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)

Sequence analysis of cDNAs has shown that the biosynthetic precursors of substance P (alpha-, beta-, and gamma-preprotachykinins) contain a common amino acid sequence in the C-terminal flanking region that has not been conserved between species. Antisera have been raised against the synthetic peptide Tyr-Glu-Arg-Ser-Ala-Met-Gln-Asn-Tyr-Glu, which represents rat beta-preprotachykinin-(117-126)-peptide, and used in radioimmunoassays. Antiserum R50 reacted strongly with C-flanking peptides in extracts of rat and bovine tissues whereas antiserum GP-4 reacted only with the rat peptides. The primary structure of the predominant molecular form of preprotachykinin C-flanking peptide in an extract of bovine corpus striatum was established as: Ala-Leu-Asn-Ser-Val5-Ala-Tyr-Glu-Arg-Ser10-Val-Met-Gln-Asp-Tyr1 5-Glu. This sequence represents beta-preprotachykinin-(111-126)-peptide which is equivalent to gamma-preprotachykinin-(96-111)-peptide. A C-flanking peptide with similar chromatographic properties was identified in extracts of rat brain and gut together with a second immunoreactive component that may represent a fragment or a posttranslationally modified variant. A peptide corresponding to the 37-amino-acid residue C-flanking peptide derived from alpha-preprotachykinin was not detected in the extracts as expected from the known low abundance of alpha-preprotachykinin mRNA in rat brain and gut.
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PMID:Quantitation and characterization of peptides from the C-terminal flanking region of rat and bovine preprotachykinins. 280 97

The neurokinin A-like immunoreactivity in an extract of rabbit small intestine was resolved into two molecular forms by gel permeation chromatography. These components were purified to apparent homogeneity by reverse-phase HPLC. The primary structure of the larger component was established as the following: Asp-Ala-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val- Gly-Leu - Met.NH2. This amino acid sequence represents residues (72-92) of gamma-preprotachykinin, as predicted from the nucleotide sequence of a cloned cDNA from the rat. The peptide, termed neuropeptide-gamma, lacks residues (3-17) of neuropeptide K, and this segment is specified exactly by exon 4 in the preprotachykinin gene. The smaller form of neurokinin A-like immunoreactivity was identical to neurokinin A. Neuropeptide K was not present in the extract, demonstrating that the pathways of post-translational processing of beta- and gamma-preprotachykinins in the rabbit gut are different.
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PMID:Neuropeptide-gamma: a peptide isolated from rabbit intestine that is derived from gamma-preprotachykinin. 283 12

The pattern of developmental changes in concentrations of substance P, somatostatin and neuropeptide Y immunoreactivity and amino acids was studied in baboon cortex. Samples of occipital or frontal neocortex were obtained from preterm (100-105 days gestation), near-term (170-176 days gestation), and young adult animals. Substance P concentrations were low at preterm, highest at near-term, and then declined to adult levels. Neuropeptide Y and somatostatin immunoreactivity increased steadily across the three age groups. Concentrations of aspartate and gamma-aminobutyric acid (GABA) also increased progressively from preterm to adulthood, whereas glutamate concentrations showed small increases that were not statistically significant. Concentrations of taurine and alanine were highest preterm and declined progressively to adulthood. Levels of neuropeptides and amino acids show distinct patterns of change during development of neocortex in the baboon.
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PMID:Developmental changes of neuropeptides and amino acids in baboon cortex. 290 20

A dipeptidyl carboxypeptidase, which cleaved the Gly3-Phe4 bond of enkephalins, was purified from guinea pig serum 420-fold. The optimum pH of the enzyme was in the neutral range (pH 7.25), and the molecular weight was estimated to be approx. 280,000. The enzyme hydrolyzed Met- and Leu-enkephalin with Km values of 0.30 and 0.50 mM, respectively. The enzyme was inhibited by metal chelators and p-chloro-mercuribenzoate. Captopril showed high inhibitory potency, while phosphoramidon and Phe-Ala showed no effect on the enzyme activity. Therefore, the obtained enzyme can be classified as an angiotensin-converting enzyme (EC 3.4.15.1). Among the bioactive peptides examined, bradykinin and angiotensin I were hydrolyzed by the enzyme. Angiotensin III showed a stronger inhibitory effect than that of angiotensin II. Substance P, gastrin I, and secretin were also inhibitory toward the enzyme activity. On high-performance liquid chromatography analysis, Met-enkephalin-Arg6-Phe7 and Leu-enkephalin-Arg6 were cleaved sequentially at the second peptide bond of the C terminus. Thus, the dipeptidyl carboxypeptidase in guinea pig serum may play a role not only in the angiotensin-bradykinin system but also in the metabolism of circulating enkephalins and other bioactive peptides.
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PMID:Enkephalin-degrading dipeptidyl carboxypeptidase in guinea pig serum: its properties and action on bioactive peptides. 299 Mar 46

