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

Kamei, Hideo; Ueki, Tomokazu; Obi, Yumiko; Fukagawa, Yasuo; Oki, Taikan

doi:10.1254/jjp.60.377

Cited by 15 publications

(9 citation statements)

References 13 publications

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“…POP is implicated in the metabolism of peptide hormones and neuropeptides [2][3][4] although some of the previously identified neuropeptide substrates do not appear to be hydrolyzed in vivo upon closer inspection [5]. Specific inhibitors have been shown to relieve scopolamine-induced amnesia [6], to ameliorate memory loss caused by age, brain lesions, or amnesic drugs [7,8] and were neuroprotective under various conditions [9][10][11], resulting in significant pharmaceutical and academic interest. It was reported that POP has roles in the phosphoinositide cycle [12][13][14], intracellular transport [15], cellular differentiation [16], inflammation [17], angiogenesis [18], and cancer development [19].…”

Section: Introductionmentioning

confidence: 99%

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

Szeltner

Juhász

Szamosi

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Prolyl oligopeptidase (POP) has emerged as a drug target for neurological diseases. A flexible loop structure comprising loop A (res. 189-209) and loop B (res. 577-608) at the domain interface is implicated in substrate entry to the active site. Here we determined the kinetic and structural properties of POP with mutations in loop A, loop B and in two additional flexible loops. POP lacking loop A proved to be an inefficient enzyme as did POP with a mutation in loop B (T590C). Both constructs displayed an altered substrate preference profile. Ligand binding become markedly degraded. Conversely, the T202C mutation increased the flexibility of loop A, enhancing the catalytic efficiency beyond that of the native enzyme. The T590C mutation in loop B increased the preference for shorter peptides, indicating a role in substrate gating. Loop A and the His loop housing the catalytic histidine are disordered in the H680A mutant crystal structure, implying coordinated structural dynamics of these loops. A 17-mer peptide could not inhibit variants possessing malfunctioning loop A. This substrate may bind non-productively to an exosite involving loop A or to an open enzyme form. Biophysical studies suggest that mammalian POP resides in a predominantly closed conformational state, especially at physiological conditions. The flexible loop A, loop B and His loop system at the active site is the main regulator of substrate gating and specificity and represents a new inhibitor target.

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Section: Introductionmentioning

confidence: 99%

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

Szeltner

Juhász

Szamosi

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…All prolyl oligopeptidase inhibitors tested were effective. An amino derivative of SUAM-1221 significantly reversed scopolamine-induced amnesia in mice (Atack et al, 1991), as did eurystatins A and B in the rat (Kamei et al, 1991).…”

mentioning

confidence: 87%

“…Derivatives of SUAM 1221 {N-IIN-(phenyl)butyryl-L-prolyl I pyrrolidine } potently inhibit the rat brain enzyme (K, values = 4-7 nM) (Atack et al, 1991). Two inhibitors isolated from Flavobacterium, termed eurystatins A and B, are potent inhibitors (Kamei et al, 1991), as are peptidyl-a-keto heterocycles (Tsutsumi et al, 1994).…”

mentioning

confidence: 99%

Inhibition of Prolyl Oligopeptidase by Fmoc‐Aminoacylpyrrolidine‐2‐Nitriles

Wilk

1996

Journal of Neurochemistry

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Prolyl oligopeptidase (EC 3.4.21.26), a widely distributed cytosolic enzyme, cleaves peptidylprolyl peptide and peptidyiprolyl amino acid bonds in many neuropeptide substrates. Its action on vasopressin has been proposed as the underlying mechanism accounting for the ability of inhibitors of prolyl oligopeptidase to reverse scopolamine-induced amnesia in rats. Future behavioral studies would be facilitated by the availability of potent inhibitors readily synthesized from common intermediates. A series of Fmoc-aminoacylpyrrolidine-2-nitriles prepared by a simple two-step synthesis were found to be potent noncompetitive inhibitors of the rabbit brain enzyme. The most potent inhibitors, Fmoc-prolyl-pyrrolidine-2-nitrile and Fmoc-alanyl-pyrrolidine-2-nitrile, each have a K, of 5 nM. The compounds are cell permeable and stable. They do not inhibit the related enzyme dipeptidyl peptidase IV (EC 3.4.14.5). When administered intraperitoneally to mice, Fmoc-alanyl-pyrrolidine-2-nitrile crosses the blood-brain barrier to inhibit brain prolyl oIlgopeptidase. The ease of synthesis, potency, efficacy in vivo, stability, and specificity of Fmoc-aminoacylpyrrolidine-2-nitriles may make them inhibitors of choice in studies probing the physiological significance of prolyl oligopeptidase.

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“…Oki and co-workers in 1997 first reported the isolation of Eurystatin A( 28)f rom the cultured broth of Streptomyces eurythermus R353-21 ( Figure 20). [82] It has significant inhibitory activity against serine protease prolyl endopeptidase. [83,86] Synthetic approaches using non-AA routes…”

Section: Isolation Characterization and Biological Activitymentioning

confidence: 99%

A Comparative Synthetic Strategy Perspective on α‐Amino Acid‐ and Non‐Amino Acid‐Derived Synthons towards Total Syntheses of Selected Natural Macrolides

Manda

Tripathi

Ghoshal

et al. 2020

Chemistry A European J

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other methods derived from miscellaneous synthons towards the total synthesiso fn on-peptidic macrolides.T he synthetic routes and the key strategies involved in the total syntheses of ten natural macrolides have been discussed. Both the amino acid-derived and non-amino acid-derived synthetic routes have been illustratedt op resentacomparative study between the two approaches.Scheme3.Prusov's approach towards the total synthesis of Ripostatin B( 5).Scheme4.To tal synthesis of Ripostatin B( 5)b yA ltmann's approach. Figure 3. Biologically active analogues of Ripostatin.

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

Cited by 15 publications

References 13 publications

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

Inhibition of Prolyl Oligopeptidase by Fmoc‐Aminoacylpyrrolidine‐2‐Nitriles

A Comparative Synthetic Strategy Perspective on α‐Amino Acid‐ and Non‐Amino Acid‐Derived Synthons towards Total Syntheses of Selected Natural Macrolides

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