HUMANGGP:012528 - FACTA Search

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Query: HUMANGGP:012528 (thyrotropin-releasing hormone)
3,440 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An extract of porcine brain acetone powder incubated with thyrotropin-releasing hormone (TRH; pGlu-His-ProNH2) produces acid TRH (pGlu-His-Pro), histidine, and prolineamide. Fractionation of the brain extract by DEAE-cellulose chromatography produces three protein fractions which metabolize TRH. The activity of these fractions was characterized using TRH with a 3H-label on the histidine or proline as well as [His-3H]His-ProNH2. Fraction I contains pyroglutamate aminopeptidase and Fraction II contains TRH deamidase. Fraction III was found to contain a previously unrecognized enzyme which cleaves His-ProNH2 to histidine and proline. The histidylprolineamide imidopeptidase has been characterized. A competition study using a variety of compounds containing histidine or proline suggests that the best substrates for the imidopeptidase contain a free alpha-amino group on histidine and a blocked carboxyl group on proline, as is found in His-ProNH2. A survey of a variety of polypeptide hormones indicates that many of them inhibit the imidopeptidase activity. A kinetic study of the inhibition of the enzyme by adrenocorticotropic hormone (1-24) shows that the inhibition by polypeptide hormones is noncompetitive. We hypothesize that pituitary hormones may stimulate the production of (cyclo)-His-Pro by inhibiting alternate routes of TRH metabolism.
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PMID:Metabolism of thyrotropin releasing hormone in brain extracts. Isolation and characterization of an imidopeptidase for histidylprolineamide. 10 59

More than 150 hypothalamic fractions were reassayed for luteinizing hormone-releasing hormone (LHRH) and follicle stimulating hormone-releasing hormone (FSHRH) activities in search for LHRH and FSHRH which differ from the decapeptide (pyro)Glu-His-Trp-Ser-Try-Gly-Leu-Arg-Pro-Gly-NH2 (I). Among the porcine fractions tested were those obtained: 1) from the isolation of thyrotropin-releasing hormone; 2) from two isolation procedures for LHRH; and 3) from methanolic and aqueous 2N acetic acid extracts which were subjected to Biogel P-2 filtration and partition chromatography. Some bovine hypothalamic fractions were also tested. Both in vivo and in vitro assays were used for measuring LHRH and FSHRH activities. The values obtained were in each case compared with those resulting from the administration of pure natural or synthetic LHRH decapeptide I. A radioimmunoassay for LHRH (I) was also utilized for some fractions. In all the purification steps the location of LHRH and FSHRH activity, as determined by in vivo assays, corresponded to that of the decapeptide I. Purification of hypothalamic extracts on Biogel P-2 and by partition chromatography separated a fraction from the decapeptide I, which released more FSH than LH in vitro from the pituitaries of immature female rats. However, this material was inactive in vivo and in other in vitro systems, so that its significance is obscure. The results suggest that if material with LHRH and FSHRH activity other than the decapeptide I is present in acid extracts of porcine hypothalami, then its FSHRH and LHRH activity would be a minor part of the total LHRH/FSHRH activity in the extracts. (Pyro)-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 appears to account for most of all of the LHRH and FSHRH activity found.
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PMID:Re-examination of porcine and bovine hypothalamic fractions for additional luteinizing hormone and follicle stimulating hormone-releasing activities. 76 20

