Role of tryptophan in the luteinizing hormone-releasing hormone

Coy, David H.; Coy, Esther J.; Hirotsu, Yoshihiro; Vilchez‐Martinez, Jesus A.; Nispen, J. W. van; Tesser, G. I.

doi:10.1021/bi00714a022

Cited by 40 publications

(16 citation statements)

References 15 publications

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“…The compounds with a variation in position 9(VIII-XI) are markedly less active. In both pairs of corresponding analogues (VIII, IX and X, XI) the pentamethylphenyl-3) Recently it has been shown (Coy et al 1974), that the influence of various sub¬ stitutions of tryptophan in position 3 in LH-RH is in full agreement with this hypothesis: In [Pmp3]LH-RH, 69 %> of the biological activity was preserved, whereas replacement by amino acid residues having much lower or no charge transfer properties, produced very weakly active analogues. alanine peptides are even less active than the phenylalanine analogues.…”

Section: Steroidogenesis In Vitromentioning

confidence: 84%

Biological Activities of Acth-Analogues Varied in the Active Site

Nispen

Tesser

Barthe

et al. 1977

Acta Endocrinologica

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The steroidogenic and lipolytic activities of corticotrophin-(1-24)-tetracosapeptide and [Lys17,18]corticotrophin-(1-18)-octadecapeptide amide were compared with those of corresponding analogues substituted in position 8 with norarginine and homoarginine, and in position 9 with phenylalanine and pentamethylphenylalanine. The norarginine containing analogues demonstrated a rewarding activity, although they were generally somewhat less active than the homoarginine containing compounds. This confirms the previous conclusions concerning the indispensability of arginine as a guanidinium derivate. The analogues in which phenylalanine was a substitute for tryptophan, constituted partial agonists with a low activity in steroidogenesis and lipolysis but a rather high melanophore stimulating activity. Insertion of the permethylated derivative of phenylalanine in this position, which ensures the presence of an aminoacyl residue with the full electron donor properties of tryptophan, destroyed the low steroidogenic and lipolytic activity, but increased the MSH\x=req-\ activity about 2-fold.In earlier investigations a striking difference has been found between the bio¬ logical importance of the arginyl residue in the information locus (position 8) of corticotrophic peptides and that of the arginyl residues occurring in the binding site (positions 17 and 18). Replacement of Arg17 and Arg18 by lysine

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Section: Steroidogenesis In Vitromentioning

confidence: 84%

Biological Activities of Acth-Analogues Varied in the Active Site

Nispen

Tesser

Barthe

et al. 1977

Acta Endocrinologica

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“…Amino acid analyses were run on a Beckman model 119 equipped with a system AA computing integrator. The modified single-column method used has been described (10).…”

Section: Methodsmentioning

confidence: 99%

“…2) suggests the correctness of the structure and also serves to demonstrate the homogeneity of the synthetic product. A further indication of the identity of prosomatostatin is that the natural and synthetic peptides were immunologically indistinguishable from each other, although both showed less affinity than somatostatin for the antiserum A101 directed toward residues [5][6][7][8][9][10][11][12][13] active than somatostatin on a weight basis in suppressing plasma glucagon (about twice as active on a molar basis) and more than 5 times as active as somatostatin in inhibiting plasma insulin on a weight basis (more than 10 times as active on a molar basis). The reasons for the strong and somewhat selective actions of prosomatostatin are not known, but one possibility is that this extended form has a longer biological half-life than somatostatin.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological actions of prosomatostatin.

Meyers¹,

Murphy²,

Redding³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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The recently isolated 28-residue sequence of prosomatostatin, a putative somatostatin precursor from pig hypothalamus and intestine, was synthesized by solid-phase methodology, characterized, and tested in rats for its effects on the release of insulin, glucagon, growth hormone, and prolactin. The synthetic product strongly suppressed plasma levels of insulin, glucagon, and growth hormone, and it appeared to be more active in the pancreas than in the pituitary. It inhibited insulin release about 5 times more effectively than somatostatin on a weight basis. The prohormone also suppressed growth hormone and prolactin levels in vitro. A time-course experiment for the effect of prosomatostatin on growth hormone release in vivo showed a significant suppression of plasma growth hormone for at least 90 min.The presence of larger forms of somatostatin in porcine hypothalamus (1, 2) and in rat pancreas, stomach, and duodenum (3) has been recognized, and it has been suggested that these substances may represent precursors of somatostatin (1-3). Recently, the isolation, characterization, and determination of the primary structure of putative prosomatostatin from porcine hypothalami was described (4). Hypothalamic prosomatostatin is an NH2-terminally extended form of somatostatin that has an amino acid sequence identical to that of the porcine intestinal octacosapeptide, somatostatin-28, reported by Pradayrol et al.(5) (Fig. 1).The recent successful use of the rapid solid-phase method of peptide synthesis for the preparation of comparably large biologically active peptides [e.g., f,-endorphin (6, 7), vasoactive intestinal polypeptide (8), and human pancreatic polypeptide (9)], encouraged us to apply this technique to the preparation of prosomatostatin. We report here the first solid-phase synthesis and the biological actions of prosomatostatin. MATERIALS AND METHODSAmino acids were of the L configuration. Solid-phase synthesis was run in a Beckman model 990 peptide synthesizer. Highperformance liquid chromatography (HPLC) was performed on a Waters Associates model 204 liquid chromatograph equipped with two model 6000A pumps and a model 660 gradient programmer. Amino acid analyses were run on a Beckman model 119 equipped with a system AA computing integrator. The modified single-column method used has been described (10).Peptide Synthesis and Purification. Prosomatostatin was synthesized stepwise by using the solid-phase method described for somatostatin analogs (11,12). The standard polystyrene/1%The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 6171 divinylbenzene resin was used. Amino acids were coupled as their Na-tert-butyloxyearbonyl (Boc) derivatives, and reactive side-chains were protected as follows: Cys, 4-methylbenzyl (11); Thr and Ser, berizyl; Glu, 4-chlorobenzyl; Lys, 2-chlorocarbobenzoxy; Arg, tosyl. After attachment of the first protected ami...

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“…Since pentamethylphenylalanine is very dissimilar both structurally and chemically to the indole ring system of tryptophan, it is remarkable that this replacement result in retention of high Ievels of biological activity. Since the only similarity in the properties of the two amino acids, apart from aromaticity, is their ability to form n-n electron complexes with certain aromatic molecules, it was suggested that similar electronic interactions occur between tryptophan or pentamethylphenylalanine and an aromatic moiety on the pituitary receptor (90).…”

Section: 3luteinizing Hormone-releasing Hormonementioning

confidence: 99%

“…For these reasons, Cov et al (90) suggested that the essential feature oftryptophan in maintaining hormonal action was due to its electron-donating properties.…”

Section: 3luteinizing Hormone-releasing Hormonementioning

confidence: 99%