Chemistry:Imperatoxin
Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.
There are two subtypes of this toxin:
- Imperatoxin A (activator): a peptide toxin which enhances the influx of Ca2+ from the sarcoplasmatic reticulum into the cell.
- Imperatoxin I (inhibitor): a peptide toxin which decreases the influx of Ca2+ from the sarcoplasmatic reticulum into the cell.
Imperatoxin A
The toxin comes from the venom of the African scorpion Pandinus imperator.[1] The structure of IpTxa consists of:
- 33 amino acids peptide (sequence GDCLPHLKRCKADNDCCGKKCKRRGTNAEKRCR, disulfide bonds Cys3-Cys17, Cys10-Cys21, Cys16-Cys32).
- the formula is C148H260N58O45S6.
- shares the structure and function of the dihydropiridine receptor (DHPR). It corresponds to the II-III loop of the α1s subunit.
- three cysteine residues that form disulfide bridges to stabilize the three-dimensional structure.
The molecular weight of the toxin is 3.7 kDa.
IpTxa acts on the Ryanodine receptors (RyR), which are intracellular Ca2+ release channels mainly known for their role in regulating Ca2+ release from the sarcoplasmatic reticulum of striated muscles.[2] The peptide acts better on RyR type 1 than on type 3. RyR type 2 seems to be insensitive to IpTxa.[3]
The part of the peptide that looks like the II-III loop of the (DHPR) binds directly to RyR and enhances ryanodine binding to trigger Ca2+ release.[3]
Imperatoxin I
The toxin comes from the venom of the African scorpion Pandinus imperator.[1] The structure of IpTxi consists of:
- Two polypeptides. A large subunit of 104 amino acids (sequence TMWGTKWCGSGNEATDISELGYWSNLDSCCRTHDHCDNIPSGQTKYGLTNEGKYTMMNCKCETAFEQCLRNVTGGMEGPAAGFVRKTYFDLYGNGCYNVQCPSQ) and a smaller one of 27 amino acids (sequence SEECPDGVATYTGEAGYGAWAINKLNG).
- Subunits are linked by a disulfide bond.
- Phospholipase A2 (PLA2) activity on the large subunit.
The molecular weight of the toxin is 15 kDa.
Like IpTxa, IpTxi acts on RyR.
When an action potential reaches the muscle, RyR channels open and Ca2+ becomes available in the cell to induce contraction. The presence of Ca2+ induces the large subunit of IpTxi to hydrolyze the Sn2 fatty acyl bond from the membrane of the sarcoplasmatic reticulum. This process is executed by PLA2 activity. The freed fatty acids bind to the RyR itself or to a closely associated protein linked to gating. Binding of the RyR induces blocking of the channel. When the concentration of free fatty acids is low there will be an incomplete block of RyR; higher concentrations will give a complete block.[4]
Because IpTxi also works on the RyR channels of the heart muscles, it could potentially be used as a drug against arrhythmia. This has not yet been proven, and must be studied in vivo first.[5]
References
- ↑ 1.0 1.1 Valdivia, Hector H.; Kirby, Mark S.; Lederer, W. Jonathan; Coronado, Roberto (1992). "Scorpion Toxins Targeted Against the Sarcoplasmic Reticulum Ca2+- Release Channel of Skeletal and Cardiac Muscle". Proceedings of the National Academy of Sciences 89 (24): 12185–9. doi:10.1073/pnas.89.24.12185. PMID 1334561. Bibcode: 1992PNAS...8912185V.
- ↑ Franzini-Armstrong, C; Protasi, F (1997). "Ryanodine receptors of striated muscles: A complex channel capable of multiple interactions". Physiological Reviews 77 (3): 699–729. doi:10.1152/physrev.1997.77.3.699. PMID 9234963. http://physrev.physiology.org/cgi/pmidlookup?view=long&pmid=9234963.
- ↑ 3.0 3.1 Simeoni, Ilenia; Rossi, Daniela; Zhu, Xinsheng; Garcı́a, Jesus; Valdivia, Hector H.; Sorrentino, Vincenzo (2001). "Imperatoxin A (IpTxa) from Pandinus imperator stimulates [3H]ryanodine binding to RyR3 channels". FEBS Letters 508 (1): 5–10. doi:10.1016/S0014-5793(01)03013-7. PMID 11707258.
- ↑ Zamudio, F. Z.; Conde, R; Arévalo, C; Becerril, B; Martin, BM; Valdivia, HH; Possani, LD (1997). "The Mechanism of Inhibition of Ryanodine Receptor Channels by Imperatoxin I, a Heterodimeric Protein from the Scorpion Pandinus imperator". Journal of Biological Chemistry 272 (18): 11886–94. doi:10.1074/jbc.272.18.11886. PMID 9115249.
- ↑ Santonastasi, Marco; Wehrens, Xander H T (2007). "Ryanodine receptors as pharmacological targets for heart disease". Acta Pharmacologica Sinica 28 (7): 937–44. doi:10.1111/j.1745-7254.2007.00582.x. PMID 17588328.
 |  |