We have used an in vitro transcription-translation system to study initial protein processing events of the rat substance P/neurokinin A gene products. cDNA clones for three different mRNA species, which are derived by differential RNA splicing, were subcloned into a plasmid, pGEM1, which contains the promoter for the bacteriophage SP6 RNA polymerase. In vitro synthesized mRNAs for alpha-, beta-, and gamma-preprotachykinin were translated in a wheat germ or rabbit reticulocyte cell-free system. When analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the translated protein products migrate consistent with the deduced molecular masses of alpha (13,035 Da)-, beta (15,003 Da)-, and gamma (13,343 Da)-preprotachykinin. The addition of dog pancreatic microsomal membranes to either cell-free translation system causes the production of a protease-resistant form of each of the three preprotachykinins which migrates with an apparent increase in molecular mass of approximately 2,000 Da. Each of these modified preprotachykinins lacks the putative signal peptide of the prepro- form, with signal peptidase cleavage occurring after the alanine residue at position 19. Both the prepro- and proforms of each tachykinin precursor molecule are recognized by antiserum R-140, an antiserum specific for the mid-portion of the undecapeptide substance P. The most likely explanation for the apparent increase in molecular mass is anomalous electrophoretic migration, since beta-preprotachykinin mRNA lacking the signal peptide encoding sequence is translated, in the absence of microsomal membranes, into a protein with the same apparent molecular mass as the modified form of beta-preprotachykinin. Therefore, each of the three preprotachykinin mRNAs are translatable, and their products are targeted to the secretory pathway by the presence of a cleavable signal peptide.
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PMID:Posttranslational processing of alpha-, beta-, and gamma-preprotachykinins. Cell-free translation and early posttranslational processing events. 304 2

The specificity of action of bovine brain cortex cathepsin D (EC 3.4.23.5) and high-Mr aspartic endopeptidase (EC 3.4.23.-) was studied with the vasoactive peptides renin substrate tetradecapeptide (RSTP), substance P (SP), and angiotensins I and II, and with model peptides--Lys-Pro-Ala-Glu-Phe-Phe (NO2)-Ala-Leu (I), Gly-Gly-His-Phe (NO2)-Phe-Ala-Leu-NH2 (II), and Abz-Ala-Ala-Phe-Phe-pNA (III). Cerebral aspartic peptidases show identical substrate specificity, cleaving the Leu10-Leu bond in RSTP and Phe-Phe in SP and peptide I-III, and not splitting angiotensins I and II. Because of the higher catalytic efficiency of cathepsin D (Kcat value), the specificity constants (Kcat/Km) for cathepsin D-catalyzed hydrolysis of substrates 1-111 are much higher than those for the high-Mr enzyme. High-Mr aspartic peptidase shares a number of properties with cathepsin D (sensitivity to pepstatin, substrate specificity, pH activity profile) and shows partial immunological identity; however, high-Mr aspartic peptidase has a specific activity 7-10 times lower than that of cathepsin D. The kinetic parameters of proteolysis of model peptides presented indicate that the high-Mr enzyme may be a complex of a single-chain cathepsin D with another polypeptide, although the possibility that it is an independent aspartic peptidase cannot be excluded.
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PMID:Substrate specificity of cerebral cathepsin D and high-Mr aspartic endopeptidase. 328 13

The first sequence-related competitive inhibitors of the classic kinin in vitro (rat uterus guinea pig ileum) and in vivo (rat blood pressure) assays have been developed. Replacement of the proline residue at position 7 of bradykinin (BK) with a D-phenylalanine residue is the key modification which converts BK agonists into antagonists. [D-Phe7]-BK exhibits moderate (pA2 = 5.0) inhibition of BK activity on the guinea pig ileum but possesses weak BK-like myotropic activity on the isolated rat uterus and 2-4% of BK depressor potency in the rat blood pressure assay. The additional replacement of the phenylalanine residues at positions 5 and 8 of [D-Phe7]-BK with the isosteric beta-(2-thienyl)-alanine residue produces a potent antagonist of BK activity on the uterus (pA2 = 6.4), ileum (pA2 = 6.3), and in the rat blood pressure assay. The antagonism of BK action on smooth muscle is specific for kinins (BK, kallidin, Met-Lys-BK), but neither inhibitor antagonizes the smooth muscle activity of angiotensin or substance P. Inhibition is competitive and fully reversible.
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PMID:Competitive antagonists of bradykinin. 403 8

