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)

Electron capture dissociation (ECD) has previously been shown by other research groups to result in greater peptide sequence coverage than other ion dissociation techniques and to localize labile posttranslational modifications. Here, ECD has been achieved for 10-13-mer peptides microelectrosprayed from 10 nM (10 fmol/microL) solutions and for tryptic peptides from a 50 nM unfractionated digest of a 28-kDa protein. Tandem Fourier transform ion cyclotron resonance (FTICR) mass spectra contain fragment ions corresponding to cleavages at all possible peptide backbone amine bonds, except on the N-terminal side of proline, for substance P and neurotensin. For luteinizing hormone-releasing hormone, all but two expected backbone amine bond cleavages are observed. The tandem FTICR mass spectra of the tryptic peptides contain fragment ions corresponding to cleavages at 6 of 12 (1545.7-Da peptide) and 8 of 21 (2944.5-Da peptide) expected backbone amine bonds. The present sensitivity is 200-2000 times higher than previously reported. These results show promise for ECD as a tool to produce sequence tags for identification of peptides in complex mixtures available only in limited amounts, as in proteomics.
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PMID:High-sensitivity electron capture dissociation tandem FTICR mass spectrometry of microelectrosprayed peptides. 1151 Aug 24

Fibromyalgia is a form of non-articular rheumatism characterised by long term (>3 months) and widespread musculoskeletal aching, stiffness and pressure hyperalgesia at characteristic soft tissue sites, called soft tissue tender points. The biophysiology of fibromyalgia, however, has remained elusive and the treatment remains mainly empirical. This article reviews the neuroendocrine-immune pathophysiology of fibromyalgia. There is no major evidence that fibromyalgia is accompanied by activation of the inflammatory response system, by immune activation or by an inflammatory process. There is some evidence that fibromyalgia is accompanied by some signs of immunosuppression, suggesting that immunomodifying drugs could have potential in the treatment of fibromyalgia. Recent trials with cytokines, such as interferon-alpha, have been undertaken in patients with fibromyalgia. Immunotherapy with these agents, however, may induce symptoms reminiscent of fibromyalgia and depression in a considerable number of patients. Lowered serum activity of prolyl endopeptidase (PEP), a cytosolic endopeptidase that cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass, may play a role in the biophysiology of fibromyalgia through diminished inactivation of algesic and depression-related peptides, e.g. substance P. Trials with PEP agonists could be worthwhile in fibromyalgia. The muscle energy depletion hypothesis of fibromyalgia is supported by findings that this condition is accompanied by lowered plasma levels of branched chain amino acids (BCAAs), i.e. valine, leucine and isoleucine. Since there is evidence that BCAA supplementation decreases muscle catabolism and has ergogenic values, a supplemental trial with BCAAs in fibromyalgia appears to be justified.
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PMID:Neuroendocrine and immune aspects of fibromyalgia. 1154 93

Prolyl endopeptidase (PEP, EC 3.4.21.26) has been proposed to play a role in degradation of proline-containing neuropeptides involved in the processes of learning and memory, e.g., vasopressin, substance P, and thyrotropin-releasing hormone (TRH). In the course of our search for bioactive constituents in medicinal plants, we studied the PEP inhibitory constituents of the roots of Lindera strychnifolia F. VILL and isolated two known tannins, epicatechin (1) and aesculitannin B (2), and four known sesquiterpenes, linderene (3), linderene acetate (4), linderalactone (5) and isolinderalactone (6) as inhibitors. On the inhibitory activities of six compounds against PEP from Flavobacterium meningosepticum and that from rat brain supernatant, compounds 1, 2 and 4 inhibited the enzyme from Flavobacterium more strongly than that from rat brain supernatant. However, compounds 3, 5 and 6 inhibited the enzymes from both origins to the same extent and furthermore, compound 6 was the strongest natural inhibitor against PEP from rat brain supernatant. The kinetic study of these inhibitors indicated that compounds 1, 2 are noncompetitive inhibitors and compounds 3-6 are competitive inhibitors. This is the first example of non-phenolic constituents showing significant competitive inhibitory activity being isolated from natural medicines.
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PMID:Prolyl endopeptidase inhibitors from the roots of Lindera strychnifolia F. Vill. 1218 8

