Noxiustoxin

Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion Centruroides noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels.

Synonyms	NTx; NXT; NXT-1; Toxin II.11; Potassium channel toxin alpha-KTx 2.1.[1]
Organism	Centruroides noxius Hoffmann (Mexican scorpion)[2]
CAS Number	85205-49-8 (143074-44-6)[3]
Protein Data Bank	1SXM[4]
UniProt ID	P08815[5]
Molar Mass	4195.06[1]
Chemical Formula	C174H286N52O54S7[3]
Amino Acid Sequence	TIINVKCTSPKQCSKPCKELYGSSAGAKCMNGKCKCYNN-NH2 (Cys7-Cys29, Cys13-Cys34, Cys17-Cys36)[1]

3D molecular structure of noxiustoxin.

Sources

NTX was first purified from homogenized crude venom extract of the Mexican scorpion Centruroides noxius Hoffmann,^[2] found in the Mexican state of Nayarit.^[6] NTX accounts for only about 1% of the scorpion venom.^[7] NTX is one of the best-studied toxic peptides from scorpion venoms.^[6] It was the second purified toxin obtained from the genus Centruroides after neurotoxin II^[8] and the first short peptide from scorpion venom to be reported in the literature.^[9] The name for noxiustoxin was first proposed in 1982,^[2] before which it was known as toxin II-11^[9]

Chemistry

NTX is a peptide consisting of 39 amino acid residues. It has a molar mass of 4195.06 and the following primary amino acid sequence: TIINVKCTSPKQCSKPCKELYGSSAGAKCMNGKCKCYNN-NH2.^[1] The sequence of NTX contains no histidine, arginine, tryptophan, or phenylalanine. NTX has three disulfide bridges^[2] (Cys7-Cys29, Cys13-Cys34, Cys17-Cys36) and contains an amidated C-terminus.^[10] NTX is similar in sequence to the margatoxin (79% identity), the kaliotoxin (51% identity), the charybdotoxin (49% identity), and the iberiotoxin (38% identity).^[10] The three-dimensional solution structure of NTX has been solved by nuclear magnetic resonance (NMR).^[11]

Target

NTX blocks the pore of several types of voltage-gated K⁺ channels by reversibly binding to the channel receptor site.^[2] Furthermore, it affects calcium-activated potassium channels of skeletal muscles.^[12] In the squid axon, NTX was found to have relatively low binding affinity with their target site on the channel protein (KD = 300nM).^[9]

Mode of action

NTX associates reversibly with K⁺ channels and thus decreases K+ permeability in brain synaptosomes.^[13] 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 portion of the toxin as administration of synthetic-nonapeptide NTX_1-9, which corresponds to the N-Terminal sequences of NTX, leads to symptoms of intoxication that are very similar to native NTX, while a second synthetic active fragment, corresponding to the C-Terminal of NTX, did not lead to symptoms of intoxication.^[14]

Furthermore, the mode of action 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.^[15] The blocking of K+ channels 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.^[15]

Toxicity

LD₅₀ of the venom is 0.26 μg/g in albino mice after intraperitoneal injection.^[16] Intoxication symptoms of mice include hyperexcitability, lacrimation, convulsions, salivation, dyspnea, and eventually death by respiratory paralysis.^[14]

Treatment

Although the venom of Centruroides noxius Hoffmann is the most toxic of all the Mexican scorpions,^[17] it is less medically important, because Centruroides noxius does not cohabitate with humans^[18]

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.^[19]