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)

Any biological function is at least bimolecular and its evolution therefore is at least dual, with variations in two lines of molecules. The hormone specificity results from a particular fit between the three-dimensional structure of the agent and that of the receptor but, because receptors are not known at the structural level, a discussion on the evolution of the polypeptide hormones is mainly limited to the possible progressive changes of the latter. As for other proteins (enzymes, oxygen carriers etc.) two degrees of complexity can be distinguished according to whether the hormone comprises one or several polypeptide chains. Protein assembly can bring new biological properties, each subunit playing a particular role. In this case, the 'internal' evolution (chain-chain interactions) overlaps the 'external' evolution (hormone-receptor contacts). The 'monomeric' hormones present the following problems: evolution of the prohormone and of the converting enzyme (for insulin), duplication and differentiation of two lines of hormones either by amino acid substitutions (neurohypophysial hormones and neurophysins) or by substitutions and size modifications (corticotropin and lipotropin), duplication and fusion leading to internal homology in the single polypeptide chain (somatotropin, prolactin, placental lactogen). The 'dimeric' hormones lead to several problems: successive duplications giving different subunits, selective associations between subunits, unequal rates of evolution of the subunits, the function of each subunit (lutropin, follitropin, thyrotropin, choriogonadotropin). An attempt is made to integrate the evolution of polypeptide hormones in the frame of the evolution of proteins.
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PMID:Molecular evolution of the polypeptide hormones. 78 77

Acrylamide is an efficient quencher of tryptophanyl fluorescence which we report to be very discriminating in sensing the degree of exposure of this residue in proteins. The quenching reaction involves physical contact between the quencher and an excited indole ring, and can be kinetically described in terms of a collisional and a static component. The rate constant for the collisional component is a kinetic measure of the exposure of a residue in a protein, and values ranging from 4 X 10(9) M-1 S-1 for the fully exposed tryptophan in the polypeptide, adrenocorticotropin, to less than 5 X 10(8) M-1 S-1 for the buried residue in azurin have been found. Static quenching is readily detected in proteins that are denatured, or contain only a single fluorophor. Quenching patterns for most multi-tryptophan containing proteins are difficult to analyze precisely, but qualitative information can, nevertheless, be extracted. Applications of this probing technique for monitoring protein conformational changes, such as the acid-induced expansion of human serum albumin, and inhibitor binding to enzymes, are presented. The value of this method lies in its ability to sense not only the steady-state exposure of a residue in a protein, but also its dynamic exposure.
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PMID:Exposure of tryptophanyl residues in proteins. Quantitative determination by fluorescence quenching studies. 125 18

Diazepam-binding inhibitor (DBI) is a 9-kDa polypeptide that colocalizes in glial, adrenocortical, and Leydig cells with the mitochondrial DBI receptor (MDR). By binding with high affinity to the MDR, DBI and one of its processing products--DBI-(17-50)--regulate pregnenolone synthesis and have been suggested to participate in the immediate activation of adrenal steroidogenesis by adrenocorticotropic hormone (ACTH). In adrenals of hypophysectomized rats (1 day after surgery), ACTH failed to acutely affect the amount of adrenal DBI and the density of MDR but increased the rate of DBI processing, as determined by the HPLC profile of DBI-(17-50)-like immunoreactivity. The similar latency times for this effect and for ACTH stimulation of adrenal steroidogenesis suggest that the two processes are related. The ACTH-induced increase in both adrenal steroidogenesis and rate of DBI processing were completely inhibited by cycloheximide; this result suggests the requirement for the de novo synthesis of a protein with a short half-life, probably an endopeptidase. This enzyme, under the influence of ACTH, may activate formation of a DBI-processing product that stimulates steroidogenesis via the MDR. In support of this hypothesis is the demonstration that in hypophysectomized rats the MDR antagonist PK 11195 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide completely inhibited the adrenal steroidogenesis stimulated by ACTH and by the high-affinity MDR ligand 4'-chlorodiazepam.
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PMID:Diazepam-binding inhibitor (DBI)-processing products, acting at the mitochondrial DBI receptor, mediate adrenocorticotropic hormone-induced steroidogenesis in rat adrenal gland. 127 86

