Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-protein and pro-hormone convertases are subtilisin/kexin-like enzymes implicated in the activation of numerous precursors by cleavage at sites mostly composed of pairs of basic amino acids. Six members of this family of enzymes have been identified in mammals and named furin (also called PACE), PC1 (also called PC3), PC2, PACE4, PC4, and PC5 (also called PC6). Multiple transcripts are produced for all the mammalian convertases, but only in the cases of PC4, PACE4, and PC5 does differential splicing result in the modification of the C-terminal sequence of these enzymes. A similar molecular diversity is also observed for the convertases of Hydra vulgaris, Caenorhabditis elegans, and Drosophila melanogaster. In the third species, two genes homologous to human furin called Dfur1 and Dfur2 have been identified. The Dfur1 gene undergoes differential splicing to generate three type I membrane-bound proteins called dfurin1, dfurin1-CRR, and dfurin1-X, which differ only in their C-terminal sequence. By using recombinant vaccinia viruses that express each of the dfurin proteins, we investigated the potential effect of the C-terminal domain on their catalytic specificities. For this purpose, these enzymes were coexpressed with the precursors pro-7B2, pro-opiomelanocortin, and pro-dynorphin in a number of cell lines, and the processed products obtained were characterized. Our studies demonstrate that these proteases display cleavage specificities similar to that of mammalian furin but not to that of PC2. In contrast, we noted significant differences in the biosynthetic fates of these convertases. All dfurins undergo rapid removal of their transmembrane domain within the endoplasmic reticulum, resulting in the release of several truncated soluble forms. However, in the media of cells containing secretory granules, such as GH4C1 and AtT-20, dfurin1-CRR and dfurin2 predominate over dfurin1, whereas dfurin1-X is never detected. While pro-segment removal occurs predominantly in the trans-Golgi network for all the dfurins, in the presence of brefeldin A, only dfurin1-CRR and dfurin2 can undergo partial zymogen cleavage. The conclusions drawn from the results of this study may well be applicable to the mammalian convertases PC4, PACE4, and PC5, which also display C-terminal sequence heterogeneity.
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PMID:Processing specificity and biosynthesis of the Drosophila melanogaster convertases dfurin1, dfurin1-CRR, dfurin1-X, and dfurin2. 783 54

Met-enkephalin concentration-dependently and transiently inhibited the ileal twitch contraction and this inhibition gradually recovered with time. Bacitracin, phosphoramidon, thiorphan and captopril did not influence the twitch inhibition of met-enkephalin, but bestatin increased the twitch inhibitory potency of met-enkephalin and terminated it in a manner which almost paralleled that of untreated tissue. Transient inhibition of twitch contraction after tetanic stimulation (post-tetanic twitch inhibition) was obtained. Bestatin increased the potency of met-enkephalin and this was terminated within 2 min. Phosphoramidon tended to increase the potency and delayed the termination of post-tetanic twitch inhibition. Bacitracin, thiorphan and captopril did not influence either the potency or the termination of post-tetanic twitch inhibition. Morphine-induced twitch inhibition was not influenced by bacitracin, bestatin or phosphoramidon. These results suggest that bestatin-sensitive aminopeptidase and phosphoramidon-sensitive enkephalinase take part in post-tetanic twitch inhibition, acting in a different mode of action, and have an important role in the termination of the pharmacological action of endogenous opioids (post-tetanic twitch inhibition) in MPLM. This different mode of response of bestatin and phosphoramidon upon post-tetanic twitch inhibition may underlie that aminopeptidase is a more soluble enzyme and enkephalinase is membrane-bound in myenteric plexus-longitudinal muscle (MPLM).
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PMID:Effect of some peptidase inhibitors on exogenous and endogenous opioid actions in guinea-pig ileum. 814 19

