There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct fropm angiotensin coverting enzyme (ACE), might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, we have designed a potent and specific enkephalinase inhibitor. We report here that this compound, thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.

The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice

Numerous peptides appear to be neurotransmitter candidates in the brain. Some, such as the opioid peptide enkephalins, neurotensin, and substance P, were first isolaterd from the brain. Peptides, such as cholecystokinin and vasoactive intestinal polypeptide, were known as intestinal hormones and later recognized as brain constituents. Certain hypothalamic-releasing hormones, pituitary peptides, and blood-derived peptides like angiotensin II and bradykinin, may also be central neurotransmitters. The diversity of localization of these peptides throughout the brain implies a multiplicity of potential roles.

https://science.sciencemag.org/content/sci/209/4460/976.full.pdf

Brain peptides as neurotransmitters.

Neprilysin (NEP), a thermolysin-like zinc metalloendopeptidase, plays an important role in turning off peptide signalling events at the cell surface. It is involved in the metabolism of a number of regulatory peptides of the mammalian nervous, cardiovascular, inflammatory and immune systems. Examples include enkephalins, tachykinins, natriuretic and chemotactic peptides. NEP is an integral plasma membrane ectopeptidase of the M13 family of zinc peptidases. Other related mammalian NEP-like enzymes include the endothelin-converting enzymes (ECE-1 and ECE-2), KELL and PEX. A number of novel mammalian homologues of NEP have also recently been described. NEP family members are potential therapeutic targets, for example in cardiovascular and inflammatory disorders, and potent and selective inhibitors such as phosphoramidon have contributed to understanding enzyme function. Inhibitor design should be facilitated by the recent three-dimensional structural solution of the NEP–phosphoramidon complex. For several of the family members, however, a well-defined physiological function or substrate is lacking. Knowledge of the complete genomes of Caenorhabditis elegans and Drosophila melanogaster allows the full complement of NEP-like activities to be analysed in a single organism. These model organisms also provide convenient systems for examining cell-specific expression, developmental and functional roles of this peptidase family, and reveal the power of functional genomics. BioEssays 23:261–269, 2001. © 2001 John Wiley & Sons, Inc.

The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.

Hematopoietic differentiation antigens that are membrane-associated enzymes: cutting is the key!

Atrial natriuretic peptide, B-type natriuretic peptide and C-type natriuretic peptide constitute a family of three structurally related, but genetically distinct, signaling molecules that regulate the cardiovascular, skeletal, nervous, reproductive and other systems by activating transmembrane guanylyl cyclases and elevating intracellular cGMP concentrations. This review broadly discusses the general characteristics of natriuretic peptides and their cognate signaling receptors, and then specifically discusses the tissue-specific metabolism of natriuretic peptides and their degradation by neprilysin, insulin-degrading enzyme, and natriuretic peptide receptor-C.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2011.08082.x

Natriuretic peptide metabolism, clearance and degradation

CONSIDERABLE evidence now exists to suggest that the endogenous opioid pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) function as neurotransmitters in the central nervous system. A correlate of this hypothesis is that a specific inactivation mechanism must operate in the vicinity of opiate receptors to turn off rapidly the enkephalin signal. Indeed recent studies have shown that the pentapeptides are subject to extremely rapid inactivation in various tissues, occurring primarily by cleavage of the Tyr–Gly amide bond1–5. This feature accounts for the short-lasting biological activity of these peptides, contrasting with the potent activity of synthetic analogues such as (D-Ala2)-Met-enkephalinamide in which this bond is protected6. However, many tissues including brain contain a spectrum of peptidases with low specificities and affinities7 and no evidence has been yet provided for the involvement of a specific enzyme in the regulation of enkephalinergic transmission. We now report the presence of a high-affinity peptidase in a particulate fraction of mouse striatum splitting the Leu-enkephalin molecule with release of a tripeptide fragment (Tyr-Gly-Gly) and exhibiting definite substrate specificity. The marked and selective increase in the activity of this peptidase in the striatum of mice chronically treated with morphine suggests that it might be associated with enkephalinergic transmission.

High-affinity enkephalin-degrading peptidase in brain is increased after morphine

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High-affinity enkephalin-degrading peptidase in brain is increased after morphine