Using in situ hybridization histochemistry, we have investigated the effect of thyroid hormone on the expression of several peptide mRNAs in the hypothalamic paraventricular nucleus (PVN) of adult male rats. Hypothyroidism was induced by surgical ablation of the thyroid gland. The animals (control sham-operated, thyroidectomized, thyroidectomized+T4 replaced rats) were studied 28 and 50 days after surgery. Sections of the PVN were hybridized using synthetic oligonucleotide probes complementary to mRNA for thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), galanin (GAL), enkephalin (ENK), neurotensin (NT), vasoactive intestinal polypeptide (VIP) and vasopressin (VP). GAL mRNA was also analyzed in the anterior paraventricular, arcuate, and dorsomedial nuclei of the hypothalamus. At the PVN level, a feedback effect of thyroid hormone on TRH synthesis was demonstrated by the TRH mRNA increase in hypothyroidism and by its decrease in hyperthyroidism. Hypothyroidism caused a dramatic decrease in GAL mRNA in parvo- and magnocellular PVN neurons both 28 and 50 days after thyroid ablation, whereas no effect was seen in VP mRNA, the main peptide hormone coexisting with GAL. The T4 replacement prevented the GAL mRNA impairment. Hypothyroidism did not influence GAL mRNA in the anterior PVN, perifornical area or in the arcuate nucleus, whereas a decrease in GAL mRNA was observed in the dorsomedial nucleus. VIP mRNA, which is undetectable in the PVN of normal animals, was present in several PVN neurons after thyroidectomy. CRH mRNA was decreased after thyroidectomy, whereas the T4 restitution caused an upregulation. The levels of ENK or NT mRNA were not significantly affected by the thyroid status. The present results show that, in addition to TRH mRNA, other hypothalamic peptide mRNAs are affected by thyroid hormone levels.
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PMID:Response of hypothalamic peptide mRNAs to thyroidectomy. 128 6

Eight kinds of neuropeptides and four kinds of neuropeptide receptors were examined in the right and left hemispheres of mongolian gerbils after unilateral carotid ligation-induced stroke and in normal controls. Five hours after ligation of the right common carotid artery, beta-endorphin concentration in the right hemisphere (ischemic side) of the stroke group was significantly increased compared with that in the contralateral hemisphere (non-ischemic side), but there were no differences between sides in other neuropeptides either with or without stroke. Furthermore, although there were no differences in [3H]naloxone binding, [3H]thyrotropin-releasing hormone binding or 125I-vasoactive intestinal polypeptide binding in the brain in this model of stroke, [3H]enkephalin binding was significantly lower on the ischemic side than on the non-ischemic side in the stroke group. These results suggest that increased activity in the beta-endorphinergic system in the brain might be partly caused by ischemic brain failure.
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PMID:Changes of neuropeptides and their receptors in experimental stroke gerbil brains. 132 Jun 63

The hallmark of ACTH oversecretion in Cushing's disease is its partial resistance to the normal suppressive effect of glucocorticoids. Because ACTH secretion by the pituitary tumor is not normally restrained ACTH is overproduced with subsequent chronic hypercortisolism. Since peripheral tissues have retained their normal sensitivity to the action of cortisol they appropriately develop the features of Cushing's disease. The question of whether a collection of corticotroph cells, eventually arranged in an adenomatous-like fashion, is a primary pituitary event or is corticotropin-releasing factor driven has had no response so far. Clonal composition of such lesions has been determined by X chromosome inactivation using DNA probes which detect multiallelic polymorphism in females. A monoclonal pattern is found in all macroadenomas. ACTH is co-secreted with other peptide fragments derived from their common polypeptide precursor, proopiomelanocortin (POMC). As a rule POMC processing in pituitary tumors is qualitatively unaltered: plasma values of the N-terminal fragment, the joining peptide, the beta- and gamma-lipotropins, and beta-endorphin all are valid alternate markers of the tumor activity. Tumor POMC peptides including ACTH and its phosphorylated form usually show no peculiar or unexpected molecular forms in contrast with what is often found when POMC expression occurs in a non-pituitary tumor.
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PMID:Unrestrained production of proopiomelanocortin (POMC) and its peptide fragments by pituitary corticotroph adenomas in Cushing's disease. 132 71