A 40-year-old Black man presenting with increasing nasal discharge of bloody, mucoid pus as well as nasal obstruction over a 2-month period is described. Magnetic resonance imaging of the skull showed a tumor eroding through the skull base into the clivus and extending into the sphenoid sinus. Endoscopy of the sphenoid sinus demonstrated a polypoid mass extending into the posterior choanae. The lesion was partially resected. Histologic evaluation showed a cellular small blue cell tumor punctuated by bland, epithelial-lined microcysts. Electron microscopy revealed epithelial cells with abundant rough endoplasmic reticulum and electron-dense membrane-bound endocrine granules, some undergoing misplaced exocytosis. Immunohistochemical evaluation demonstrated cytoplasmic reactivity for neuron-specific enolase, synaptophysin, and prolactin. Stains for leukocyte common antigen, HMB-45, desmin, cytokeratin, chromogranin, and the remaining spectrum of pituitary hormones including growth hormone, corticotropin, luteinizing hormone, follicle-stimulating hormone, and thyrotrophic hormone were negative. In contrast, the epithelium lining the cysts was cytokeratin positive and synaptophysin negative. This ostensibly small cell tumor therefore represented a remarkably extensive and aggressive prolactin cell adenoma with unusual light microscopic features. Characterization of the lesion required electron microscopy and further confirmation by immunocytology. The distinction of pituitary adenomas and particularly of prolactin cell tumors from other adenoma types and from other small cell lesions markedly affects therapy and patient prognosis.
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PMID:Aggressive small cell tumor of the skull base. 819 26

The cellular nature of the giant eosinophilic cells of tuber and of the cells comprising subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) remains unclear. To assess the characteristics of these lesions, 13 tubers and 6 SEGA were immunohistochemically studied with glial and neuron-associated antigens. In addition to conventional ultrastructure, 6 tubers and 8 SEGA were subjected to immunoelectron microscopic study for glial fibrillary acidic protein (GFAP) and somatostatin. Eosinophilic giant cells of tubers were positive for vimentin (100%), GFAP (77%) and S-100 protein (92%); such cells were also found to a various extent to be reactive for neuron-associated antigens, including neurofilament (NF) proteins (38%) or class III beta-tubulin (77%). SEGA also showed variable immunoreactivity for GFAP (50%) or for S-100 protein (100%); NF epitopes, class III beta-tubulin, and calbindin 28-kD were expressed in 2 (33%), 5 (83%) and 4 (67%) cases, respectively. Cytoplasmic staining for somatostatin (50%), met-enkephalin (50%), 5-hydroxytryptamine (33%), beta-endorphin (33%) and neuropeptide Y (17%) was noted in SEGA, but not in tubers. Ultrastructurally, the giant cells of tubers and the cells of SEGA contained numerous intermediate filaments, frequent lysosomes and occasional rectangular or rhomboid membrane-bound crystalloids exhibiting lamellar periodicity and structural transition to lysosomes. Some SEGA cells showed features suggestive of neuronal differentiation, including stacks of rough endoplasmic reticulum, occasional microtubules and a few dense-core granules. Furthermore, in one case of tuber, a process of a single large cell was seen to be engaged in synapse formation. Intermediate filaments within a few cells of both lesions were decorated by gold particle-labeled GFAP antiserum. Within the tumor cells of SEGA, irregular, non-membrane-bound, electron-lucent areas often contained somatostatin-immunoreactive particles, whereas the latter could not be detected in tuber. The present study provides further evidence of divergent glioneuronal differentiation, both in the giant cells of tubers and the cells of SEGA. The findings of similar cells at different sites, including the subependymal zone, white matter ("heterotopias"), and cortex indirectly supports the idea that these lesions of TS result from a migration abnormality.
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PMID:Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. 854 29

Endothelin-converting-enzyme-1 (ECE-1) belongs to the family of zinc metallopeptidases and is responsible for generating endothelin (ET) peptides from their inactive precursors the big endothelins (bigET). The enzyme is a type II integral membrane protein consisting of a short amino-terminal cytosolic domain of 56 amino acids, a single transmembrane domain and a large putative extracellular domain containing the catalytic site. Recombinant and native ECE-1 are expressed as a dimer. We have constructed a soluble form of ECE, named sECE*, by fusing the cleavable signal peptide of pro-opiomelanocortin in frame to the complete extracellular domain of human ECE-1. Stable expression of this construct in CHO cells resulted in the secretion of a fully active enzyme. In contrast to membrane-bound ECE, sECE* was expressed as a monomer, highly glycosylated, as assessed by gel filtration and Western blot. However, recombinant sECE* converted bigET-1 with similar specific activity as ECE-1a. This activity was completely inhibited by phosphoramidon, but not by thiorphan and captopril. sECE* was active in a broad range of pH, showing an optimum of 6.6-6.8 for bigET-1. Thus, the extracellular domain alone is sufficient for conferring full ECE-1 activity, inhibitors recognition and substrate specificity.
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PMID:Construction, expression and characterization of a soluble form of human endothelin-converting-enzyme-1. 940 53

