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)

The minimal sequence required for biological activity of alpha-MSH (alpha-melanotropin, alpha-melanocyte stimulating hormone) was determined in the frog (Rana pipiens) skin bioassay. The sequence required to elicit measurable biological activity was the central tetrapeptide sequence, Ac-His-Phe-Arg-Trp-NH2 (Ac-alpha-MSH6-9-NH2), which was about 6 orders of magnitude less potent than the native tridecapeptide. Smaller fragments of this sequence (Ac-His-Phe-NH2, Ac-Phe-Arg-NH2, Ac-His-Phe-Arg-NH2) were devoid of melanotropic activity at concentrations as high as 10(-4) M. We were unable to demonstrate biological activity for the tetrapeptide, Ac-Phe-Arg-Trp-Gly-NH2 (Ac-alpha-MSH7-10-NH2), and for several carboxy terminal analogues including Ac-Lys-Pro-Val-NH2 (Ac-alpha-MSH11-13-NH2). We prepared a series of fragment analogues of alpha-MSH in an attempt to determine the contribution of each individual amino acid to the biological activity of the native hormone. The minimal potency of Ac-alpha-MSH6-9-NH2 could be enhanced about a factor of 16 by the addition of glycine to the C-terminus, yielding Ac-alpha-MSH6-10-NH2 (Ac-His-Phe-Arg-Trp-Gly-NH2). Addition of glutamic acid to the N-terminus provided the peptide, Ac-alpha-MSH5-10-NH2, which was only slightly more potent than Ac-alpha-MSH6-10-NH2, indicating that position 5 contributes little to the biological potency of alpha-MSH in this assay. Addition of methionine to the N-terminus of Ac-alpha-MSH5-10-NH2 resulted in the heptapeptide, Ac-alpha-MSH4-10-NH2, which was only about 4-fold more potent than Ac-alpha-MSH5-10-NH2. Addition of lysine and proline to the C-terminal of the Ac-alpha-MSH4-10-NH2 sequence yielded the peptide, Ac-alpha-MSH4-12-NH2 with a 360-fold increase in potency relative to Ac-alpha-MSH4-10-NH2. This peptide was only about 6-fold less potent than alpha-MSH. A series of Nle-4-substituted analogues also were prepared. Ac-[Nle4]-alpha-MSH4-10-NH2 was about 4 times more potent than Ac-alpha-MSH4-10-NH2. Ac-[Nle4]-alpha-MSH4-11-NH2 also was about 4 times more potent than Ac-alpha-MSH4-10-NH2, demonstrating that lysine-11 contributes somewhat to the biological activity of alpha-MSH on the frog skin melanocyte receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:alpha-Melanotropin: the minimal active sequence in the frog skin bioassay. 282 31

Intermediate pituitary lobe cells from newborn rats were maintained in culture to determine the extent to which they continue to exhibit the tissue-specific properties of the newborn and adult intermediate pituitary lobes. At all times examined these cultures contained mostly alpha MSH-sized and corticotropin-like intermediate lobe peptide-sized peptides; the alpha MSH-sized peptides were predominantly diacetyl-ACTH-(1-13)NH2. After 6 days in culture, the intermediate pituitary lobe cells retained the ability to synthesize diacetyl-ACTH-(1-13)NH2. Compared to that of the adult, the newborn anterior pituitary lobe is enriched in high mol wt forms of ACTH-related molecules. Therefore, the ability of newborn anterior pituitary lobe cell cultures to develop the adult processing pattern in culture was investigated. After 6 days in culture, peptides the size of alpha MSH predominated rather than ACTH-(1-39), which is the major form found in the adult. Immunocytochemical studies showed that all cultured newborn corticotropes strongly stained for alpha MSH-related material. The alpha MSH-sized molecules were identified as ACTH-(1-13)NH2 by reverse phase HPLC. In 6-day-old cultures of neonatal anterior pituitary lobes grown in the presence of a synthetic glucocorticoid, dexamethasone, the amount of alpha MSH-sized material was diminished, and instead, precursor forms of the ACTH-related peptides were detected. In biosynthetic labeling experiments, the ratio of newly synthesized ACTH-(1-13)NH2 to ACTH-(1-39) was greatly reduced by treatment of the cells with dexamethasone. The extensive cleavage of ACTH-(1-39) and its regulation by dexamethasone are unique to newborn anterior pituitary lobe corticotropes; such plasticity is not observed in cultures of adult tissue.
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PMID:Plasticity in the adrenocorticotropin-related peptides produced by primary cultures of neonatal rat pituitary. 282 15

