Human Neutral Endopeptidase 24.11 (NEP, Enkephalinase) ; Function, Distribution and Release

Abstract

Neutral endopeptidase 24.11 (NEP), although discovered in 1974 (1), received much attention recently because of its very wide distribution and many potential functions in the body (2). NEP is also known as enkephalinase (3). This name wrongfully indicates that it only cleaves enkephalins, whereas it actually hydrolyzes a variety of vaso- and CNS-active peptides (2-7). NEP, a metalloendopeptidase, was first detected in the brush border of animal kidney by Kerr and Kenny (1), who used the B-chain of insulin as substrate. The name “enkephalinase” was given later to an enzyme present in brain which cleaved enkephalins at the same bond as the angiotensin I converting enzyme (kininase II or ACE) (8). Schwartz et al (3) suggested that this “enkephalinase” was a second peptidyl dipeptidase present in the striatum of mouse brain. Because the Km of enkephalins with the latter enzyme was lower than with ACE, the second peptidyl dipeptidase was named the true “enkephalinase”. Both enzymes are membranebound and contain zinc as a cofactor, but human NEP is not a second peptidyl dipeptidase. It differs from ACE in its substrate specificity; for example, it releases a tetrapeptide from angiotensin II and inactivates angiotensin I by cleaving the C-terminal tripieptide instead of activating it as ACE does by releasing His-Leu (4,7). It does not crossreact with antiserum to human ACE (9), and is inhibited by phosphoramidon and thiorphan (2,5) but not by captopril or enalapril. Human NEP can be classified as a thermolysin-type metalloendopeptidase (2,10,11).