Neprilysin

This chapter describes structural properties of neprilysin. Neprilysin is essentially an oligopeptidase hydrolyzing peptides up to 40–50 amino acids in length, although generally the efficiency of hydrolysis declines with increasing length of peptide. One of the most efficiently hydrolyzed substrates is the amidated, undecapeptide substance P. The substrate specificity of neprilysin has been explored with a wide range of synthetic and natural peptide substrates, although those for which neprilysin has been established to have a physiological role in metabolism are limited. The principal substrates in vivo appear to be the enkephalins, tachykinins such as substance P, endothelins, bradykinin and the atrial natriuretic peptide family. Thus, inhibitors of neprilysin may have potential in treatment of pain, inflammation, and cardiovascular disease. The natural substrates of neprilysin include adrenomedullin, members of the vasoactive intestinal peptide family, thymopentin basic fibroblast growth factor and, most significantly in relation to human disease, the Alzheimer's β-amyloid peptide. Neprilysin is a widely distributed enzyme and phosphoramidon-sensitive activities with the appropriate specificity have been identified in diverse species including the nematode worm, Caenorhabditis elegans, and the fly, Drosophila melanogaster.