Using a radioimmunoassay method for thyrotropin-releasing hormone, the presence of thyrotropin-releasing hormone-metabolizing activity in various hamster tissues was demonstrated. While there was substantial activity degrading thyrotropin-releasing hormone in hypothalamus, there was a notable absence of such activity in pituitary. The enzymatic activity in the hypothalamus was shown to be soluble and separable into two fractions. Analysis of the metabolic products formed by the two enzymes indicated that one possessed an amidase activity (less than Glu-His-Pro-NH2 leads to less than Glu-His-Pro) and the other possessed pyroglutamylpeptidase activity (less than Glu-His-Pro-NH2 leads to less than Glu+His-Pro-NH2). Other peptides containing NH2-terminal pyroglutamic acid or COOH-terminal amide groups did not block the hydrolysis of thyrotropin-releasing hormone, suggesting that the enzymes were specific. Some inhibitors preferentially blocked the activity of one or the other enzymes. Of possible biological significance is the observation that thyroid-stimulating hormone inhibited the amidase activity while hydrocortisone inhibited the pyroglutamylpeptidase activity.
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PMID:Demonstration of pyroglutamylpeptidase and amidase activities toward thyrotropin-releasing hormone in hamster hypothalamus extracts. 81 29

Attempts were made to study the reported biosynthesis of the thyrotropin-releasing hormone (TRH = pyroGlu-His-Pro-amide) by incubating extracts of freeze-dried hypothalamic tissue with radioactively labeled precursor amino acids. Chromatographic analysis indicated a fast incorporation of radioactivity into many metabolites, including one that initially co-migrated with TRH. However, on two-dimensional chromatography, such coincidence disappeared and thus a biosynthesis of TRH could not be confirmed. A very fast degradation of TRH by serum, as well as by brain tissue preparations, was observed and was studied in detail because it could be a cause of difficulties encountered in detecting an in vitro synthesis. In hypothalamic and cortical tissue preparations, on incubation with TRH labeled with [3H]proline, fast formation of radioactively labeled deamido-TRH and liberation of prolineamide and free proline were found. On incubation of serum with labeled TRH there was a similar rapid breakdown, but different products were yielded. Degradation of TRH by serum has been reported to be strongly inhibited by pyroGlu-His-OCH3, a dipeptide analogue of TRH (10). The peptidolytic cleavage of TRH by brain enzymes, yielding proline and prolineamide as split products, was also effectively reduced using comparatively high concentrations of the dipeptide ester without, however, preventing TRH deamidation. Presuming deamido-TRH to be a biosynthetic intermediary, we decided to continue studying the synthesis of TRH with hypothalamic tissue preparations in the presence of inhibitory concentrations of the dipeptide ester, aiming at the isolation of deamido-TRH. Using [14C]proline as the label, it appeared that rather large amounts of radioactively labeled deamido-TRH, which was identified as such by vigorous purification, could be isolated from such incubates. However, only proline was incorporated, but labelled histidine or glutamic acid were not, and ATP addition was, if anything, inhibitory. Therefore, this proline incorporation could not have been due to de novo synthesis. Since the inhibiting pyroGlu-His-methyl ester was rapidly split during incubation, and, therefore, presumably inhibited the tissue peptidase by competition, we have concluded that ester-derived peptidase-bound dipeptide had reacted with [3H]proline in reverse to form the radioactive deamido-TRH in a process unrelated to biosynthesis.
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PMID:Attempts toward biosynthesis of the thyrotropin-releasing hormone and studies on its breakdown in hypothalamic tissue preparations. 82 May 46

A study was made of the effect of replacement of the second and third amino acid residues of the thyrotropin-releasing hormone on the manifestation of the specific biological activity assessed by the radioimmune method of determination of the thyrotropic hormone in rats. Replacement of histidine by alanine caused a 100-fold and by phenylalanine - a 10-fold reduction of the activity. Glycine analogue proved to be inactive. The biological activity of TRH analogue (Glu-Phe-Pro CH3) was only 10 times less in comparison with the activity of the standard. The second double modified analogue of this hormone (Glu-Gly-Ser NH2) was incapable of influencing the release of the thyrotropic hormone by the hypophysis.
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PMID:[Comparative assessment of the specific activity of several thyrotropin-releasing-hormone analogs]. 82 71