The response of six mRNAs (for prepro-corticotropin-releasing hormone, prepro-enkephalin, prepro-vasoactive intestinal polypeptide/peptide histidine isoleucine, prepro-neurotensin/neuromedin N, prepro-cholecystokinin, and prepro-tyrosine hydroxylase) was measured in the hypothalamic paraventricular and supraoptic nuclei after increasing periods of osmotic stimulation caused by the replacement of regular drinking water with hypertonic saline (up to five days) or by forced dehydration (up to three days). In addition, hematocrits and concentrations of corticosterone were determined after the different periods of osmotic stimulation and correlated with the effects on the content of the various mRNAs. The temporal response of the mRNAs within the paraventricular and supraoptic nuclei to osmotic stimulation was different within the three compartments of these nuclei. First, in response to overnight osmotic stimulation, magnocellular neurosecretory neurons increased their mRNA content for two molecules (prepro-corticotropin-releasing hormone and tyrosine hydroxylase). As the stimulus was maintained over the next two to four days, these cells accumulated the mRNAs for at least three other peptides (cholecystokinin, vasoactive intestinal polypeptide/peptide histidine isoleucine and enkephalin). Second, the response of peptide-coding mRNAs in parvicellular neurosecretory neurons of the paraventricular nucleus appeared to be slower; no changes could be measured after overnight stimulation. However, after a further two- to four-days of continued osmotic stimulation, the content of the mRNA coding for corticotropin-releasing hormone markedly decreased while that for cholecystokinin increased. No change in the content of the mRNAs coding for prepro-vasoactive intestinal polypeptide/peptide histidine isoleucine, enkephalin, and prepro-neurotensin/neuromedin N could be seen at any time after osmotic stimulation in parvicellular neurosecretory neurons. Third, increases in the content of mRNA coding for corticotropin-releasing hormone in the parvicellular neurons that provide descending projections from the paraventricular nucleus could only be detected after longer periods of osmotic stimulation. The effect of osmotic stimulation on plasma corticosterone concentrations was quickly apparent; plasma corticosterone concentrations were significantly elevated on the first morning after the beginning of salt-loading, and demonstrated the rapid effects of osmotic stimulation on the mechanisms controlling corticosterone release. These results show that the synthetic capability of cells in all three compartments of the paraventricular and supraoptic nuclei are modified by osmotic stimulation over different time scales, thereby allowing differential modulation of the neuroendocrine, autonomic, and behavioral components of the animal's response to disturbances in fluid homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Disturbance of fluid homeostasis leads to temporally and anatomically distinct responses in neuropeptide and tyrosine hydroxylase mRNA levels in the paraventricular and supraoptic nuclei of the rat. 134 11

Thymosin alpha 1 (T alpha 1) is a well-characterized immunopotentiating polypeptide originally isolated from calf thymus. We have recently shown in vivo, probable hypothalamic effects of T alpha 1 to decrease the release of the pituitary hormones, TSH, PRL and ACTH from the pituitary gland. Therefore, in the present study we evaluated the effect of the peptide on the release of hypothalamic regulatory hormones: thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), as well as somatostatin (SRIH), from medial basal hypothalamic (MBH) fragments incubated in vitro. After a preliminary time-course study indicated that a 30-min incubation period was optimal, it was used for all the other experiments. At the end of the incubation the tissue was still able to respond to a depolarizing K+ concentration for 15 min by a 4-fold increase of TRH concentration compared to control basal release during the preceding 30 min. T alpha 1 was shown to inhibit the release of TRH and CRH from MBH fragments incubated in vitro with a minimal effective dose (MED) of 10(-11) M. SRIH and CRH release was also inhibited but the MED for these peptides was 10(-9) M. The relative responsiveness to the action of T alpha 1 was TRH greater than CRH, which was greater than SRIH. This correlated with our previous in vivo results for pituitary hormone release, except in the case of SRIH since we previously did not detect any significant effect of the peptide on growth hormone release. Finally, we evaluated the possible involvement of other neurotransmitters in the effect of T alpha 1 on TRH release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of thymosin alpha 1 on hypothalamic hormone release. 136 97

