Sarafotoxins

Definition
Sarafotoxins (SRTXs) are a group of 21-residue cardiotoxic peptides from snake venom that induce coronary vasoconstriction, show high-affinity binding to rat atrial and brain membranes and activate the hydrolysis of phosphoinositides1.

Related Peptides
SRTXs amino acid sequence shows a high degree of homology with that of endothelin, a recently described 21-residue vasoconstrictor peptide found in porcine aortic endothelium. This is remarkable, since endothelin is a natural compound of the mammalian vascular system while sarafotoxins are highly toxic components of snake venom 1. The SRTXs and endothelins (ETs) spontaneously fold into a defined tertiary structure with specific pairing of four cysteines into two disulfide bonds. Their structures show an interesting topological similarity to the core of the metalloproteinase interaction sites of the tissue inhibitors of metalloproteinases 2.

Discovery
SRTXs constitute a family of vasoactive peptides that were initially isolated from the venom of Atractaspis engaddensis, and that are structurally and functionally related to ETs. The first report on the structural similarity between SRTXs and ETs was published by Takasaki et al., in 1988 3.

Structural Characteristics
Four SRTXs-SRTX-a, SRTX-b,SRTX-c, and SRTX-d (6)-have been characterized so far. The four cysteinyl residues in the ETs and in the SRTXs are interconnected by disulfide bridges between positions 1 and 15 and 3 and 11, forming an intramolecular loop structure. Another characteristic of these peptides is their conserved hydrophobic C-terminal tail. Early reports indicate that SRTX-b binds with high affinity to certain sites in rat atrium and brain and stimulates inositol phospholipid hydrolysis 4. Studies suggest that the very low activities of SRTc are caused mainly by the Lys9 to Glu9 substitution, but not by the Ser2 to Thr2 substitution, which was suggested to be responsible for the weak bioactivities of SRTd [( Thr2,Ile19]SRTb) 5.

Analysis of the venom of Atractaspis microlepidota microlepidota revealed several new SRTX molecules manifesting some new structural and functional characteristics. These novel SRTXs are longer by three amino acids than the previously described SRTXs, and are designated here “long-SRTXs”. Six isoforms, derived from new poly-cistronic precursors, have been identified so far in the venom of this snake. One of these isoforms, designated SRTX-m, was chemically synthesized and its biological properties were studied. Results show that SRTX-m induces toxicity in mice, mostly due to vasoconstriction, and also that it has a lower toxicity and potency than the more potent SRTX described up to now: sarafotoxin-b (SRTX-b) from A. engaddensis 6.

SRTXs S6: several isotoxins from Atractaspis engaddensis (burrowing asp) venom that affect the heart. Three isotoxins, named SRTXs S6a1, S6b and S6c, with strong cardiotoxic activity were isolated from the venom of a snake, Atractaspis engaddensis. All three SRTXs are homologous peptides (four or less than four residue replacements) consisting of 21 amino acid residues. Their structure and activity is novel among snake venom components 7.

Mode of Action
Two ET-receptor subtypes have been characterized. The ETA receptor, which has a higher affinity for ET-1, ET-2 and sarafotoxin (SX) 6b than for ET-3 or SX6c and the ETB receptor which is non-isopeptide selective . It has been generally assumed that the ETA receptor is located on vascular smooth muscle cells, where it mediates the constrictor responses, and the ETB receptor on the endothelial cell, where it mediates prostacyclin and endothelium-derived relaxing factor (EDRF) release by endothelins. There may also be a third subtype of ET receptor selective for ET-3 and SX6c. The systemic pressor effects of the ET/SX peptides are mediated via ETA receptors, the vasoconstriction in the kidney in vivo may be mediated predominantly via ETB-like receptors 8.

Functions
SRTXs induce toxicity, mostly due to vasoconstriction. S6a and S6c produce both vasodilation and vasoconstriction in the systemic vascular bed and increase lobar vascular resistance and those hindquarters vasodilator responses are mediated, in part, by the release of endothelium-derived relaxing factor 9.

References
1.Kloog Y, Ambar I, Sokolovsky M, Kochva E, Wollberg Z, Bdolah A (1988). Sarafotoxin, a novel vasoconstrictor peptide: phosphoinositide hydrolysis in rat heart and brain. Science, 242(4876):268-270
2.Lauer-Fields JL, Cudic M, Wei S, Mari F, Fields GB, Brew K (2007). Engineered Sarafotoxins as Tissue Inhibitor of Metalloproteinases-like Matrix Metalloproteinase Inhibitors. J. Biol. Chem., 282(37):26948-26955.
3.Takasaki C, Yanagisawa M, Kimura S, Goto K, Masaki T (1988). Similarity of endothelin to snake venom toxin. 1988. Nature, 335(6188):303.
4.Sokolovsky M, Galron R, Kloog Y , Bdolah A, Indig FE, Blumberg S, Fleminger G (1990). Endothelins are more sensitive than sarafotoxins to neutral endopeptidase: Possible physiological significance (neutral endopeptidase /proteolysis /receptor binding sites/inositol phospholipid turnover/structure activity relationship). PNAS., 87:4702-4706.
5.Takasaki C, Aimoto S, Kitazumi K, Tasaka K, Shiba T, Nishiki K, Furukawa Y, Takayanagi R, Ohnaka K, and Nawata H (1991). Structure-activity relationships of sarafotoxins: chemical syntheses of chimera peptides of sarafotoxins S6b and S6c. Euro J pharmacol.,198(2-3):165-169.
6.Hayashi MA, Ligny-Lemaire C, Wollberg Z, Wery M, Galat A, Ogawa T, Muller BH, Lamthanh H, Doljansky Y, Bdolah A, Stöcklin R, Ducancel F(2004). Long-sarafotoxins: characterization of a new family of endothelin-like peptides. Peptides, 25(8):1243-1251.
7.Takasaki C, Tamiya N, Bdolah A, Wollberg Z, Kochva E (1988). Sarafotoxins S6: Several isotoxins from Atractaspis engaddensis (burrowing asp) venom that affect the heart. Toxicon., 26(6):543-548.
8.Cristol JP, Warner TD, Thiemermann C, Vane JR (1993). Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat. Br. J. Pharmacol., 108(3):776-779.
9.Minkes RK, Bellan JA, Higuera TR, Kadowitz PJ. (1992). Comparison of responses to sarafotoxins 6a and 6c in pulmonary and systemic vascular beds. Am J Physiol., 262:852-861.

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