Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion ''

Centruroides ''Centruroides'' is a genus of scorpions of the family Buthidae. Several North American species are known by the common vernacular name bark scorpion. Numerous species are extensively found throughout the southern United States, Mexico, Centr ...

'' noxius Hoffmann which block

voltage-dependent potassium channel Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...

s and

calcium-activated potassium channel Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that calcium levels inside of a cell ...

Sources

NTX was first purified from homogenized crude venom extract of the Mexican scorpion ''

noxius'' Hoffmann, found in the Mexican state of

Nayarit Nayarit (), officially the Free and Sovereign State of Nayarit ( es, Estado Libre y Soberano de Nayarit), is one of the 31 states that, along with Mexico City, comprise the Federal Entities of Mexico. It is divided in 20 municipalities and its ...

. NTX accounts for only about 1% of the scorpion venom. NTX is one of the best-studied toxic

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

from scorpion venoms. It was the second purified

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

obtained from the genus ''

'' after

neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and matur ...

II and the first short peptide from scorpion venom to be reported in the literature. The name for noxiustoxin was first proposed in 1982, before which it was known as toxin II-11

Chemistry

NTX is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

consisting of 39

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

residues. It has a

molar mass In chemistry, the molar mass of a chemical compound is defined as the mass of a sample of that compound divided by the amount of substance which is the number of moles in that sample, measured in moles. The molar mass is a bulk, not molecula ...

of 4195.06 and the following primary amino acid sequence: TIINVKCTSPKQCSKPCKELYGSSAGAKCMNGKCKCYNN-NH2. The sequence of NTX contains no

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromati ...

, or

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

. NTX has three

disulfide bridges In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

(Cys7-Cys29, Cys13-Cys34, Cys17-Cys36) and contains an amidated

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 i ...

. NTX is similar in sequence to the

margatoxin Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of '' Centruroides margaritatus'', also known as the Central American Bark Scorpion. Margatoxin was first discovered in ...

(79% identity), the

kaliotoxin {, style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="280" !The amino acid sequence of Kaliotoxin , - , bgcolor="#eeeeee" , N - Gly - Val - Glu - Ile ...

(51% identity), the

charybdotoxin Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion '' Leiurus quinquestriatus hebraeus'' (''deathstalker'') that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous syst ...

(49% identity), and the

iberiotoxin Iberiotoxin (IbTX) is an ion channel toxin purified from the Eastern Indian red scorpion '' Hottentotta tamulus''. Iberiotoxin selectively inhibits the current through large-conductance calcium-activated potassium channels. Chemistry Iberioto ...

(38% identity). The three-dimensional solution structure of NTX has been solved by

nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

(

NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

Target

NTX blocks the pore of several types of voltage-gated K⁺ channels by reversibly binding to the channel receptor site. Furthermore, it affects

s of

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

s. In the squid axon, NTX was found to have relatively low

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mo ...

with their target site on the

channel protein Channel, channels, channeling, etc., may refer to: Geography * Channel (geography), in physical geography, a landform consisting of the outline (banks) of the path of a narrow body of water. Australia * Channel Country, region of outback Austra ...

(KD = 300nM).

Mode of action

NTX associates reversibly with K⁺ channels and thus decreases K+ permeability in brain synaptosomes. The location of the active site of NTX is not completely known yet. However, it is believed to be located close to the

N-Terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

portion of the toxin as administration of synthetic-nonapeptide NTX_1-9, which corresponds to the N-Terminal sequences of NTX, leads to

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

s of

intoxication Intoxication — or poisoning, especially by an alcoholic or narcotic substance — may refer to: * Substance intoxication: ** Alcohol intoxication ** LSD intoxication ** Toxidrome ** Tobacco intoxication ** Cannabis intoxication ** Cocaine in ...

that are very similar to native NTX, while a second synthetic active fragment, corresponding to the

C-Terminal 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 ...

of NTX, did not lead to symptoms of intoxication. Furthermore, the

mode of action A mode of action (MoA) describes a functional or anatomical change, resulting from the exposure of a living organism to a substance. In comparison, a mechanism of action (MOA) describes such changes at the molecular level. A mode of action is impor ...

of NTX is thought to be concentration dependent. K+ currents are found to be blocked by NTX at concentrations lower than 1.5 μM in a voltage-independent manner and above 1.5 μM in a voltage-dependent manner. The blocking of

K+ channels K, or k, is the eleventh letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''kay'' (pronounced ), plural ''kays''. The letter K u ...

by NTX is never complete, which indicates that NTX is either not able to fully block a channel or that not all channels have a receptor site for NTX.

Toxicity

LD₅₀ of the venom is 0.26 μg/g in albino mice after

intraperitoneal injection Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...

. Intoxication symptoms of mice include hyperexcitability,

lacrimation Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

s, salivation,

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...

, and eventually death by

respiratory paralysis Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a ri ...

Treatment

Although the venom of ''

noxius'' Hoffmann is the most toxic of all the Mexican scorpions, it is less medically important, because ''Centruroides'' noxius does not cohabitate with

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

Medical significance

It is suggested that due to structural similarity between toxins, a vaccine against ''Centruroides noxius'' could be efficient against other, more dangerous, ''Centruroides'' species that cause more public health problems.

References

{{reflist

External links

*https://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?Dopt=s&uid=74293 *http://kaliumdb.org/toxins/86 *http://www.ebi.ac.uk/pdbe/entry/pdb/1sxm Ion channel toxins Scorpion toxins