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.

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. The sequence of NTX contains no histidine, arginine, tryptophan, or phenylalanine. NTX has three disulfide bridges (Cys7-Cys29, Cys13-Cys34, Cys17-Cys36) and contains an amidated C-terminus. NTX is similar in sequence to the margatoxin (79% identity), the kaliotoxin (51% identity), the charybdotoxin (49% identity), and the iberiotoxin (38% identity). The three-dimensional solution structure of NTX has been solved by nuclear magnetic resonance (NMR).

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

Mode of action
NTX associates reversibly with K+ channels and thus decreases K+ permeability in brain synaptosome s. 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 NTX1-9, 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.

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. 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.

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

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

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.