Endothelin-converting enzyme ECE

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. 

The sterol sulfate, halistanol disulfate B (544) was isolated from a South African Pachastrella sp. The structure and stereochemistry of compound 544 were established mainly by interpretation of spectral data. Halistanol disulfate B (544) was active in the endothelin converting enzyme (ECE) assay at a micromolar concentration [451]. Three sterol trisulfates (545-547) have been isolated from the sponges Trachyopsis halichondrioides and Cymbastela coralliophila [452]. 

Endothelin was first identified by Yanagisawa et al. [1] as a 21 amino acid peptide which was released from porcine aortic endothelial cells. This mature form of endothelin, which contains two disulphide bridges between residues Cys -Cys and Cys -Cys", is derived from a 39 amino acid precursor, big endothelin , by means of a putative endothelin converting enzyme (ECE) which cleaves the Trp -VaP bond Figure 8.1). Big endothelin itself is derived from a 203 amino acid precursor by means of dibasic pairspecific endopeptidases. 

Endothelin converting enzyme (ECE) has yet to be fully characterized. It is a membrane-located enzyme found in the vascular endothelium. It is essential in the production of endothelin in the body since it converts the inactive precursor big ET-1 to endothelin-1. It is an unusual enzyme because it cleaves at a Tyr-Val link. Like endopeptidase-24.11, it is inhibited by phosphoramidon (so is a metalloproteinase), and these two enzymes are often colocated. Furthermore, monoclonal antibody co-precipitation studies indicate they share a common epitope, and a homology to the extent of about 39%, ECE is also similar to the bacterial metalloprotease thermolysin, but is more specific. If a specific inhibitor is discovered that can act in vivo, then clearly such a drug could modulate endothelin production throughout the body, which would have important consequences (e.g. in antihypertensive therapy). 

Endothelin converting enzyme (ECE) inhibitors have been shown to be useful... 

Wallace et alP in a series of inhibitors of endothelin-converting enzyme (ECE-1) derived from the biphenyl compound CGS 26 303 and its analogues. ... 

WS7S624-A and B. Endothelin-converting enzyme (ECE) inhibitors from fermentation broths of Saccha-rothrix sp. no. 75624. ECE inhibitors are a new therapeutic principle for therapy of cardiac insufficiency, kidney failure and other circulatory diseases. W. belong to the few non-peptidic small molecules with this effect, IC50 (W. B) 30 ng/mL. 

WS75624B (123) is an endothelin-converting enzyme (ECE) inhibitor that is potentially useful in the treatment of hypertension. Stannane 120 reacting with iodide 121 afforded 122 which was further elaborated into 123. 

Endothelin-converting enzyme (ECE)-1 activates ET-1, both are abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-l/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution (207). ET system is upregulated by LDL and oxLDL in cultured human coronary SMC and human monocyte-derived macrophages (208). 

Bach, T. and Heuser, S. (2002) Total synthesis of the naturally occurring endothelin converting enzyme (ECE) inhibitor WS 75624 A. Synlett, (12), 2089-2091. 

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