An analogue of thyrotropin-releasing hormone (TRH, pGlu-His-ProNH2), i.e. pGlu-His-ProNH-(CH2)6-(4-azidosalicylamide) (TRH-ASA), has been synthesized and, in a radioiodinated form (TRH-IASA), characterized and used as a photoaffinity reagent to label the TRH receptor on rat pituitary GH4C1 cells. TRH-IASA bound to GH4C1 cells with high affinity (Kd = 8 nM), comparable with that of TRH binding. The binding of TRH-IASA was competitive with binding of TRH, two TRH analogues and a TRH receptor antagonist, chlordiazepoxide. TRH-IASA did not bind to or label GH12C1 cells, which lack functional TRH receptors. Labelling of GH4C1 cells with TRH-IASA followed by SDS/PAGE and autoradiography of membrane proteins demonstrated labelling of a single polypeptide which ran as a diffuse band between 71 and 91 kDa, centred at 76 kDa. No change in this labelling pattern was observed as a function of the length of time (between 5 min and 2 h) that GH4C1 cells were incubated with 3 nM-TRH-IASA. Using either a very short (5 s) photolysis interval or low TRH-IASA concentrations, only the 76 kDa band was labelled. Minor bands appeared only after extended photolysis and use of high TRH-IASA concentrations. We conclude that the TRH receptor from rat pituitary GH4C1 cells is a single peptide with an apparent molecular mass of 76 kDa. Details of the chemical synthesis of TRH-ASA are given in Supplementary Publication SUP 50167 (5 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1992) 281, 5.
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PMID:Synthesis and characterization of a high-affinity photoactivatable analogue of thyrotropin-releasing hormone. 131 4

Analogs of thyrotropin-releasing hormone (Glp-His-Pro-NH2, TRH) have been prepared which contain thioamide moieties in the pyroglutamic acid ring, the carboxyamide proline terminus, and in both positions (dithio). These compounds have been tested for TSH-releasing activities (in vitro and in vivo), and for binding to TRH receptors in rat pituitary and cortex. The monothionated analogs showed no significant differences in TSH-releasing potency from TRH either in vitro or in vivo. However, with two thioamide replacements the potency decreases about 50%. Significantly, in terms of receptor selectivity, thionation has resulted in differentiation between brain receptors (pituitary and cortex). The Pro psi[CSNH2] and dithio analogs were more selective (higher affinity to pituitary receptors) than the parent hormone, while the analog containing a thioamide replacement in the pyroglutamyl ring had lower affinity and was not selective. These results suggest that the subtle exchange of sulphur for oxygen can have an important impact on both receptor selectivity and affinity within a biologically active peptide.
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PMID:Biological activities of thionated thyrotropin-releasing hormone analogs. 131 91

We demonstrate that two enzymes, soluble unspecific pyroglutamyl peptidase I and prolyl endopeptidase, able to degrade thyrotropin-releasing hormone (TRH) in vitro were present in pancreas at the early stage of rat development. Specific particulate pyroglutamyl peptidase II remained undetectable during ontogenesis. Pyroglutamyl peptidase I specific activity increased until day 3 and decreased after day 5. Furthermore, prolyl endopeptidase specific activity rose slightly to a peak on postnatal day 20. A good correlation between immunoreactive TRH and deaminated TRH (TRH-OH) was found in the 1st wk after birth. However, His-Pro diketopiperazine (DKP) levels were stable and low during development. We show that hot acidic extraction conditions could artefactually generate His-Pro DKP. In vivo, active site-directed inhibitors of pyroglutamyl peptidase I and prolyl endopeptidase enzymes do not show any TRH-deamidating and/or pyroglutamyl peptidase I pathways in neonatal rat pancreas. The data suggest that these two enzymes are not involved in intra- or extracellular control of TRH levels in neonatal rat pancreas and that pancreatic TRH content appears to be principally regulated by biosynthetic steps. Nevertheless, low levels of endogenous His-Pro DKP and TRH-OH identified in neonatal rat pancreas suggest that TRH or TRH-like peptides may be metabolized in this tissue in intact rats, albeit at low rates.
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PMID:Ontogeny of prolyl endopeptidase, pyroglutamyl peptidase I, TRH, and its metabolites in rat pancreas. 135 85

