress faster in children, and in severe cases can result in limb amputations, prolonged paralysis, permanent deficits or death. [7] While treatment includes administration of anticholinergics and anti-venom, anti-venom is costly and is not readily available, particularly to the populations that require it most. [7] When patients are treated with anticholinergics and anti-venom, often there is delayed recovery of paralysis. This has been attributed to the β-BTX component of the venom which makes up 20% of the venom and is the most potent of the toxins. [8]

Toxin mechanism

Bungarotoxins function by modulating acetylcholine neurotransmission in both muscles and neurons. α-Bungarotoxin irreversibly blocks the binding of acetylcholine (ACh) to postsynaptic nicotinic acetylcholine receptors (nAchR) on both muscle and neurons. In addition to being found in the venom of kraits, it is also in venoms of the elapids and sea snakes. [9] Similarly, κ-bungarotoxin acts to block postsynaptic nAchRs, but its effect is primarily on neuronal receptors rather than muscular nicotinic receptors. Conversely, β- and γ-bungarotoxins act presynaptically to cause excessive acetylcholine release and subsequent depletion, resulting in paralysis. [9]

Structure

The three-finger protein family is a family of proteins that share similar 3-dimensional structure. They are found in a wide variety of organisms including snakes. In snakes and kraits, venomous toxins largely consist of those with a three-finger structure. [10] The structure of the α-BTX has been most studied; its three-finger structure consists of a hydrophobic globular core from which 3 beta-pleated-sheet loops extend as well as a C-terminus. [9] Within the family of three-finger α-neurotoxins, the protein structure is further subcategorized as short chain, long chain, atypical long chain and non conventional α-neurotoxins. This subclassification describes additional structural aspects of the toxin as well as the receptors they act on. For example, α-BTX is a long chain toxin meaning it is composed of 66-70 amino acids and possesses a three-finger structure. Long chain toxins act on nAchR in both muscle and neurons whereas short chain α-neurotoxins act on nAchR in muscle only. [9] While all α-neurotoxins of the three-finger family will act on muscle nAchR, these differences in structure determine selectivity of the toxin for its receptor as well as affinity and dissociation. [10]

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Acetylcholine receptor</span> Integral membrane protein

An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

<span class="mw-page-title-main">Neurotoxin</span> Toxin harmful to nervous tissue

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

<i>Bungarus</i> Genus of venomous snakes

Bungarus is a genus of elapids native to Asia. Often found on the floor of tropical forests in South Asia, Southeast Asia and Southern China, they are medium-sized, highly venomous snakes with a length typically not exceeding 2 metres. These are nocturnal ophiophagious predators which prey primarily on other snakes at night, occasionally taking lizards, amphibians and rodents. Most species are with banded patterns acting as a warning sign to their predators. Despite being considered as generally docile and timid, kraits are capable of delivering highly potent neurotoxic venom which is medically significant with potential lethality to humans. The genus currently holds 16 species and 5 subspecies.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.

<span class="mw-page-title-main">Cricothyroid muscle</span> Muscle of the larynx

The cricothyroid muscle is the only tensor muscle of the larynx aiding with phonation. It is innervated by the superior laryngeal nerve. Its action tilts the thyroid forward to help tense the vocal cords, thus increasing the pitch of the voice.

α-Bungarotoxin Chemical compound

α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.

Taipoxin is a potent myo- and neurotoxin that was isolated from the venom of the coastal taipan Oxyuranus scutellatus or also known as the common taipan. Taipoxin like many other pre-synaptic neurotoxins are phospholipase A2 (PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia). It is the most lethal neurotoxin isolated from any snake venom to date.

Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause. This abnormal condition may be caused by disease or by trauma affecting the nerves associated with the involved muscles. For example, if the somatic nerves to a skeletal muscle are severed, then the muscle will exhibit flaccid paralysis. When muscles enter this state, they become limp and cannot contract. This condition can become fatal if it affects the respiratory muscles, posing the threat of suffocation. It also occurs in the spinal shock stage in complete transection of the spinal cord occurring in injuries such as gunshot wounds.

<span class="mw-page-title-main">Cobratoxin</span> Chemical compound

α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR.

β-Bungarotoxin Chemical compound

β-Bungarotoxin is a form of bungarotoxin that is fairly common in Krait venoms. It is the prototypic class of snake β-neurotoxins. There are at least five isoforms, coded β1 to β5, assembled from different combinations of A and Bchains.

