ABSTRACT
Endothelin converting enzyme (ECE) catalyses the final step in the biosynthesis of the potent vasoconstrictor peptide endothelin (ET). This involves cleavage of the Trp-Val bond in the inactive intermediate, big endothelin. ECE-1 is a zinc metallopeptidase which is homologous with neutral endopeptidase-24.11 (NEP; neprilysin; EC 3.4.24.11). Like NEP, ECE-1 is inhibited by the compound phosphoramidon and is a type II integral membrane protein. Unlike NEP, however, ECE-1 exists as a disulphide-linked dimer and is not inhibited by other NEP inhibitors such as thiorphan. Site-directed mutagenesis has highlighted critical residues involved in dimer formation and catalytic activity and has allowed structural comparisons with NEP. Immunocytochemical studies indicate a predominant cell-surface location for ECE-1 where it exists as an ectoenzyme. ECE-1 is localized to endothelial cells and some secretory cells, e.g. {3-cells in the pancreas. Alternative splicing of the ECE-1 gene results in two isoforms of the protein (ECE-1oc and ECE-1{3) with distinct Nterminal tails. A homologue of ECE-1, designated ECE-2, resembles ECE-1 in specificity but has an acidic pH optimum and is more sensitive to inhibition by phosphoramidon. The relative importance of the members of the ECE family in endothelin biosynthesis remains to be resolved. Potent and selective inhibitors of ECE, or dual inhibitors of ECE and NEP, may have therapeutic applications in cardiovascular and renal medicine.
