Enkephalin-degrading enzyme (EDE)

Enkephalin-degrading enzymes are a group of zinc-metallopeptidases, primarily neprilysin (NEP) and aminopeptidase N (APN), that catalyze the inactivation of endogenous opioid peptides known as enkephalins [1][2]. Neprilysin, also known as neutral endopeptidase or enkephalinase, cleaves the Gly3-Phe4 bond of enkephalins, while aminopeptidase N cleaves the N-terminal Tyr1-Gly2 bond [2][3]. These enzymes are widely distributed in the central nervous system and peripheral tissues, where they limit the duration and magnitude of opioid receptor signaling [1]. In therapeutic contexts, inhibiting these enzymes prevents the breakdown of enkephalins, thereby enhancing natural antinociceptive and anti-secretory responses [4]. This mechanism is utilized in the treatment of conditions such as acute diarrhea and is being investigated for chronic pain management through dual enkephalinase inhibitors (DENKIs) [4][5]. Additionally, neprilysin inhibition is a key component in treating heart failure, as the enzyme also degrades natriuretic peptides [6].

Other names

EnkephalinaseNeutral endopeptidaseNEPCD10Aminopeptidase NAPNCD13Membrane metallo-endopeptidaseMMEAlanyl aminopeptidaseANPEP

Inhibition of the enzymatic degradation of endogenous enkephalins (met-enkephalin and leu-enkephalin), leading to increased local concentrations of these peptides and prolonged activation of mu- and delta-opioid receptors.