<span class="mw-page-title-main">Red-headed krait</span> Species of snake

The red-headed krait is a large highly venomous elapid snake with dramatic coloration. The red-headed krait can grow to a length of up to 2.1 metres (7 ft). It lives in lowland rain forest, including those on islands, but it is considered uncommon. It feeds primarily on specific snakes, probably semiaquatic and fossorial snakes. In Southeast Asia, the red-headed krait occurs in Malaysia, Singapore, Thailand and Indonesia (Sumatra), with a subspecies in Borneo. The venom potency is little-studied, as bites from this species are extremely rare.

α-Neurotoxin Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

κ-Bungarotoxin Protein neurotoxin of the bungarotoxin family

κ-Bungarotoxin is a protein neurotoxin of the bungarotoxin family that is found in the venom of the many-banded krait, a snake found in Taiwan. κ-Bungarotoxin is a high affinity antagonist of nicotinic acetylcholine receptors (nAChRs), particularly of CHRNA3; it causes a post-synaptic blockade of neurotransmission. Although there is significant variability in the clinical effects of snake bites, neuromuscular paralysis and respiratory failure are associated with krait bites.

<span class="mw-page-title-main">Three-finger toxin</span> Toxin protein

Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).

Mipartoxin-I is a neurotoxin produced by Micrurus mipartitus, a venomous coral snake distributed in Central and South America. This toxin causes a neuromuscular blockade by blocking the nicotinic acetylcholine receptor. It is the most abundant component in the venom.

Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.

References

  1. ↑ Kullmann, Florenta Aura; Chet de Groat, William; Artim, Debra Elaine (2009-01-01), Jankovic, Joseph; Albanese, Alberto; Atassi, M. Zouhair; Dolly, J. Oliver (eds.), "35 - Bungarotoxins", Botulinum Toxin, Philadelphia: W.B. Saunders, pp. 425–445, ISBN   978-1-4160-4928-9 , retrieved 2021-12-25
  2. ↑ Bungarotoxins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. 1 2 Kullmann, Florenta Aura; Chet de Groat, William; Artim, Debra Elaine (2009-01-01), Jankovic, Joseph; Albanese, Alberto; Atassi, M. Zouhair; Dolly, J. Oliver (eds.), "35 - Bungarotoxins", Botulinum Toxin, Philadelphia: W.B. Saunders, pp. 425–445, ISBN   978-1-4160-4928-9 , retrieved 2021-12-25
  4. ↑ Chang C (1999). "Looking back on the discovery of alpha-bungarotoxin". J. Biomed. Sci. 6 (6): 368–75. doi:10.1159/000025412. PMID   10545772. S2CID   84443027.
  5. ↑ Chu N (2005). "Contribution of a snake venom toxin to myasthenia gravis: the discovery of alpha-bungarotoxin in Taiwan" (PDF). Journal of the History of the Neurosciences. 14 (2): 138–48. doi:10.1080/096470490881770. PMID   16019658. S2CID   20028814.
  6. ↑ Nirthanan, Selvanayagam (2020-11-01). "Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine". Biochemical Pharmacology. Pharmacology and Therapeutic Potential of Venom Peptides. 181: 114168. doi:10.1016/j.bcp.2020.114168. ISSN   0006-2952. PMID   32710970. S2CID   220773156.
  7. 1 2 3 4 "Snakebite envenoming". www.who.int. Retrieved 2021-12-25.
  8. ↑ Kullmann, Florenta Aura; Chet de Groat, William; Artim, Debra Elaine (2009-01-01), Jankovic, Joseph; Albanese, Alberto; Atassi, M. Zouhair; Dolly, J. Oliver (eds.), "35 - Bungarotoxins", Botulinum Toxin, Philadelphia: W.B. Saunders, pp. 425–445, ISBN   978-1-4160-4928-9 , retrieved 2021-12-25
  9. 1 2 3 4 Kullmann, Florenta Aura; Chet de Groat, William; Artim, Debra Elaine (2009-01-01), Jankovic, Joseph; Albanese, Alberto; Atassi, M. Zouhair; Dolly, J. Oliver (eds.), "35 - Bungarotoxins", Botulinum Toxin, Philadelphia: W.B. Saunders, pp. 425–445, ISBN   978-1-4160-4928-9 , retrieved 2021-12-25
  10. 1 2 Nirthanan, Selvanayagam (2020-11-01). "Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine". Biochemical Pharmacology. Pharmacology and Therapeutic Potential of Venom Peptides. 181: 114168. doi:10.1016/j.bcp.2020.114168. ISSN   0006-2952. PMID   32710970. S2CID   220773156.
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