Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones ¹

Abstract

This report summarizes the recent rapid development of research on neutral endopeptidase 24.11 (enkephalinase; NEP) and on two other metalloenzymes, meprin and endopeptidase 24.15. NEP cleaves a variety of active peptides, including enkephalins, at the amino side of hydrophobic amino acids. The cDNA for human, rat, and rabbit NEP has been cloned and the deduced protein sequences revealed a high degree of homology (93-94%). Site-directed mutagenesis proved that an active site glutamic acid is involved in catalysis and two active site histidines are responsible for binding the zinc cofactor. Although NEP was originally discovered in the kidney, it is widely distributed in the body including specific structures in the central nervous system, lung, male genital tract, and intestine and in neutrophils, fibroblasts, and epithelial cells. In tissues and cells NEP is bound to plasma membrane through a hydrophobic membrane-spanning domain near the NH2 terminus, but it is present in soluble form in urine and blood. In addition to enkephalins, NEP cleaves kinins, chemotactic peptide, atrial natriuretic factor (ANF), and substance P in vivo. NEP in the lung is a major inactivator of substance P, which constricts the airway smooth muscles. Because of the possible involvement of NEP in the metabolism of opioid peptides and the cardiac hormone ANF, orally active inhibitors have been synthesized. Compounds that inhibit both aminopeptidase and NEP were reported to prolong the analgesic effects of enkephalins. Other inhibitors given per os prolonged the renal effects of exogenous ANF. A newly synthesized specific inhibitor of NEP was also active in animal experiments as an analgesic. Studies on the structure and function of NEP should lead to further development of therapeutically applicable inhibitors.

Neutral endopeptidase and angiotensin I converting enzyme insertion/deletion gene polymorphism in humans

“…[25][26][27][28] NEP also contributes to the degradation of extracellular BK (specially when ACE is inhibited). 29 In human cardiac tissue, NEP accounts for nearly 50% of the metabolism of BK.…”

Sensitive substrates for neprilysin (neutral endopeptidase) and thermolysin that are highly resistant to serine proteases

“…NEP has been implicated in the metabolism and regulation of a variety of biologically active peptides, e.g. the enkephalins, substance P, atrial natriuretic factor, bradykinin and the chemotactic peptide fMet-Leu-Phe [7,8]. The amino acid sequence of human NEP is identical with that of the common acute lymphoblastic leukemia antigen (CALLA; CD 10) and is highly conserved in different species [9][10][11].…”

The Expression and Localization of Neutral Endopeptidase 24.11/CD10 in Human Gestational Trophoblastic Diseases

“…A variety of active peptides are known to be NEP substrates in vitro (Erdös and Skidgel, 1989). It has been shown that NEP regulates the biological activity of the peptide substrates in vivo by modulating their local concentrations available for receptor bind- Immunohistochemical staining of NEP/CD10 in gestational choriocarcinoma tissues.…”

“…However, the enzyme is also expressed on a variety of nonhematopoietic cells and certain solid tumor cell lines (Chu and Arber, 2000). Because NEP cleaves small peptides on the aminoterminal side of hydrophobic amino acids, there are many known NEP substrates including enkephalins, atrial natriuretic factor, substance P, bombesin, and endothelins (Erdös and Skidgel, 1989). The physiological role of the enzyme depends on available substrates in specific organs and cell types (Shipp and Look, 1993).…”