Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolyl endopeptidase, which has long been recognised for its importance in the degradation of several neuropeptides such as thyroliberin, luteinising hormone releasing hormone, angiotensin, substance P and neurotensin, has been widely characterised as a cytosolic enzyme. However, in this paper, we report the presence of a prolyl endopeptidase activity in the particulate fractions of bovine brain, which is distinct from that in the cytoplasm. This previously uncharacterised activity was found to reside in the synaptosomal membranes, a location which is highly significant for the inactivation of neuropeptides in brain. Following vigorous salt washing and osmotic shock, the prolyl endopeptidase activity was released from the membranes by treatment with the detergent Triton X-100, and was partially purified by gel filtration on a Sephacryl S-200HR column. This prolyl endopeptidase activity was shown to have a molecular mass (87 kDa) higher than the cytosolic prolyl endopeptidase but, from initial investigation, appears to demonstrate a similarly broad substrate specificity towards proline-containing neuropeptides. The partially purified enzyme was inhibited by certain thiol-protease inhibitors and was also found to be sensitive to the metal chelator 1,10-phenanthroline.
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PMID:Identification and localisation of a synaptosomal membrane prolyl endopeptidase from bovine brain. 785 96

The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine-carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP-4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP-4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP-LI as well as hippocampal TRH-LI.
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PMID:Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain. 869 93

We studied behavioral and pharmacological effects of a novel prolyl endopeptidase inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)- 1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidine-car boxamide (JTP-4819), in rats with middle cerebral artery occlusion. Administration of JTP-4819 (0.1 and 1 mg/kg p.o for 7 days) significantly prolonged passive avoidance latency, while the latency of rats with middle cerebral artery occlusion receiving the vehicle was significantly shorter than that of sham-operated rats. The prolonged escape latency in the Morris water maze task in rats with middle cerebral artery occlusion was also significantly reduced by administration of JTP-4819 (0.3 and 1 mg/kg p.o.). Interestingly, administration of JTP-4819 (0.3-3 mg/kg p.o. for 15 days) restored the decreased cortical thyrotropin-releasing hormone (TRH)-like immunoreactivity content of rats with middle cerebral artery occlusion but did not affect the cortical and hippocampal substance P- or arginine vasopressin-like immunoreactivity content. These results suggest that JTP-4819 ameliorates memory impairment due to middle cerebral artery occlusion by restoring the cortical TRH content.
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PMID:Pharmacological studies of a novel prolyl endopeptidase inhibitor, JTP-4819, in rats with middle cerebral artery occlusion. 881 28

Prolyl endopeptidase has been predominantly described as a cytosolic activity capable of cleaving a number of important neuropeptides (including TRH, LHRH, Bradykinin, Angiotensin, Substance P, Neurotensin, Oxytocin and Vasopressin) on the carboxy side of proline. In this paper, we report, for the first time, on the complete purification and characterization of a membrane-bound form of prolyl endopeptidase. This novel activity has been isolated from the synaptosomal (plasma membranes) membranes of bovine brain. Following gel filtration, hydroxylapatite and hydrophobic interaction chromatographies, the prolyl endopeptidase activity was purified 1400-fold with a 23% recovery of activity. The enzyme was shown to have a relative molecular mass of 87 kDa and a Km of 60 microM for its specific fluorimetric substrate, Z-GlyProMCA. The purified enzyme demonstrated a relatively broad substrate specificity and a relatively high affinity for proline-containing neuropeptides. It was shown to be inhibited by certain thiol-protease inhibitors and by the metal chelator, 1,10-phenanthroline, thus possibly classifying it as a 'thimet' activity. The purified particular form of proyl endopeptidase displayed a similar substrate specificity to the previously reported cytosolic forms of the enzyme. However, there were differences between the two forms in term of their sensitivity to inhibitors, their affinities for the peptide substrates and their relative molecular masses. The different subcellular location (i.e. the synaptosomal membrane) of the particulate prolyl endopeptidase is also of potential physiological significance given that here it is more likely to come in contact with the vesicle-bound neuropeptides than is its cytosolic counterpart.
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PMID:Purification and characterization of a novel membrane-bound form of prolyl endopeptidase from bovine brain. 902 55