In contraction studies corticotropin-releasing hormone (CRH) was found to relax ileal but not gastric and jejunal smooth muscles of the guinea-pig, precontracted with BaCl2. Under whole-cell patch-clamp conditions, CRH concentration-dependently activated Ca2+-sensitive K+ currents (IK) with ED50=20 pM at 100 nM and ED50=0. 13 pM at 500 nM intracellular Ca2+ respectively. This increase was accompanied by significant hyperpolarization of the cell membranes. CRH 9-41 peptide fragment did not affect IK amplitude, membrane potential or contraction. The CRH-induced increase of IK densities was accelerated in the presence of high intracellular Ca2+ concentrations (500 nM) and was abolished by pretreatment of cells with either ryanodine or thapsigargin, which cause depletion of intracellular Ca2+ stores, as well as in cells treated under conditions prohibiting intracellular Ca2+ store refilling. The effect of CRH on IK was not affected by bath application of various selective inhibitors of membrane-bound phospholipases, protein kinase C, cGMP-dependent protein kinase or Ca2+/calmodulin-dependent protein kinase II, but was effectively antagonized by blockers of protein kinase A (PKA) or adenylyl cyclase. Neither forskolin nor the catalytic subunit of PKA could mimic the effect of CRH on IK. Thus, it was suggested that CRH exerts its relaxing activity on ileal smooth muscle cells via PKA-dependent phosphorylation of some intracellular target coupled to sarcoplasmic reticulum Ca2+ storage machinery.
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PMID:Corticotropin-releasing hormone acts on guinea pig ileal smooth muscle via protein kinase A. 1037 Jan 7

N-Linked oligosaccharides terminating with the sequence SO(4)-4-GalNAcbeta1,4GlcNAcbeta1,2Manalpha are present on the pituitary hormones lutropin (LH), thyrotropin, and pro-opiomelanocortin. The sulfated structures on LH are essential for expression of its biologic function in vivo. We have cloned the N-acetylgalactosamine-4-sulfotransferase (GalNAc-4-ST1, GenBank(TM) accession number ), which mediates sulfate addition to the N-linked oligosaccharides on LH and other pituitary glycoproteins with terminal (beta1,4-linked GalNAc based on its homology to HNK-1 sulfotransferase (HNK-1 ST). GalNAc-4-ST1 displays 23% identity to HNK-1 ST and 28% to chondroitin 4-sulfotransferase 1 (C4ST-1) and 26% to chondroitin 4-sulfotransferase 2 (C4ST-2). The cDNA predicts a type II transmembrane protein of 424 amino acids with four potential N-linked glycosylation sites and a single membrane-spanning domain. GalNAc-4-ST1 has putative 5'-phosphosulfonate and 3'-phosphate binding sites. Three more carboxyl-terminal regions of unknown function also show a high degree of identity with HNK-1 ST, C4ST-1, and C4ST-2. The membrane-bound form of GalNAc-4-ST1 transfers sulfate to GalNAcbeta1, 4GlcNAcbeta-R but not to chondroitin, whereas truncated forms of GalNAc-4-ST1 that are released into the medium transfer sulfate to both GalNAcbeta1,4GlcNAcbeta-R and chondroitin. The first 118 amino acids of GalNAc-4-ST1 appear to contribute to both its activity and specificity for terminal beta1,4-linked GalNAc. GalNAc-4-ST1 also efficiently transfers sulfate to N-linked oligosaccharides on native LH and other glycoproteins terminating with beta1,4-linked GalNAc. A single transcript of 2.4 kilobases is most highly expressed in the pituitary and other regions of the central nervous system. The GalNAc-4-ST1 gene is located on human chromosome 19q13.1.
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PMID:Molecular cloning and expression of the pituitary glycoprotein hormone N-acetylgalactosamine-4-O-sulfotransferase. 1098