The effect of an acute dexamethasone administration on thyrotropin-releasing hormone (TRH) and TRH precursor peptide (Lys-Arg-Gln-His-Pro-Gly-Arg-Arg) (p-8) levels in various rat organs has been studied. Rats were injected i.p. with 25 micrograms of dexamethasone/100 g body weight (group A), 500 micrograms of dexamethasone/100 g body weight (group B) or saline (group C). The rats were serially decapitated after the injection. TRH and p-8 levels in the hypothalamus, cerebrum, cerebellum and brain stem, stomach and eye and plasma TRH and thyrotropin (TSH) levels were measured by individual radioimmunoassays. P-8 levels in the hypothalamus decreased significantly in both group A and B at 1-4 hours after the injection, and then returned to pretreated levels at 24 hours after the injection. TRH levels in the hypothalamus increased significantly in both group A and group B at 1-4 hours after dexamethasone injection. No changes in p-8 and TRH levels were observed in other organs. In group A, plasma TRH levels tended to decrease at 1-2 hours, then to increase at 3 hours. In group B, plasma TRH levels decreased 1-4 hours after the dexamethasone injection, then increased at 24 hours. The plasma TSH levels decreased significantly at 1-4 hours in group A and group B, returned to pretreatment levels at 24 hours in group A, and increased significantly in group B at 24 hours after dexamethasone injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of dexamethasone on TRH and TRH precursor peptide (Lys-Arg-Gln-His-Pro-Gly-Arg-Arg) levels in various rat organs. 142 Dec 5

The tripeptide pyroGlu-Tyr-Pro amide was isolated from an aqueous extract prepared from dried alfalfa pellets. The tripeptide was quantitated using a competitive radioimmunoassay in which 125I-labeled thyrotropin-releasing hormone (TRH), is displaced from antibody specific to TRH (pyroGlu-His-Pro amide). The pyroGlu-Tyr-Pro amide was purified by passing the filtered extract through QAE-Sephadex A25 at pH 5, followed by open bed chromatography on C18 silica using an H2O/methanol gradient, then preparative high performance liquid chromatography (HPLC) on microbondapak C18 using a 10 mM HCl/methanol gradient, followed by G-10-Sephadex chromatography, SP-C25-Sephadex chromatography, QAE-Sephadex chromatography at pH 10.1, analytical HPLC on a microbondapak C18 column eluted with 10 mm HCl/acetonitrile, and analytical HPLC reverse phase chromatography on an APEX phenyl column eluted with H2O/acetonitrile. The tripeptide was essentially homogeneous after the final chromatography step, as judged by correspondence of immunoreactivity with A280. The sequence of the alfalfa tripeptide was determined to be Glu-Tyr-Pro by gas phase sequencing, after hydrolysis of pyroglutamic acid by mild acid hydrolysis. The mass of the alfalfa tripeptide was 389.1, as determined by fast ion bombardment mass spectroscopy, and was found to be identical to the mass of synthetic pyroGlu-Tyr-Pro amide. The sequence of the alfalfa tripeptide was also verified using B/E-linked scanning. I conclude that the tripeptide isolated from alfalfa differs from human thyrotropin-releasing hormone only by the substitution of tyrosine for histidine at position 2. The role of pyroGlu-Tyr-Pro amide in alfalfa is not known, but the existence of a family of thyrotropin-related peptides occurring in both the animal and the plant kingdoms indicates that the thyrotropin related peptides have a wide phylogenetic distribution.
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PMID:Isolation and structural determination of a novel TRH-like tripeptide, pyroGlu-Tyr-Pro amide, from alfalfa. 151 3

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