The pharmacological actions of JTP-4819, a new prolyl endopeptidase (PEP) inhibitor targeted for the treatment of Alzheimer's disease, are reviewed with respect to its effects on PEP activity, brain neurotransmitters, and memory-related behaviour in rats. JTP-4819 was shown to be a very potent and specific inhibitor of PEP. At nanomolar concentration, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone by PEP in supernatants of the rat cerebral cortex and hippocampus. Repeated administration of JTP-4819 reversed the aging-induced decrease in brain substance P-like and thyrotropin-releasing hormone-like immunoreactivity, suggesting that this drug may be able to improve the imbalance of peptidergic neuronal systems that develops with senescense by inhibiting PEP activity. JTP-4819 increased acetylcholine release from the frontal cortex and hippocampus, regions closely associated with memory, in both young and aged rats. In addition, it improved performance in several memory and learning-related tests (e.g., the Morris water maze task in aged or MCA-occluded rats and the passive avoidance test). This memory-enhancing effect of JTP-4819 may result from prevention of the metabolic degradation of brain neuropeptides by PEP as well as from the enhancement of acetylcholine release. Taken together, these unique and potent pharmacological actions of JTP-4819 suggest that it may have the potential to be used for treating Alzheimer's disease.
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PMID:A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease. 906 74

The effects of a novel prolyl endopeptidase inhibitor (PEP), (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)- 1-pyrrolidinecar-boxamide (JTP-4819), on performance of the Morris water maze task and on central cholinergic function were investigated in aged rats. Spatial memory (escape latency, path length, and swimming speed to the platform) was impaired in aged rats performing the Morris water maze task when compared to young rats. Administration of JTP-4819 (1 mg/kg, p.o.) for 14 days improved this memory deficit in aged rats, as shown by the decrease in escape latency and path length. In addition, when JTP-4819 (at doses of 1 and 3 mg/kg, p.o.) was administered for 3 wk, it reversed the age-related increase of ChAT activity in the cerebral cortex and the decrease of 3H-choline uptake in the hippocampus. These data suggest that JTP-4819 ameliorates age-related impairment of spatial memory and partly reverses central cholinergic dysfunction, possibly due to the enhancement of neuropeptide function by inhibition of PEP mediated degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone.
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PMID:Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and central cholinergic neurons in aged rats. 907 79

Prolyl endopeptidase (PEP, EC 3.4.21.26) is an enzyme to play a role in metabolism of proline-containing neuropeptides, such as vasopressin, substance P and thyrotropin-releasing hormone (TRH), which were suggested to be involved with learning and memory processes. Then, specific inhibitor of PEP is expected to have antiamnesic effects, and thus we screened forty-six water- and methanol-extracts from crude drugs selected on the basis of traditional Chinese medicine theory, for Flavobacterium prolyl endopeptidase inhibition. Among them, the water-extracts of Rhodiola sacra (IC50, 0.77 microgram/ml) and the methanol-extracts of Lycopodium clavatum (IC50, 1.3 micrograms/ml), Paeonia lactiflora var. trichocarpa (IC50, 5.7 micrograms/ml), Paeonia veitchii (IC50, 2.4 micrograms/ml) and Rhodiola sacra (IC50, 0.67 microgram/ml) showed strong inhibitory activity. In addition, we also examined the PEP inhibitory activity of eleven compounds from Salvia deserta, and found that in addition to a catechol group alpha-hydroxy-para-quinone group may be related to the PEP inhibition.
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PMID:Screening of crude drug extracts for prolyl endopeptidase inhibitory activity. 1043 85

We conducted behavioral and neurochemical studies of a novel prolyl endopeptidase inhibitor, (S)2-[[(S)-2-(hydroxyacetyl)-1pyrrolidinyl]carbonyl]-N-(phenylmeth yl)-1-pyrrolidine-carboxamide (JTP-4819), in rats with lesions of the nucleus basalis magnocellularis (NBM-lesioned rats) induced by ibotenate. Administration of JTP-4819 (1 and 3 mg/kg, p.o.), on and after the 8th day, significantly shortened the escape latency in the Morris water maze as compared to the vehicle-treated group. JTP-4819 also significantly increased the path length in the quadrant with the platform removed in the spatial probe trial. Neurochemical studies of brains removed after the Morris water maze task showed that choline acetyltransferase activity in the cerebral cortex, but not the hippocampus, was significantly reduced by NBM lesioning, while there were no changes of muscarinic M1 receptor binding activity detected using [3H]pirenzepine. JTP-4819 had almost no effect on these cholinergic parameters in NBM-lesioned rats. Substance P-like immunoreactivity (LI), thyrotropin-releasing hormone (TRH)-LI, and arginine-vasopressin-LI were not significantly changed in the cerebral cortex and hippocampus of NBM-lesioned rats as compared to sham-operated rats. However, these neuropeptide levels were significantly increased in both brain regions by repeated administration of JTP-4819 (1, 3 and/or 10 mg/kg, p.o.). These results suggest that JTP-4819 ameliorated memory impairment due to NBM lesioning by potentiating SP, TRH and AVPergic neurons secondary to PEP inhibition.
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PMID:Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and on cholinergic and peptidergic neurons in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis. 1051 68

