neprilysin

Neprilysin, also known as neutral endopeptidase (NEP), is a zinc-dependent metallopeptidase of the M13 family. It is encoded by the MME gene in humans and functions as a membrane-bound ectoenzyme that is active on the cell surface in many tissues.

Biochemical properties and substrates: Neprilysin is a type II transmembrane glycoprotein with an extracellular catalytic domain that contains a zinc-binding HEXXH motif. It cleaves a broad spectrum of peptides, including natriuretic peptides (A-type, B-type, and C-type natriuretic peptides), enkephalins, substance P, bradykinin-derived peptides, and amyloid beta peptides. Its activity depends on zinc and can be inhibited by specific NEP inhibitors.

Distribution and physiological roles: Neprilysin is widely expressed, with notable presence in the kidney, vascular endothelium, smooth muscle, and central nervous system. By degrading natriuretic peptides, it contributes to regulation of vascular tone, fluid balance, and blood pressure. Through degradation of various neuropeptides, it also modulates neuronal signaling. In the brain, neprilysin participates in the clearance of amyloid beta peptides, linking its activity to discussions of Alzheimer's disease pathology.

Clinical significance and therapeutics: Inhibitors of neprilysin are used to enhance natriuretic peptide signaling in cardiovascular disease. A prominent therapy is the neprilysin inhibitor sacubitril combined with the angiotensin II receptor blocker valsartan (licensed as an ARNI, such as Entresto), which reduces cardiovascular death in heart failure with reduced ejection fraction. Potential adverse effects include hypotension and angioedema, particularly with concomitant ACE inhibitors. Because neprilysin also degrades amyloid beta, its inhibition has implications for brain peptide homeostasis and is a consideration in research on neurodegenerative diseases. The MME gene remains a focal point in studies of neprilysin expression and function.