Secretion systems engineered for the expression of heterologous protein in E. coli provide several advantages for subsequent isolation of purified product. Proteins released from the periplasmic space, which represent a small fraction (i.e., 4-10%) of total cell protein, can readily be separated from other cellular proteins by centrifugation of the remaining cellular debris or cross-flow ultrafiltration. The starting material derived from secretion systems is generally of higher purity than comparable material produced from strains expressing cytoplasmically for systems exhibiting similar expression levels. The available evidence suggests that recombinant proteins derived from the periplasm are generally, but not always (44-46), soluble in a nonaggregated form. Consequently, simple purification protocols can be effectively employed for producing homogeneous product with a high yield. The majority of the secreted recombinant proteins reviewed in this chapter were purified by simple one- or two-step chromatography procedures. High-resolution techniques such as reversed phase HPLC were found necessary only in cases where the secreted polypeptides were contaminated with proteolytic degradation variants, e.g., hirudin (51) and beta-endorphin (22). The fact that a high level of biological activity has been shown to be characteristic of purified recombinant proteins secreted into the periplasmic space suggests the presence of a native conformation stabilized by the expected disulfide linkages. Intramolecular disulfide bonds most probably form either as the polypeptide is translocated through the cytoplasmic membrane into the periplasm or within the periplasmic compartment, which has a higher oxidation potential than that found in the cytoplasm (57). Studies performed with hGH (31) and muIL-2 (35) provide excellent examples of differences observed in protein folding and disulfide bond formation between heterologous proteins expressed in the cytoplasmic and periplasmic compartments. Thus, hGH and muIL-2 extracted from the cytoplasm of E. coli have been characterized as high molecular weight disulfide-bonded oligomers. It is likely that oligomerization occurs as the polypeptides are released from the reducing environment of the cytoplasm. In contrast, secreted hGH and muIL-2 extracted from the periplasm of E. coli by osmotic shock displayed the properties of a property folded native protein with correct disulfide pairing. In the case of muIL-2 only a small residual fraction (approximately 15%) of the purified secreted protein exhibited incomplete oxidation of cysteine (35). Secretion of heterologous proteins into the periplasm prevents their exposure to the action of proteases located in the cytoplasm of E. coli (58). The smaller polypeptides such as somatostatin (59), IGF-1 (46), and hEGF (54) are known to be particularly susceptible to intracellular degradation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purification of secreted recombinant proteins from Escherichia coli. 136 83

Specimens of the sigmoid colon were obtained from male and female patients (n = 11) with carcinoma of the colon or rectum and studied immunohistochemically for vasoactive intestinal polypeptide-, somatostatin-, substance P-, neuropeptide Y-, calcitonin gene-related peptide-, met- and leu-enkephalin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-containing nerves. In the subdivisions of the submucous plexus (namely, Schabadasch's, Meissner's, and the intermediate plexuses), substance P- and vasoactive intestinal polypeptide-immunoreactive nerve fibers were the most numerous, and equal densities of these nerves were found in all three layers. In contrast, few neuropeptide Y-, met-enkephalin-, leu-enkephalin-, calcitonin gene-related peptide-, somatostatin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-immunoreactive nerves were found in these regions. The nerve cell bodies of the submucous plexus contained vasoactive intestinal polypeptide, substance P, leu-enkephalin, somatostatin, and 5-hydroxytryptamine but not neuropeptide Y, met-enkephalin, calcitonin gene-related peptide, and dopamine beta-hydroxylase. Vasoactive intestinal polypeptide-containing nerve cell bodies were found in all three subdivisions. Substance P-, leu-enkephalin-, and somatostatin-immunoreactive nerve cell bodies were found in Schabadasch's plexus and the intermediate region of the submucous plexus, but they were absent from Meissner's plexus; 5-hydroxytryptamine-containing nerve cell bodies were only observed in Schabadasch's plexus. The possible function of the neuropeptide-, dopamine beta-hydroxylase-, and 5-hydroxytryptamine-containing neurons in the different layers of the submucous plexus is discussed.
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PMID:Peptide-containing neurons in different regions of the submucous plexus of human sigmoid colon. 848 77


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