Exploring the structure and function of zinc metallopeptidases: old enzymes and new discoveries.

Neprilysin [or neutral endopeptidase (NEP)] and angiotensin-converting enzyme (ACE) are zinc metallopeptidases involved in the extracellular metabolism of biologically active peptides. Recent genomic advances have led to the identification of novel homologues of each of these ectoenzymes and new physiological and pathological roles are emerging for them. The structures of each of these peptidases have recently been solved providing insight into their distinct catalytic sites. In addition to its originally identified role in neuropeptide metabolism in the nervous system, NEP is implicated in regulation of the cardiovascular system and is protective in prostate and certain other cancers. Hence the cellular concentration of NEP is critical to tissue homoeostasis. Most recently, NEP has been shown to exert neuroprotective actions, principally through its ability to catabolize the neurotoxic Alzheimer's amyloid peptide. The only known homologue of ACE, termed ACE2, is critical to cardiovascular function, but its physiological substrates and precise metabolic roles remain to be elucidated. Other members of these growing metallopeptidase families await further characterization and possible exploitation as therapeutic targets.