Melanocytes play critical roles in mammals, including the regulation of constitutive pigmentation in the skin, hair, and eyes, in embryological development, and in photoprotection from ionizing radiation. The pigments themselves, possibly due to the inherent cytotoxic properties of their precursors, are synthesized and deposited within membrane-bound organelles known as melanosomes. However, the structure of melanosomes, and thus their characteristic properties, varies widely, from relatively disorganized, poorly pigmented pheomelanosomes to highly structured, melanized eumelanosomes. Melanocytes respond to various physiological stimuli, such as melanocyte-stimulating hormone (MSH), agouti signal protein (ASP), endothelins and/or ultraviolet light (UVL) by highly complex intracellular signaling mechanisms that can elicit dramatic changes in melanosome and melanocyte morphology. MSH and UVL stimulate transcription of melanogenic genes that elicit dramatic increases in the amount of eumelanins produced, whereas ASP serves as an antagonist of MSH and inhibits the transcription of those same genes. Recent studies have shown that melanocyte-specific transcription factors, such as MITF, play important roles in these responses, but ubiquitous transcription factors, such as ITF2 and E2A, are also involved. Virtually all known intracellular signaling pathways affect one or more parameters of pigmentation, and it is clear that both melanocyte-specific and basic housekeeping processes are affected by such modulation. The properties of melanins, including their photoprotective function, may be optimized by such stimulatory responses. Studies targeted at elucidating the regulatory mechanisms involved and the functional changes that result demonstrate that the melanosome is the perfect model to study such biological response mechanisms.
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PMID:The melanosome: the perfect model for cellular responses to the environment. 1104 54

The biological actions of corticotropin-releasing hormone (CRH) in the human myometrium during pregnancy and labor are unknown. We hypothesized that CRH may modulate the nitric oxide system, and influence myometrial relaxation/contractility. Incubation of myometrial cells with CRH, but not urocortin II or urocortin III, for 8-16 h significantly induced mRNA and protein expression of endothelial and brain but not inducible nitric oxide synthase (NOS) isoforms. This action resulted in increased activity of soluble guanylate cyclase (GC(s)), demonstrated by the enhanced cGMP-producing capacity of the NO donor, sodium nitroprusside. CRH also caused acute activation of the membrane-bound GC, shown by increased basal or atrial natriuretic peptide (ANP)-stimulated cGMP production. These effects appeared to be mediated via the R1 receptors because the CRH receptor antagonists, astressin and antalarmin but not anti-sauvagine 30, could block them. The acute effects of CRH were significantly reduced by inhibition of protein kinase A (PKA) activity, suggesting it is partially PKA dependent. Activation of protein kinase C (PKC) resulted in significant inhibition of both ANP-and CRH-stimulated cGMP production, suggesting a direct effect of PKC on membrane-bound GC. In conclusion, CRH appears to have a dual effect on myometrial NOS/GC pathway, a short term effect predominantly mediated by PKA, and a long-term effect increasing constitutive NOS expression, mediated by a PKA-independent mechanism. This mechanism could potentially be active during human pregnancy, and, because cGMP stimulates myometrial relaxation, these findings further suggest that during pregnancy CRH primarily activates intracellular signals that contribute to the maintenance of myometrial quiescence.
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PMID:Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells. 1185 58

The present work comparatively analyzes the interaction of alpha-MSH and its more potent and long-acting analog [Nle4, D-Phe7]alpha-MSH (NDP-MSH) with lipid bilayers. The peptides were spin labeled with Toac (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) at the N-terminal, as those derivatives had been previously shown to keep their full biological activity. Due to the special rigidity of the Toac covalent binding to the peptide molecule, this spin label is highly sensitive to the peptide backbone conformation and dynamics. The peptides were investigated both by the electron spin resonance (ESR) of Toac0 and the time resolved fluorescence of Trp9 present in the peptides. The Toac0 ESR of the membrane-bound peptides indicates that the two peptides are inserted into the bilayer, close to the bilayer surface, in rather similar environments. A residue titration around pKa 7.5, possibly that of His6, can be clearly monitored by peptide-lipid partition. Trp9 time resolved fluorescence indicates that the peptides, and their Toac-labeled derivatives, present rather similar conformations when membrane bound, though Trp9 in NDP-MSH, and in its Toac-labeled derivative, goes somewhat further down into the bilayer. Yet, Toac0 ESR signal shows that the Toac-labeled N-terminal of NDP-MSH is in a shallower position in the bilayer, as compared to the hormone.
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PMID:Peptide-lipid interaction monitored by spin labeled biologically active melanocortin peptides. 1600 9


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