Soluble neutral metallopeptidases: physiological regulators of peptide action

Shrimpton, Corie N.; Smith, Ann

doi:10.1002/1099-1387(200006)6:6<251::aid-psc266>3.0.co;2-o

Cited by 10 publications

(9 citation statements)

References 71 publications

(126 reference statements)

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“…Neurolysin (EC 3.4.24.16) is a zinc metalloprotease that inactivates particular biologically active peptides, such as neurotensin and dynorphin A, by specific cleavage [1]. Whereas the kappa-opioid receptor agonist dynorphin A is a well-known and obvious endogenous pain-relieving peptide, neurotensin has been reported to have analgesic properties when applied centrally in animal models [2].…”

Section: Introductionmentioning

confidence: 99%

Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin

et al. 2005

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The agaricoglycerides are a new class of fungal secondary metabolites that constitute esters of chlorinated 4-hydroxy benzoic acid and glycerol. They are produced in cultures of the edible mushroom, Agaricus macrosporus, and several other basidiomycetes of the genera Agaricus, Hypholoma, Psathyrella and Stropharia. The main active principle, agaricoglyceride A, showed strong activities against neurolysin, a protease involved in the regulation of dynorphin and neurotensin metabolism (IC 50 ϭ200 nM), and even exhibited moderate analgesic in vivo activities in an in vivo model. Agaricoglyceride monoacetates (IC 50 ϭ50 nM) showed even stronger in vitro activities. Several further co-metabolites with weaker or lacking bioactivities were also obtained and characterized. Among those were further agaricoglyceride derivatives, as well as further chlorinated phenol derivatives such as the new compound, agaricic ester. The characteristics of the producer organisms, the isolation of bioactive metabolites from cultures of A. macrosporus, their biological activities, and preliminary results on their occurrence in basidiomycetes, are described. Keywords agaricoglycerides, pain, fermentation, fungi, in vivo activity IntroductionNeurolysin (EC 3.4.24.16) is a zinc metalloprotease that inactivates particular biologically active peptides, such as neurotensin and dynorphin A, by specific cleavage [1]. Whereas the kappa-opioid receptor agonist dynorphin A is a well-known and obvious endogenous pain-relieving peptide, neurotensin has been reported to have analgesic properties when applied centrally in animal models [2]. Therefore, neurolysin inhibitors are likely to enhance the analgesic properties of neurotensin and/or dynorphin A by inhibiting cleavage and inactivation of these peptides. Accordingly, selective inhibitors of neurolysin are likely to emphasize the analgesic effects of the aforementioned peptides, which accumulate if their inactivation is prevented. Hence, neurolysin inhibitors appear useful alternatives to complement or substitute therapy with morphine and other opiates in the treatment of severe pain. However, only few specific inhibitors of this target have hitherto been found. Those Bioanalytical Chemistry, GKSS-Forschungszentrum Geesthacht GmbH, Max-Planck-Str. 1, D-21502 Geesthacht/Germany from microbial crude extracts was carried out, followed by identification of bioactive principles from the most promising hits by bioassay-guided fractionation.The current paper deals with the discovery of a new class of biologically active natural products from cultures of edible mushrooms and other basidiomycetes. Their production, isolation, and biological properties are described here, while their physicochemical parameters, structure elucidation, derivatization and total synthesis have been compiled in a patent application [7]. Further details on their structure elucidation will be reported concurrently. Results and DiscussionIsolation and Biological Activities of Agaricoglycerides (1ϳ4) and Their Co-metabolites...

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Section: Introductionmentioning

confidence: 99%

Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin

et al. 2005

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“…The exact role of the soluble members of this family, particularly EP24.15 and EP24.16, is less clear; they are believed to be involved in the metabolism of a number of bioactive peptides, such as BK, neurotensin, and gonadotropin-releasing hormone (GnRH) [9], although definitive evidence is still lacking. Both enzymes are true peptidases, in that substrates are restricted to less than about 15 residues.…”

Section: Discussionmentioning

confidence: 99%

“…There is also a tendency for these peptidases to cleave Cterminal to a hydrophobic residue, such as Phe 5 in BK. However, this is not strictly the case; for example, EP24.15 cleaves between two arginine residues in neurotensin [9]. This neuropeptide represents one of very few naturally occurring substrates in which the cleavage site differs between EP24.15 and EP24.16, the latter cleaving at a Pro-Tyr bond.…”

Section: Discussionmentioning

confidence: 99%

Bradykinin analogues with ?-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC 3.4.24.15 and EC 3.4.24.16

Lew

Boulos²,

Stewart³

et al. 2000

J. Peptide Sci.

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“…The conjugate addition was again performed at room temperature in methanol and was complete after overnight reaction to give (5). The hydrogenation of (5) was carried out as described for the synthesis of i3-Ala and the reaction was complete overnight.…”

Section: Synthesis Of -Amino Acidsmentioning

confidence: 99%

“…In vitro, EP 24.15 cleaves bradykinin, gonadotrophin releasing hormone, neurotensin, dynorphin A 1-8, somatostatin and substance P [3,4]. However, the precise role of EP 24.15 in vivo is still to be characterized, although it has been implicated in the metabolism of vasoactive peptides and neuropeptides [5]. The inability to characterize the physiological role of EP 24.15 is due in part to the lack of stable and specific inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

et al. 2000

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Soluble neutral metallopeptidases: physiological regulators of peptide action

Cited by 10 publications

References 71 publications

Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin

Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin

Bradykinin analogues with ?-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC 3.4.24.15 and EC 3.4.24.16

Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

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