Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect.

Yoshimoto, Tadashi; Kado, Kunio; Matsubara, Futoshi; Koriyama, Nobuhiro; Kaneto, Hiroshi; Tsuru, Daisuke

doi:10.1248/bpb1978.10.730

Cited by 172 publications

(103 citation statements)

References 28 publications

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“…The archetypical member of this family, prolyl oligopeptidase (POP; EC 3.4.21.26), exclusively hydrolyzes peptide bonds C terminal to proline residues in peptides (31). It has been implicated in the pathophysiology of depression (20) and has attracted pharmaceutical attention, since POP inhibitors have shown potential in the treatment of amnesia (39) and Alzheimer's disease (36). Prolyl oligopeptidase has also served as a model for structural studies of serine oligopeptidases.…”

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confidence: 99%

Substrate Recognition Properties of Oligopeptidase B fromSalmonella entericaSerovar Typhimurium

2002

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Oligopeptidase B (OpdB) is a serine peptidase broadly distributed among unicellular eukaryotes, gramnegative bacteria, and spirochetes which has emerged as an important virulence factor and potential therapeutic target in infectious diseases. We report here the cloning and expression of the opdB homologue from Salmonella enterica serovar Typhimurium and demonstrate that it exhibits amidolytic activity exclusively against substrates with basic residues in P 1 . While similar to its eukaryotic homologues in terms of substrate specificity, Salmonella OpdB differs significantly in catalytic power and inhibition and activation properties. In addition to oligopeptide substrates, restricted proteolysis of histone proteins was observed, although no cleavage was seen at or near residues that had been posttranslationally modified or at defined secondary structures. This supports the idea that the catalytic site of OpdB may be accessible only to unstructured oligopeptides, similar to the closely related prolyl oligopeptidase (POP). Salmonella OpdB was employed as a model enzyme to define determinants of substrate specificity that distinguish OpdB from POP, which hydrolyzes substrates exclusively at proline residues. Using site-directed mutagenesis, nine acidic residues that are conserved in OpdBs but absent from POPs were converted to their corresponding residues in POP. In this manner, we identified a pair of glutamic acid residues, Glu 576 and Glu 578 , that define P 1 specificity and direct OpdB cleavage C terminal to basic residues. We have also identified a second pair of residues, Asp 460 and Asp 462 , that may be involved in defining P 2 specificity and thus direct preferential cleavage by OpdB after pairs of basic residues.The oligopeptidase B (OpdB; EC 3.4.21.83) subfamily of serine peptidases represents one of two branches of the prolyl oligopeptidase family of serine peptidases (the S9 family, in the nomenclature of Barrett and Rawlings [2]). The archetypical member of this family, prolyl oligopeptidase (POP; EC 3.4.21.26), exclusively hydrolyzes peptide bonds C terminal to proline residues in peptides (31). It has been implicated in the pathophysiology of depression (20) and has attracted pharmaceutical attention, since POP inhibitors have shown potential in the treatment of amnesia (39) and Alzheimer's disease (36). Prolyl oligopeptidase has also served as a model for structural studies of serine oligopeptidases. A 1.4-Å crystal structure analysis of POP recently revealed that an N-terminal regulatory domain, consisting of a seven-bladed ␤-propeller, regulates substrate access to the C-terminal catalytic domain (7) by a gating filter mechanism (8).In contrast to the POPs, the OpdB branch of the POP family has received much less attention. These enzymes demonstrate a trypsin-like substrate specificity, hydrolyzing peptide bonds on the C-terminal side of basic amino acid residues of lowmolecular-mass (Ͻ3 kDa) peptides (17,30,37,41). Of great importance for potential therapeutic applications, OpdB is only found i...

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confidence: 99%

Substrate Recognition Properties of Oligopeptidase B fromSalmonella entericaSerovar Typhimurium

2002

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“…(2)(3)(4)(5), al though its physiological role still remains obscure. Since vasopressin, among these peptides, has been suggested to be deeply involved in the process of learning and memory in animal experiments (6-9), Yoshimoto et al synthesized a variety of PED inhibitors and demon strated a probable relationship between their PED in hibition in vitro and anti-amnesic activity in vivo (10). In addition, a significant elevation of PED activity has recently been observed in the brain of patients with Alzheimer's disease (11).…”

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Protective Effect of Eurystatins A and B, New Prolyl Endopeptidase Inhibitors, on Scopolamine-Induced Amnesia in Rats

Kamei

Ueki

Obi

et al. 1992

Japanese Journal of Pharmacology

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-Eurystatins A and B, which are produced by Streptomyces eurythermus R353-21, potently inhibited Flavobacterium prolyl endopeptidase (PED) with IC50 values of 0.004 and 0.002,ug/ml, res pectively, while no inhibition was observed against another 5 proteases, even at 100 1tg/ml. The pro tective effect of eurystatins A and B against scopolamine (3 mg/kg, i.p.)-induced amnesia in rats was evaluated by the step-through one-trial passive avoidance method. When administered i.p. 30 min prior to the acquisition trial, both eurystatins A, at 2 8 mg/kg, and B, at 4 8 mg/kg, significantly protected rats from the amnesic effect of scopolamine without behavioral side effects.

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“…PREP is widely distributed in the brain (Irazusta et al, 2002;Myöhänen et al, 2007Myöhänen et al, , 2008 and increased activity of PREP has been associated with cell death processes in various neurodegenerative diseases, including Alzheimer's and Parkinson's diseases (Brandt et al, 2008;Mantle et al, 1996). PREP is believed to act in the extracellular space with involvement in the maturation and degradation of peptide hormones and neuropeptides (Bellemere et al, 2004;Cunningham and O'Connor, 1997;Shishido et al, 1999), which has been proposed to be the mechanism underlying some beneficial effects of PREP inhibitors in animal memory models (Shishido et al, 1998;Toide et al, 1997;Yoshimoto et al, 1987) and in aged mice (Kato et al, 1997). Besides its extracellular action, PREP has been shown to act intracellularly and important roles of PREP have been demonstrated in signaling pathways or in transport and secretion of proteins and peptides associated with neurodegeneration (Brandt et al, 2008;Di Daniel et al, 2009;Rossner et al, 2005;Savolainen et al, 2015;Schulz et al, 2002Schulz et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Jaako

Waniek

Parik

et al. 2016

Journal of Cell Science

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Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newlydiscovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM.

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Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect.

Cited by 172 publications

References 28 publications

Substrate Recognition Properties of Oligopeptidase B fromSalmonella entericaSerovar Typhimurium

Substrate Recognition Properties of Oligopeptidase B fromSalmonella entericaSerovar Typhimurium

Protective Effect of Eurystatins A and B, New Prolyl Endopeptidase Inhibitors, on Scopolamine-Induced Amnesia in Rats

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

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