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 Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
,
paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
and tissue damage that can result in
amputation Amputation is the removal of a limb by trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on indi ...
. The paralytic effects of venom are particularly dangerous as they can impair breathing. 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.


History

Bungarotoxins are a group of closely related
neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
proteins of the
three-finger toxin Three-finger toxins (abbreviated 3FTx) 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 prote ...
superfamily found in the venom of
kraits ''Bungarus'' is a genus of venomous elapid snakes, the kraits ("krait" is pronounced , rhyming with "kite"), found in South and Southeast Asia. The genus ''Bungarus'' has 16 species. Distribution Kraits are found in tropical Asia, from near Ir ...
including ''
Bungarus multicinctus The many-banded krait (''Bungarus multicinctus''), also known as the Taiwanese krait or the Chinese krait, is a venomous species of elapid snake found in much of central and southern China and Southeast Asia. The species was first described by t ...
'' (the many-banded krait). These toxins alter neurotransmission to yield powerful paralytic effects on skeletal muscle. Venom of the many-banded krait began to be studied by Chuan-Chiung Chang and Chen-Yuan Lee of the
National Taiwan University National Taiwan University (NTU; ) is a public research university in Taipei, Taiwan. The university was founded in 1928 during Japanese rule as the seventh of the Imperial Universities. It was named Taihoku Imperial University and served d ...
in the 1950s; however, it was not until 1963 that its components were separated and isolated. They discovered that this venom consisted of a mixture of individual toxins that act at different sites and receptors to modulate neurotransmission. Through
electrophoresis Electrophoresis, from Ancient Greek ἤλεκτρον (ḗlektron, "amber") and φόρησις (phórēsis, "the act of bearing"), is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric fie ...
the venom was found to be composed of five distinct toxins, one of which remains unnamed. The four characterized toxins are: * α-Bungarotoxin * β-Bungarotoxin (not a three-finger toxin) * γ-Bungarotoxin () * k-Bungarotoxin


Snake bites

Research involving bungarotoxins has been significant in improving our understanding of
neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
. Additionally, snake and krait bites and
envenomation Envenomation is the process by which venom is injected by the bite or sting of a venomous animal. Many kinds of animals, including mammals (e.g., the northern short-tailed shrew, ''Blarina brevicauda''), reptiles (e.g., the king cobra), spider ...
cause significant
morbidity A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
; understanding the mechanism by which bungarotoxins work can improve treatment options in such situations. According to the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
, approximately 5.4 million people are bitten by snakes each year with 2.7 million people becoming envenomed. Majority of these cases occur in
Africa Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 6% of Earth's total surface area ...
,
Asia Asia (, ) is one of the world's most notable geographical regions, which is either considered a continent in its own right or a subcontinent of Eurasia, which shares the continental landmass of Afro-Eurasia with Africa. Asia covers an area ...
and
Latin America Latin America or * french: Amérique Latine, link=no * ht, Amerik Latin, link=no * pt, América Latina, link=no, name=a, sometimes referred to as LatAm is a large cultural region in the Americas where Romance languages — languages derived f ...
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. Symptoms can be worse or progress faster in children, and in severe cases can result in limb amputations, prolonged paralysis, permanent deficits or death. While treatment includes administration of
anticholinergics Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sy ...
and
anti-venom Anti-Venom is a fictional antihero appearing in Comic books published by Marvel Comics. It first appeared in '' The Amazing Spider-Man'' #569 (August 2008), and was created by Dan Slott and John Romita Jr. The creature belongs to a race of amorp ...
, anti-venom is costly and is not readily available, particularly to the populations that require it most. 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.


Toxin mechanism

Bungarotoxins function by modulating acetylcholine neurotransmission in both muscles and neurons. α-Bungarotoxin irreversibly blocks the binding of
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
(ACh) to postsynaptic
nicotinic acetylcholine receptors 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 n ...
(nAchR) on both muscle and neurons. In addition to being found in the venom of kraits, it is also in venoms of the
elapids Elapidae (, commonly known as elapids ; grc, ἔλλοψ ''éllops'' "sea-fish") is a family of snakes characterized by their permanently erect fangs at the front of the mouth. Most elapids are venomous, with the exception of the genus Emydocep ...
and
sea snakes Sea snakes, or coral reef snakes, are elapid snakes that inhabit marine environments for most or all of their lives. They belong to two subfamilies, Hydrophiinae and Laticaudinae. Hydrophiinae also includes Australasian terrestrial snakes, wher ...
. 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.


Structure

The
three-finger protein Three-finger proteins or three-finger protein domains (3FP or TFPD) are a protein superfamily consisting of small, roughly 60-80 amino acid residue protein domains with a common tertiary structure: three beta strand loops extended from a hydrophob ...
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. The structure of the α-BTX has been most studied; its three-finger structure consists of a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
globular core from which 3 beta-pleated-sheet loops extend as well as a
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. 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. While all α-neurotoxins of the three-finger family will act on muscle nAchR, these differences in structure determine
selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...
of the toxin for its receptor as well as affinity and
dissociation Dissociation, in the wide sense of the word, is an act of disuniting or separating a complex object into parts. Dissociation may also refer to: * Dissociation (chemistry), general process in which molecules or ionic compounds (complexes, or salts ...
.


References

Ion channel toxins Nicotinic antagonists Vertebrate toxins Bungarus {{toxicology-stub