Endothelin family

The endothelium is the source of a variety of substances with vasodilator (PGI2 and nitric oxide) and vasoconstrictor activities. The latter include the endothelin family, potent vasoconstrictor peptides that were first isolated from aortic endothelial cells. 

The endothelin family consists of three members, ENDO-THELIN-l ENDOTHELIN-2 and ENDOTHELIN-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. 

Figure 8.2. Structure of the endothelin family ofpeptides. Amino acid.s with bars adjacent indicate...

Inoue A, Yanagisawa M, Kimura S, Kasuya Y, MiyauchiT, Goto K, MasakiT.The human endothelin family three structurally and pharmacologically distinct Isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A 1989 86 2863-2867. 

Endothelin. The endothelin (ET) peptide family (50) comprises thiee peptides ET-1 (133), ET-2 (134), and ET-3 (135). ET-1, the most abundant, is a 21-amino acid peptide. A 203-amino acid peptide piecuisoi, piepioET, is cleaved after translation by endopeptidases to form a 38-amino acid proET which is converted to active ET by a putative endothelin-converting enzyme (ECE). ET-3 differs from ET-1 and ET-2 by sis amino acids. 

Endothelin Concerting Enzymes (ECEs) belong to the family of metalloproteases that catalyze the proteolytic activation of big endothelins. 

Endothelins comprise a family of three vasoactive isopeptides of 21 amino acids that have an essential role in the regulation of the vascular and bronchiolar tone and the control of natriuresis in the kidney. Endothelin peptides are also involved in nociception and have a critical role in the progression of prostate and ovarian cancer. 

The autacoids comprise histamine, serotonin, angiotensin, neurotensin, NO (nitric oxide), kinins, platelet-activating factor, endothelins and the four families of traditional eicosanoids - the leukotrienes and three types of prostanoids i.e. prostaglandins, prostacyclins, and thromboxanes. Several other natural occurring molecules are sometimes called eicos-anoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. However, not... 

Endothelins are a family of vasoactive peptides secreted by endothelial cells. The three major endothelin peptides are all composed of 21 amino acids. Endothelins are the most potent vasoconstrictors known. Contraction of vascular smooth muscle in response to endothelin is associated with an increase in intracellular calcium. Increases in endothelin levels have been reported in patients with vasospastic, hypoxic, and ischemic diseases. The two identified isoforms of endothelin receptors have differing affinity for the three endothelin peptides. Selective and nonselective endothelin receptor antagonists are in development for potential use in the treatment of hypertension and other disorders associated with increased vascular resistance. 

Of this family of peptides containing two intramolecular disulfide bonds the most studied in terms of oxidative refolding are a-conotoxins with two adjacent cysteine residues, i.e. with m = 0, the bee venom toxins, for example apamin and mast cell degranulating peptide, and snake venom toxins, exemplified by sarafotoxins, and endothelins, mammalian peptide hormones with the characteristic Cys-(Xaa)rCys/Cys-(Xaa)3-Cys motif (Scheme 2). With m = 0 or 1 all these peptides are expected to show a weak tendency to form the isomer 3 with a disulfide bond between two proximal cysteine residues. This was fully confirmed by oxidative refolding experiments. 

Endothelin receptors are widespread in the body. Two endothelin receptor subtypes, termed ET and ET , have been cloned and sequenced. receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction (Figure 17-7). ETB receptors have approximately equal affinities for ET-1 and ET-3 and are primarily located on vascular endothelial cells, where they mediate release of PGI2 and nitric oxide. Some ETB receptors are also present on smooth muscle cells and mediate vasoconstriction. Both receptor subtypes belong to the G protein-coupled seven-transmembrane domain family of receptors. 

Fig. 8. (a) Primary structure of the cyclic endothelin antagonist BE18257B and (b) a family of 36 NMR structures which demonstrates the well-defined nature of the cyclic peptide backbone. (Reprinted with permission from Coles et a/.148 Copyright (1993) American Chemical Society.)... 

Endothehns constitute a family of peptides (Hart and Hart, 1992). They are very potent endogenous vasoconstrictors and vasopressors and are secreted by various cells and tissues in the human body. Of the three isoforms, endothe-hn-1 (ET-1) is one of the most potent contractors of vascular smooth muscles (Miller et al, 1993). Endothelins have very similar structures and biological properties to sarafotoxins (Kloog and Sokolovsky, 1989), and the toxic peptides are obtained from the venom of mole vipers (Atractaspidae). 

Turner. A.J. (1993) Endothelin-converting en mes and other families of metallo-endopeptidases. Bhchem. Soc. Trans., 21.697-701. 

The endothelins belong to a family of potent vasoconstrictor peptides that were originally isolated from the supernatant of cultured aortic endothelial cells. Endothehns bear striking structural similarities to the sarafotoxins, which are potent cardiotoxic peptides isolated from the venom of the burrowing asp Atractaspis engadensis. Four endothelins and four sarafotoxin isopeptides, having different receptor sub-types, have been identified (see also Figure 44). 

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