The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function

Neprilysin (NEP), a thermolysin-like zinc metalloendopeptidase, plays an im portant role in turning off peptide signalling events at the cell surface. It is involved in the metabolism of a number of regulatory peptides of the mammalian nervous, cardiovascular, inflammatory and immune systems. Example s include enkephalins, tachykinins, natriuretic and chemotactic peptides, N EP is an integral plasma membrane ectopeptidase of the M13 family of zinc p eptidases, Other related mammalian NEP-like enzymes include the endothelin- converting enzymes (ECE-1 and ECE-2), KELL and PEX. A number of novel mamma lian homologues of NEP have also recently been described. NEP family member s are potential therapeutic targets, for example in cardiovascular and infl ammatory disorders, and potent and selective inhibitors such as phosphorami don have contributed to understanding enzyme function. Inhibitor design sho uld be facilitated by the recent three-dimensional structural solution of t he MEP-phosphoramidon complex. For several of the family members, however, a well-defined physiological function or substrate is lacking. Knowledge of the complete genomes of Caenorhabditis elegans and Drosophila melanogaster allows the full complement of NEP-like activities to be analysed in a sing le organism. These model organisms also provide convenient systems for exam ining cell-specific expression, developmental and functional roles of this peptidase family, and reveal the power of functional genomics. BioEssays 23 :261-269, 2001. (C) 2001 John Wiley & Sons, Inc.