We have characterized the specific binding of human beta-endorphin (1-31) to novel binding sites which are formed in human plasma or serum in the presence of heparin. The formation of the binding sites is temperature-dependent and does not occur in the presence of other anticoagulants, such as sodium-EDTA, sodium-oxalate, or sodium-citrate. The specific binding of 125I-beta H-endorphin to heparin-induced binding sites in human plasma is saturable and reversible. It is not inhibited by morphine or naloxone or by various opioid peptides which share their NH2-terminal opioid-active sequence with beta H-endorphin. In contrast, binding is inhibited by the COOH-terminal beta H-endorphin fragment Gly-Glu indicating that binding is to nonopioid sites. Electroimmunoprecipitation techniques revealed that these binding sites are identical with S protein/vitronectin or derivatives thereof. S protein is a plasma alpha 1-glycoprotein involved in attachment and spreading of cells and also in blood coagulation and complement activation. It is possible that the interaction of beta-endorphin with S protein is of physiological significance.
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PMID:Characterization and identification of heparin-induced nonopioid-binding sites for beta-endorphin in human plasma. 282 69

To determine whether a low pH intracellular "sorting" step is required to route peptides into secretory granules, the effects of pH altering drugs on the biosynthesis and secretion of peptides by AtT-20 mouse corticotrope tumor cells and rat intermediate pituitary cells were examined. Doses of each drug maintaining normal protein synthesis and cell morphology, while obliterating the intracellular pH gradients detected by acridine orange fluorescence, were experimentally determined. Regions of the cell rich in secretory granules were localized by immunocytochemistry and were found to coincide with organelles with a low internal pH. Biosynthetic labeling experiments were coupled with immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel analyses to examine the biosynthesis and secretion of corticotropin (ACTH(1-39], alpha-melanotropin, ACTH(18-39), beta-endorphin, gamma-melanotropin, alpha-amidated joining peptide, and the NH2-terminal region of pro-ACTH/endorphin. Chloroquine (20-40 microM) and a mixture of NH4Cl and methylamine (2-5 mM each) dissipated pH gradients but had no effect on the synthetic rate of pro-ACTH/endorphin, the extent and rate of precursor processing to smaller peptides, the rate of basal secretion of the various peptides, or the extent to which secretion of each of the peptides could be stimulated by secretagogues. Monensin (0.1-1 microM) had no discernible effect on intracellular pH gradients yet totally blocked proteolytic processing of pro-ACTH/endorphin. Thus, a monensin-blockable step occurs in peptide processing, presumably in the trans Golgi region; however, a low pH chloroquine-sensitive sorting step is not required for processing or for routing peptides to a stable storage form which can be released in response to secretagogues.
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PMID:The role of a low pH intracellular compartment in the processing, storage, and secretion of ACTH and endorphin. 283

The effect of chronic dopaminergic receptor blockade using domperidone (DOM) on the immature dog pituitary content of POMC-related peptides was evaluated. Six immature dogs were treated with DOM for 15 days, 3 times/day, po (3 mg/kg) together with DOM sc (0.6 mg/kg) at 21.00 h. Placebo was administered to six control animals with the same protocol. On the 16th day, the animals were killed, the whole pituitary removed, homogenized, and submitted to reverse-phase HPLC purification prior to radioimmunoassay (RIA) evaluation of beta-endorphin, ACTH and alpha-MSH immunoreactivities (ir). DOM-treated dogs showed a pituitary concentration of beta-EP and ACTH similar to the placebo-treated dogs. The total alpha-MSH ir was similar in both groups and distributed on two main peaks: one corresponding to alpha-MSH and another coeluting with des-acetyl-alpha-MSH [1-13(ACTH)NH2]. However, the percentage of alpha-MSH on total ir in DOM-treated dogs (15.4 +/- 2.6%) was lower than in controls (37.5 +/- 4.5%, P less than 0.01); the corresponding percentage of 1-13(ACTH)NH2 content was 63.0 +/- 3.8% vs 44.7 +/- 3.7%, (P less than 0.01). The alpha-MSH/1-13(ACTH)NH2 ratio was considerably decreased by the treatment (0.25 +/- 0.06 vs 0.89 + 0.15, P less than 0.01). Acetyl beta-EP-like ir was also lower in treated (38.4 + 5.4 fmol/mg) vs control (86.6 + 19.2 fmol/mg, P less than 0.05) animals. These data indicate that the dopaminergic system plays an important role in the control of acetylation processes of POMC-related peptides in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine acts on acetylation of proopiomelanocortin-derived products in dog pituitary. 283 83