Prolyl endopeptidase (PEP) is a proline-specific oligopeptidase with a reported effect on learning and memory in different rat model systems. Using the astroglioma cell line U343, PEP expression was reduced by an antisense technique. Measuring different second-messenger concentrations revealed an inverse correlation between inositol 1,4,5-triphosphate [Ins(1,4,5)P3] concentration and PEP expression in the generated antisense cell lines. However, no effect on cAMP generation was observed. In addition, complete suppression of PEP activity by the specific inhibitor, Fmoc-Ala-Pyrr-CN (5 micro m) induced in U343 and other cell lines an enhanced, but delayed, increase in Ins(1,4,5)P3 concentration. This indicates that the proteolytic activity of PEP is responsible for the observed effect. Furthermore, the reduced PEP activity was found to amplify Substance P-mediated stimulation of Ins(1,4,5)P3. The effect of reduced PEP activity on second-messenger concentration indicates a novel intracellular function of this peptidase, which may have an impact on the reported cognitive enhancements due to PEP inhibition.
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PMID:Modulation of inositol 1,4,5-triphosphate concentration by prolyl endopeptidase inhibition. 1244 69

Short peptides with sequences derived from those found in the tegumental antigen of Fasciola hepatica have been synthesised. Incubation of some of these peptides with rat peritoneal mast cells resulted in the degranulation of the cells as measured by a histamine release assay. This activity was shown to be associated with the proline-lysine-proline motif, which is responsible for the induction of mast cell degranulation by the mammalian bioactive peptide substance P. Studies on the mode of action of the fluke-derived peptide indicated that it was operating through the same biochemical pathways as substance P. The implications of these findings for the development of immune responses during parasite infections are discussed.
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PMID:Liver fluke (Fasciola hepatica)-derived peptides activate rat peritoneal mast cells. 1275 46

Substance P is readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P < 0.05). Change in salt concentration did not appreciably affect the stability of Spantide II (P > 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.
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PMID:Preformulation stability of Spantide II, a promising topical anti-inflammatory agent for the treatment of psoriasis and contact dermatitis. 1497 97

The discovery of a potentially novel proline-specific peptidase from bovine serum is presented which is capable of cleaving the dipeptidyl peptidase IV (DPIV) substrate Gly-Pro-MCA. The enzyme was isolated and purified with the use of Phenyl Sepharose Hydrophobic Interaction, Sephacryl S-300 Gel Filtration, and Q-Sephacryl Anion Exchange, producing an overall purification factor of 257. SDS PAGE resulted in a monomeric molecular mass of 158kDa while size exclusion chromatography generated a native molecular mass of 328kDa. The enzyme remained active over a broad pH range with a distinct preference for a neutral pH range of 7-8.5. Chromatofocusing and isoelectric focusing (IEF) revealed the enzyme's isoelectric point to be 4.74. DPIV-like activity was not inhibited by serine protease inhibitors but was by the metallo-protease inhibitors, the phenanthrolines. The enzyme was also partially inhibited by bestatin. Substrate specificity studies proved that the enzyme is capable of sequential cleavage of bovine beta-Casomorphin and Substance P. The peptidase cleaved the standard DPIV substrate, Gly-Pro-MCA with a K(M) of 38.4 microM, while Lys-Pro-MCA was hydrolysed with a K(M) of 103 microM. The DPIV-like activity was specifically inhibited by both Diprotin A and B, non-competitively, generating a K(i) of 1.4 x 10(-4) M for both inhibitors. Ile-Thiazolidide and Ile-Pyrrolidide both inhibited competitively with an inhibition constant of 3.7 x 10(-7) and 7.5 x 10(-7) M, respectively. It is concluded that bovine serum DPIV-like activity share many biochemical properties with DPIV and DPIV-like enzymes but not exclusively, suggesting that the purified peptidase may play an important novel role in bioactive oligopeptide degradation.
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PMID:The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum. 1510 72