The aim of this study was to examine whether anorexia and bulimia nervosa are accompanied by lower serum activity of prolyl endopeptidase (PEP;EC 3.4.21.26; post-proline cleaving enzyme), a cytosolic endopeptidase which cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass. Substrates of PEP are, amongst others, neuroactive peptides, such as arginine vasopressin, luteinizing hormone-releasing hormone, thyrotropin releasing hormone,alpha-melanocyte secreting hormone, substance P, oxytocin, bradykinin, neurotensin and angiotensin (Ag) I and II. Serum PEP activity was measured in the serum of 18 normal women, 21 anorexia nervosa and 21 bulimia nervosa women by means of a fluoremetric method. The Bulimic Investigatory Test, Edinburgh (BITE), the Eating Disorder Inventory (EDI) and the Hamilton Depression Rating Scale (HDRS) were scored. Serum PEP activity was significantly lower in patients with bulimia nervosa and anorexia nervosa, irrespective of the restricted or binging subtype, than in normal controls. There were significant and inverse correlations between serum PEP activity and the HDRS and BITE. In anorectic patients, but not in normal or bulimic patients, there was a significant correlation between serum PEP and body mass index. In bulimic patients, but not in normal or anorectic patients, there was a significant correlation between serum PEP and duration of illness. It is concluded that lowered serum PEP activity takes part in the pathophysiology of anorexia and bulimia nervosa. It is hypothesized that a combined dysregulation of PEP and neuroactive peptides, which are substrates of PEP, could be an integral component of eating disorders.
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PMID:Lower serum activity of prolyl endopeptidase in anorexia and bulimia nervosa. 1107 Mar 31

A prolyl endopeptidase (PE) was purified 83 times from human urine by DEAE-cellulose and Sepharose Mercurial chromatographies. In this work we studied the specificity of PE using different fluorogenics substrates. Further characterization of the enzyme was carried out using BK and it's analogue, Abz-RPPGFSPFRQ-EDDnp and Abz-FPQ-EDDnp, for measure of enzymatic activity of prolyl endopeptidase (Abz=ortho-aminobenzoic acid; EDDnp=N-[2, 4-dinitrophenyl]ethylenediamine). The substrate Abz-FPQ-EDDnp was considered as specific for PE. The endopeptidase PE, with a molecular weight of 45 kDa, was inhibited 100% by EDTA and pOHMB and resistant to PMSF, thyorphan, E64 and phosphoramidon, when we used the mentioned substrates. These results suggest that PE is a metallo endopeptidase that contains a thiol group important for it's activity. It was also able to hydrolyze in Abz-RPPGFSPFRQ-EDDnp the F-R peptide bound, differing from those obtained upon BK molecule, where the enzyme prefer the peptide bound located after double proline. In the substrate Abz-FPQ-EDDnp PE hydrolyzes the P-Q peptide bound. Furthermore the urinary PE is particularly unable to hydrolyze peptides with single prolines such as substance P, neurotensin and LHRH. The determined K(m) for Abz-RPPGFSPFRQ-EDDnp and Abz-FPQ-EDDnp were 0.74 and 0.65 uM, respectively. The optimum pH for the PE activity, using the substrate Abz-RPPGFSPFRQ-EDDnp was approximately 9.0, but using the specific substrate Abz-FPQ-EDDnp was 6.5 and 8.0. Endopeptidases, which are situated at brush border surface from proximal tubules, have an important role in kidney handling of many peptides, which are filtered by the glomerulus. The prolyl endopeptidase located at distal tubule could have an important physiological function in control of kinin formed in this portion. It's known that all components from kallicrein-kinin system like low molecular weigh kininogen and kallikrein are presents in this portion.
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PMID:Characterization of a prolyl endopeptidase (kininase) from human urine using fluorogenic quenched substrates. 1113 56


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