Neuronal and glial localization of brain peptidases was investigated by means of the kainic acid (KA) lesion technique. Activities of 6 different peptidases were measured in the rat caudate-putamen (CP) and substantia nigra (SN) 2, 7 and 21 days after unilateral intra-CP injection with 2.5 micrograms of KA. As an indicator of KA lesion in CP, substance P content in both CP and SN was also determined. In addition, activities of the same peptidases in the primary and secondary glial cell cultures of fetal rats were measured and compared to those in CP homogenate. After the KA injection, prolyl endopeptidase (Pro-EP) activity was decreased in the lesioned CP and, to a lesser extent, in the ipsilateral SN. The activity of angiotensin-converting enzyme (ACE) in the lesioned CP was decreased with a complex time course, whereas a slow and progressive reduction was observed in the SN. Alanyl and leucyl aminopeptidase (Ala-AP and Leu-AP respectively) activities gave only small changes after the lesion; Ala-AP was decreased and Leu-AP was increased in the lesioned CP, while both were decreased in the SN. Dipeptidyl aminopeptidase (DAP) and arginyl endopeptidase (Arg-EP) activities were increased 5-fold in the CP 7 days after the KA injection. Their increases paralleled that of beta-glucuronidase, the lysosomal marker enzyme. Cultured glial cells contained only a trace amount of ACE activity. Ala-AP and Pro-EP activities were considerably lower in the glial culture cells than in the CP homogenate. In contrast, DAP and Arg-EP as well as lysosomal marker enzymes showed much higher activity in the former than in the latter. These results suggest that (1) Ala-AP and Pro-EP have large neuronal components, (2) ACE is preferencially localized in neurons and (3) DAP and Arg-EP are associated with glial lysosomal function. It is, therefore, concluded that at least a part of the brain peptidases are differentially localized in neurons and glia, and may be involved in specific neuronal or glial function.
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PMID:Brain peptidases: their possible neuronal and glial localization. 608 24

[125I]Iodo-Tyr1-somatostatin (SRIF) binds with high affinity to one class of sites in the rat anterior pituitary with a KD of 0.91 +/- 0.22 nM and a receptor concentration of 104.4 +/- 1.9 fmol/mg protein. This binding is saturable with respect to tissue concentration and is time-, temperature-, pH-, and calcium-dependent. It is also reversible as a function of time. The rates of association and dissociation were calculated to be 5.98 X 10(7) M-1 min-1 and 0.578 min-1, respectively. Binding of [125I]iodo-Tyr1-SRIF is not inhibited by morphine, beta-endorphin, [D-Ala2]Met-enkephalin, LHRH, TRH, histidylproline diketopiperazine, neurotensin, substance P, bombesin or vasoactive intestinal peptide. In contrast SRIF, [Tyr1]SRIF, and [D-Trp8,D-Cys14]SRIF displace [125I]iodo-Tyr1-SRIF binding with Ki values 0.10 +/- 0.05, 0.46 +/- 0.18, 0.05 +/- 0.01 nM, respectively. The constants of inhibition of a series of alanine monosubstituted analogs of SRIF are correlated (r = 0.89) with their biological potency on GH secretion. Furthermore, postnatal development patterns of [125I]iodo-Tyr1-SRIF binding sites follow the ability of SRIF to inhibit GH release. Thus, [125I]iodo-Tyr1-SRIF binding to adenohypophyseal membranes seems to reflect interaction with SRIF receptors on adenohypophyseal cells. Since biological effects of the peptide have been reported on GH, thyrotropin-stimulating hormone, and PRL secretion, further studies are required to determine the cell types upon which this binding occurs.
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PMID:Somatostatin receptors on rat anterior pituitary membranes. 612 57

Endopeptidase-24.11 (EC 3.4.24.11), purified to homogeneity from pig kidney, was shown to hydrolyse a wide range of neuropeptides, including enkephalins, tachykinins, bradykinin, neurotensin, luliberin and cholecystokinin. The sites of hydrolysis of peptides were identified, indicating that the primary specificity is consistent with hydrolysis occurring at bonds involving the amino group of hydrophobic amino acid residues. Of the substrates tested, the amidated peptide substance P is hydrolysed the most efficiently (Km = 31.9 microM; kcat. = 5062 min-1). A free alpha-carboxy group at the C-terminus of a peptide substrate is therefore not essential for efficient hydrolysis by the endopeptidase. A large variation in kcat./Km values was observed among the peptide substrates studied, a finding that reflects a significant influence of amino acid residues, remote from the scissile bond, on the efficiency of hydrolysis. These subsite interactions between peptide substrate and enzyme thus confer some degree of functional specificity on the endopeptidase. The inhibition of endopeptidase-24.11 by several compounds was compared with that of pig kidney peptidyldipeptidase A (EC 3.4.15.1). Of the inhibitors examined, only N-[1(R,S)-carboxy-2-phenylethyl]-Phe-p-aminobenzoate inhibited endopeptidase-24.11 but not peptidyldipeptidase. Captopril (D-3-mercapto-2-methylpropanoyl-L-proline), Teprotide (pGlu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) and MK422 [N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro] were highly selective as inhibitors of peptidyldipeptidase. Although not wholly specific, phosphoramidon was a more potent inhibitor of endopeptidase-24.11 than were any of the synthetic compounds tested.
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PMID:The metabolism of neuropeptides. The hydrolysis of peptides, including enkephalins, tachykinins and their analogues, by endopeptidase-24.11. 614 47


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