The toad tachykinin, bufokinin (Lys-Pro-Arg-Pro-Asp-Gln-Phe-Tyr-Gly-Leu-Met amide; BUF), acts via tachykinin NK1-like receptors to contract the intestine of the cane toad, Bufo marinus. In this structure-activity study, we used isolated segments of toad small intestine and performed binding studies with [125I] Bolton-Hunter BUF in intestinal membranes to compare the contribution of individual amino acid residues to the potencies of 18 naturally occurring tachykinins and 13 BUF analogs. Potencies were similar (r=0.94) in functional and binding studies, with BUF and ranakinin being most potent. Ranatachykinin A, physalaemin, hylambatin and cod, trout and mammalian SPs exhibited 10-60% of the potency of BUF. The Ala-substituted BUF analogs were 11-60% as potent as BUF in functional studies, with [Ala2]-BUF and [Ala4]-BUF the least efficacious, indicating the importance of both proline residues. QSAR equations were developed using 12 connectivity, shape and steric parameters for each of the 7 hypervariable amino acid residues in these peptides. For the binding data, the optimal regression equation explained 81% of the variance, and indicated the importance of the steric function at [Pro2] and simple connectivity functions at [Gln6] and [Tyr8]. The optimal functional regression equation (80% of variance) confirmed the importance of connectivity functions at [Gln6] and [Tyr8], as well as the shape of residues [Lys1] and [Pro4]. The potencies of most full-length peptides were well predicted using the leave-one-out procedure, as were the potencies of a series of model Ala-substituted BUFs, thus emphasising the potential utility of these equations in the design of new ligands interacting with tachykinin receptors.
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PMID:Quantitative structure-activity analyses of bufokinin and other tachykinins at bufokinin (bNK1) receptors of the small intestine of the cane toad, Bufo marinus. 1562 85

Prolyl endopeptidase (PEP, EC 3.4.21.26) hydrolyzes proline-containing neuropeptides, such as vasopressin, substance P, and thyrotropin-releasing hormone (TRH), and is suggested to participate in learning and memory processes. Ginkgo biloba leaves, upon examination for anti-amnestic constituents as new types of PEP inhibitors, showed significant PEP inhibition. PEP activity-guided fractionation and column chromatography of the MeOH extracts of G. biloba leaves resulted in the isolation of 6-(8'Z-pentadecenyl)salicylic acid (1) and 6-(10'Z-heptadecenyl)salicylic acid (2). The kinetic study indicated that compounds 1 and 2 are non-competitive inhibitors of prolyl endopeptidase with Ki values of 0.87 and 0.80 microM, respectively.
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PMID:Prolyl endopeptidase inhibitors from the leaves of Ginkgo biloba. 1564 62

We examined the effect of simultaneously incorporating proline or proline-amino acid chimeras in positions 9, 10, and/or 11 of substance P, on the affinity for the two NK-1 binding sites and on second-messenger activation. Because these 3-substituted prolines constrain not only the (phi,psi) values of the peptide backbone, but also the chi space of the amino acid side chain, we were able to gather data on the structural requirements for high-affinity binding to the NK-1 receptor. We were able to confirm that this C-terminal component is crucial and that it should adopt an extended conformation close to a polyproline II structure when bound to the receptor. The partial additivity of these constraints, more specifically, for the NK-1M site, suggests that the peptide backbone flexibility around the hinge-point residue Gly9 is essential to subtly position crucial side chains.
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PMID:Conformational analysis of the C-terminal Gly-Leu-Met-NH2 tripeptide of substance P bound to the NK-1 receptor. 1591 76


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