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Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Endopeptidase 24.16 was first described as an enzyme in rat brain membranes that degrades neurotensin (Checler et al., 1983) and has been called neurotensin-degrading enzyme and neurolysin (Checler et al., 1995). Although many properties are similar to those of endopeptidase 24.15, purification and characterization of the enzyme proved that it is different (Checler et al., 1986; Millican et al., 1991; Checler et al., 1995). Recently, it was shown that the enzyme is likely identical with the soluble Ang II-binding protein and rabbit microsomal endopeptidase (Rosenberg et al., 1988; Sugiura et al., 1992) and is at least partly localized in the mitochondrial intermembrane space, where it interacts noncovalently with the inner membrane (Serizawa et al., 1995; Barrett et al., 1995). Its primary sequence reveals that it belongs to the same family of enzymes as endopeptidase 24.15 (Serizawa et al., 1995; Barrett et al., 1995). A variant of this enzyme was called endopeptidase 24.16B (Rodd and Hersh, 1995). Purified endopeptidase 24.16 cleaves Bk at the same site as endopeptidase 24.15 (Fig. 1), at the Phe5-Ser6 bond (Millican et al., 1991). The cytosolic and mitochondrial localization of endopeptidase 24.16 appears to exclude its importance as a major kininase.
Small molecule neurolysin activators, potential multi-mechanism agents for ischemic stroke therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Shiva Hadi Esfahani, Thomas J. Abbruscato, Paul C. Trippier, Vardan T. Karamyan
As we often learn from nature, elucidation and understanding of the brain’s endogenous self-protective and recovery mechanisms have been an emerging approach in the stroke research field to fulfill the unmet need for development of new therapies [1]. For acute ischemic stroke, which constitutes a multifactorial pathological process involving excitotoxicity, oxidative stress, blood–brain barrier (BBB) hyperpermeability, neuroinflammation, edema formation, and cell death, the basic premise of this approach is that mimicking or engaging the brain’s self-protective mechanisms could afford cerebroprotection and effective stroke therapy. One such mechanism identified by our group is peptidase neurolysin (Nln), which is viewed as a compensatory and cerebroprotective enzyme in the post-stroke brain and is being investigated as a potential drug target for acute, ischemic stroke therapy [2]. This focused opinion paper briefly discusses the multi-faceted function of Nln and its peptide substrates in the ischemic brain and details the progress made in development of small molecule Nln activators as a potential new class of multi-mechanism agents for the treatment of acute ischemic stroke.