Degradation of enkephalins: the search for an enkephalinase

Abstract

The opioid peptides methionine-enkephalin and leucine-enkephalin appear to exert their biological effects through a receptor mediated mechanism. There appears to be three potential mechanisms for enkephalin degradation which could serve to control enkephalin levels in the vicinity of enkephalin receptors. These are, 1) cleavage of the tyrosyl-glycine bond by aminopeptidases, 2) cleavage of the glycl-glycine bond by a dipeptidyl aminopeptidase, and 3) cleavage of the glycyl-phenylalanine bond by a dipeptidyl carboxypeptidase. In this review the biochemical properties of these potential enkephalinases are described, and the evidence for each acting as an enkephalinase is reviewed.

Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase)

“…Enkephalinase (neutral endopeptidase, EC 3A.24.11) is a membrane-bound zinc-metallo peptidase which cleaves the GlyLPhe 4 amide bond of the opioid peptides, enkephalins, both in vitro and in vivo [1][2][3]. Thus, acetorphan, a parenterally active enkephalinase inhibitor, was shown to display analgesic properties in humans [4,5].…”

Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide.

“…This enzyme is identical with the enkephalinase A of brain (2,3). The richest source of NEP appears to be the kidney, and it has been purified to homogeneity from both human (4) and animal (1) kidneys.…”

“…The membrane metallo-endopeptidase (NEP; neutral endopeptidase, kidney-brush-border neutral proteinase, enkephalinase, EC 3.4.24.11), was first found in the brush border of rabbit kidney (1) and later in many other tissues (2)(3)(4)(5)(6)(7). This enzyme is identical with the enkephalinase A of brain (2,3).…”

Common acute lymphoblastic leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ("enkephalinase"): direct evidence by cDNA transfection analysis.

“…Neutral endopeptidase 24.11 is a cell-membrane-associated enzyme that cleaves peptide bonds on the amino side of hydrophobic amino acids (23). The enzyme was identified in brain as an enkephalinase because it cleaved the Gly3-Phe4 bond of enkephalins (24).…”

“…This is of particular interest, given previous studies demonstrating that the cell-surface-bound enzyme has the potential to mediate a wide range of biological activities in a variety of tissues. For example, neutral endopeptidase 24.11 has been shown to inactivate endogenous opioid pentapeptides on neurons in brain (23,24), chemotactic peptide (fMet-Leu-Phe) on polymorphonuclear granulocytes (28), and a variety of regulatory peptides on the surface of proximal tubule epithelial cells ofthe kidney (32). Amino acid sequences of the enzyme derived from three tissue sources (brain, kidney, and placenta) in three species as well as from a human lymphoblastic leukemia cell line are virtually identical (i2, 14,15,22); these results imply conservation of critical functional domains for zinc binding, substrate binding, and catalysis.…”