Chemistry:Noxiustoxin

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Short description: Toxin from the venom of the scorpion Centruroides noxius
3D molecular structure of 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]

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 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.[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] 

References

  1. ↑ 1.0 1.1 1.2 1.3 "Kalium: Scorpion Toxins Active on Potassium Channels" (in en). http://kaliumdb.org/toxins/86. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Possani, Lourival Domingos; Martin, Brian M.; Svendsen, I. B. (1982-09-01). "The primary structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann" (in en). Carlsberg Research Communications 47 (5): 285–289. doi:10.1007/bf02907789. ISSN 0105-1938. 
  3. ↑ 3.0 3.1 "Noxiustoxin | #STN-340 | Alomone labs". http://www.alomone.com/p/noxiustoxin/stn-340/58. 
  4. ↑ Dauplais, M.; Gilquin, B.; Possani, L. D.; Gurrola-Briones, G.; Roumestand, C.; Menez, A. (1995). "Determination of the three-dimensional solution structure of noxiustoxin: analysis of structural differences with related short-chain scorpion toxins.". Biochemistry 34 (51): 16563–16573. doi:10.2210/pdb1sxm/pdb. PMID 8527429. http://www.rcsb.org/pdb/explore/explore.do?structureId=1SXM. 
  5. ↑ "Potassium channel toxin alpha-KTx 2.1 - Centruroides noxius (Mexican scorpion)" (in en). https://www.uniprot.org/uniprot/P08815. 
  6. ↑ 6.0 6.1 Possani, Lourival D; Corona, Miguel; Zurita, Mario; Rodrı́guez, Mario H (2002). "From Noxiustoxin to Scorpine and Possible Transgenic Mosquitoes Resistant to Malaria". Archives of Medical Research 33 (4): 398–404. doi:10.1016/s0188-4409(02)00370-3. PMID 12234530. 
  7. ↑ Possani, Lourival D; Zurita, Mario; Delepierre, Muriel; Hernández, Fidel H; Rodrguez, Mario H (1998). "From Noxiustoxin to Shiva-3, a peptide toxic to the sporogonic development of Plasmodium berghei". Toxicon 36 (11): 1683–1692. doi:10.1016/s0041-0101(98)00161-5. PMID 9792185. 
  8. ↑ Jover, E.; Couraud, F.; Rochat, H. (1980-08-29). "Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes". Biochemical and Biophysical Research Communications 95 (4): 1607–1614. doi:10.1016/S0006-291X(80)80082-9. ISSN 0006-291X. PMID 7417336. 
  9. ↑ 9.0 9.1 9.2 Carbone, Emilio; Wanke, Enzo; Prestipino, Gianfranco; Possani, Lourival D.; Maelicke, Alfred (1982-03-04). "Selective blockage of voltage-dependent K+ channels by a novel scorpion toxin" (in en). Nature 296 (5852): 90–91. doi:10.1038/296090a0. PMID 6278313. Bibcode: 1982Natur.296...90C. 
  10. ↑ 10.0 10.1 Drakopoulou, E.; Cotton, J.; Virelizier, H.; Bernardi, E.; Schoofs, A.R.; Partiseti, M.; Choquet, D.; Gurrola, G. et al. (1995). "Chemical Synthesis, Structural and Functional Characterization of Noxiustoxin, a Powerful Blocker of Lymphocyte Voltage-Dependent K+ Channels". Biochemical and Biophysical Research Communications 213 (3): 901–907. doi:10.1006/bbrc.1995.2214. PMID 7654252. 
  11. ↑ Dauplais, Marc; Gilquin, Bernard; Possani, Lourival D.; Gurrola-Briones, Georgina; Roumestand, Christian; Menez, Andre (1995-12-01). "Determination of the Three-Dimensional Solution Structure of Noxiustoxin: Analysis of Structural Differences with Related Short-Chain Scorpion Toxins". Biochemistry 34 (51): 16563–16573. doi:10.1021/bi00051a004. ISSN 0006-2960. PMID 8527429. 
  12. ↑ Valdivia, Hector H.; Smith, Jeffrey S.; Martin, Brian M.; Coronado, Roberto; Possani, Lourival D. (1988-01-04). "Charybdotoxin and noxiustoxin, two homologous peptide inhibitors of the K+(Ca2+) channel" (in en). FEBS Letters 226 (2): 280–284. doi:10.1016/0014-5793(88)81439-x. ISSN 1873-3468. PMID 2448164. 
  13. ↑ Sitges, M.; Possani, L. D.; Bayón, A. (June 1986). "Noxiustoxin, a short-chain toxin from the Mexican scorpion Centruroides noxius, induces transmitter release by blocking K+ permeability". The Journal of Neuroscience 6 (6): 1570–1574. doi:10.1523/JNEUROSCI.06-06-01570.1986. ISSN 0270-6474. PMID 3012016. 
  14. ↑ 14.0 14.1 Gurrola, G. B.; Molinar-Rode, R.; Sitges, M.; Bayon, A.; Possani, L. D. (1989). "Synthetic peptides corresponding to the sequence of noxiustoxin indicate that the active site of this K+ channel blocker is located on its amino-terminal portion". Journal of Neural Transmission 77 (1): 11–20. doi:10.1007/BF01255815. PMID 2746197. 
  15. ↑ 15.0 15.1 Carbone, E.; Prestipino, G.; Spadavecchia, L.; Franciolini, F.; Possani, L. D. (May 1987). "Blocking of the squid axon K+ channel by noxiustoxin: a toxin from the venom of the scorpion Centruroides noxius". Pflügers Archiv: European Journal of Physiology 408 (5): 423–431. doi:10.1007/BF00585064. ISSN 0031-6768. PMID 2439979. 
  16. ↑ Possani, Lourival Domingos; Dent, Myrna A. R.; Martin, Brian M.; Maelicke, Alfred; Svendsen, Ib (1981-07-01). "The amino terminal sequence of several toxins from the venom of the Mexican scorpion Centruroides noxius Hoffmann" (in en). Carlsberg Research Communications 46 (4): 207. doi:10.1007/bf02906498. ISSN 0105-1938. 
  17. ↑ Dent, Myrna A.R.; Possani, Lourival D.; Ramírez, Guillermo A.; Fletcher, Paul L. (1980). "Purification and characterization of two mammalian toxins from the venom of the Mexican scorpion Centruroides noxius Hoffmann". Toxicon 18 (3): 343–350. doi:10.1016/0041-0101(80)90015-x. PMID 7394823. 
  18. ↑ Dehesa-Dávila, Manuel; Ramfrez, Angelina N; Zamudio, Fernando Z; Gurrola-Briones, Georgina; Liévano, Arturo; Darszon, Alberto; Possani, Lourival D (1996). "Structural and functional comparison of toxins from the venom of the scorpions Centruroides infamatus infamatus, centruroides limpidus limpidus and Centruroides noxius". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 113 (2): 331–339. doi:10.1016/0305-0491(95)02031-4. PMID 8653586. 
  19. ↑ Hernández, Ricardo; Gazarian, Tatiana G; Hérion, Pascal S; Gazarian, Karlen G (2002). "Molecular localization and crossreactivity of two epitopes of noxiustoxin from scorpion Centruroides noxius, identified by a panel of monoclonal antibodies and peptide mimotopes". Immunology Letters 80 (2): 97–103. doi:10.1016/s0165-2478(01)00320-0. PMID 11750040. 

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