Four beta-endorphins (beta-endorphin 6-17, 2-17, 1-16, and 1-17) and two adrenocorticotropic hormone (ACTH) peptides (ACTH 1-10 and (1-16)-NH2) were studied by using fast atom bombardment coupled with tandem mass spectrometry. The capability to reproduce metastable ion and collisionally activated decomposition spectra on two different commercial sector mass spectrometers in two different laboratories was found to be acceptable (deviations in relative abundance are less than +/- 50%). The endorphin peptides fragment metastably or upon collisional activation to give abundant B-series ions as well as Y-series ions, whereas Y-series ions are the principal ionic species produced upon the desorption by fast atom bombardment. The ACTH peptides also fragment to give Y-series ions, but of relatively low abundance compared to those from the endorphins. For both sets of peptides, high-energy collisionally activated decomposition and metastable ion decomposition daughter ion spectra are precise, structurally informative--even for peptides up to m/z 2000--and complementary to spectra of daughter ions produced by desorption ionization alone.
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PMID:FAB and tandem mass spectrometry for endorphin- and ACTH peptides of molecular weight to 2000. 284 51

In our previous studies, we have purified a unique, paired basic residue-specific, prohormone-converting enzyme from pituitary intermediate lobe secretory vesicles. This enzyme, an aspartyl protease, was shown to cleave the intermediate lobe prohormone, pro-opiomelanocortin (POMC), to adrenocorticotropin, beta-endorphin and a 16 kDa NH2-terminal glycopeptide, in vitro [(1985) J. Biol. Chem. 260, 7194-7205]. To provide some evidence that this enzyme plays a role in prohormone conversion in the intact cell, the ability of pepstatin A, an aspartyl protease inhibitor, to block POMC processing in the mouse intermediate pituitary was investigated. By the use of a radioactive pulse-chase paradigm, [3H]POMC processing was found to be inhibited by 36.4% in pepstatin A-treated intermediate lobes. This result is consistent with the inactivation of pro-opiomelanocortin-converting enzyme by pepstatin A in the intact pituitary and further supports a role of this enzyme in POMC processing in vivo.
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PMID:The effect of pepstatin A, an inhibitor of the pro-opiomelanocortin (POMC)-converting enzyme, on POMC processing in mouse intermediate pituitary. 284 92

N alpha-Acetyltransferase, which catalyzes the transfer of an acetyl group from acetyl coenzyme A to the alpha-NH2 group of proteins and peptides, was isolated from Saccharomyces cerevisiae and demonstrated by protein sequence analysis to be NH2-terminally blocked. The enzyme was purified 4,600-fold to apparent homogeneity by successive purification steps using DEAE-Sepharose, hydroxylapatite, DE52 cellulose, and Affi-Gel blue. The Mr of the native enzyme was estimated to be 180,000 +/- 10,000 by gel filtration chromatography, and the Mr of each subunit was estimated to be 95,000 +/- 2,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme has a pH optimum near 9.0, and its pI is 4.3 as determined by chromatofocusing on Mono-P. The enzyme catalyzed the transfer of an acetyl group to various synthetic peptides, including human adrenocorticotropic hormone (ACTH) (1-24) and its [Phe2] analogue, yeast alcohol dehydrogenase I (1-24), yeast alcohol dehydrogenase II (1-24), and human superoxide dismutase (1-24). These peptides contain either Ser or Ala as NH2-terminal residues which together with Met are the most commonly acetylated NH2-terminal residues (Persson, B., Flinta, C., von Heijne, G., and Jornvall, H. (1985) Eur. J. Biochem. 152, 523-527). Yeast enolase, containing a free NH2-terminal Ala residue, is known not to be N alpha-acetylated in vivo (Chin, C. C. Q., Brewer, J. M., and Wold, F. (1981) J. Biol. Chem. 256, 1377-1384), and enolase (1-24), a synthetic peptide mimicking the protein's NH2 terminus, was not acetylated in vitro by yeast acetyltransferase. The enzyme did not catalyze the N alpha-acetylation of other synthetic peptides including ACTH(11-24), ACTH(7-38), ACTH(18-39), human beta-endorphin, yeast superoxide dismutase (1-24). Each of these peptides has an NH2-terminal residue which is rarely acetylated in proteins (Lys, Phe, Arg, Tyr, Val, respectively). Among a series of divalent cations, Cu2+ and Zn2+ were demonstrated to be the most potent inhibitors. The enzyme was inactivated by chemical modification with diethyl pyrocarbonate and N-bromosuccinimide.
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PMID:Purification and characterization of an N alpha-acetyltransferase from Saccharomyces cerevisiae. 284 92

Two side-chain cyclic lactam analogues of the 4-11 fragment of alpha-melanocyte-stimulating hormone (alpha-MSH), Ac-[Nle4,D-Orn5,Glu8]alpha-MSH4-11-NH2 and Ac-[Nle4,D-Orn5,D-Phe7,Glu8]alpha-MSH4-11-NH2, were prepared on p-methylbenzhydrylamine resin by using a combination of N alpha-Boc and N alpha-Fmoc synthetic strategies with diphenyl phosphorazidate mediated cyclization. The melanotropin activities of these two analogues were examined and compared relative to those of alpha-MSH, Ac-[Nle4]alpha-MSH4-11-NH2, and Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the frog (Rana pipiens) skin bioassay, the L-Phe7 17-membered ring cyclic analogue was slightly more potent than the linear Ac-[Nle4]alpha-MSH4-11-NH2 and exhibited prolonged melanotropic bioactivity (greater than or equal to 4 h). In this same assay, the D-Phe7 cyclic analogue was more than 100-fold less potent than the L-Phe cyclic analogue and was 10,000 times less potent than linear Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the lizard skin (Anolis carolinensis) bioassay, the L-Phe7 cyclic analogue was 100-fold less potent than Ac-[Nle4]alpha-MSH4-11-NH2, while the D-Phe7 cyclic analogue was 10,000-fold less potent than both Ac-[Nle4]alpha-MSH4-11-NH2 and the D-Phe7 linear derivative Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. The solution conformation of these two cyclic analogues in dimethyl sulfoxide-d6 was examined by 1D and 2D 500-MHz 1H NMR spectroscopy. Our analysis suggests an H bond stabilized C10 (or C13) turn for the D-Phe7 cyclic structure while the L-Phe7 analogue is more conformationally flexible.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic lactam analogues of Ac-[Nle4]alpha-MSH4-11-NH2. 285 55

The purpose of this study was to compare the binding potency to opioid receptors of met-enkephalin-derived, hypophysiotrophic peptides with their reported growth hormone (GH)-releasing strengths in vitro and further, to determine the relative selectivity of each peptide for mu and delta opioid binding sites in the forebrain of the rat. A series of (GH)-releasing pentapeptides and hexapeptides (GHRP's), as well as rat (rGHRH) and human (hGHRH) growth hormone-releasing hormones were tested for preferential binding to specific opioid receptors. The site selectivity of each peptide was determined by its ability to compete for binding with synthetic ligands for mu (Tyr-D-Ala-Gly-MePhe-Gly-ol; DAGO) and delta ([D-Pen2,5]-enkephalin; DPDPE) opioid receptors. The various peptides differed in their selectivities for the two opioid receptors in that most of the GHRP's were mu-selective, while the naturally occurring GHRH's were delta-selective. Amidation of the C-terminal decreased delta selectivity. Besides affecting selectivity for the site, structural changes that enhanced GH-release by enkephalin-derived peptides also decreased their potency to compete for opioid binding sites. For example, dose-response curves for His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SK&F 110679) inhibition of the binding of DAGO and DPDPE yielded IC50's of 6 and 20 microM, respectively. In contrast, Tyr-D-Trp-Gly-Phe-Met-NH2 (BI360), which is 1 X 10(3) times weaker than SK&F 110679 in releasing GH, had IC50's of 0.1 microM and 0.08 microM for inhibition of the binding of DAGO and DPDPE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of growth hormone-releasing hormones and enkephalin-derived growth hormone-releasing peptides to mu and delta opioid receptors in forebrain of rat. 285 11


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