| 8463798 |
Isolation and structure of the marine sponge cell growth inhibitory cyclic peptide phakellistatin 1 |
10.1021/np50092a011. |
J Nat Prod |
Isolation and structure of the marine sponge cell growth inhibitory cyclic peptide phakellistatin 1
Abstract
- A new cell growth inhibitory (P-388 murine leukemia ED50 7.5 micrograms/ml) cycloheptapeptide designated phakellistatin 1 was isolated from two Indo-Pacific sponges, Phakellia costata and Stylotella aurantium. Structural elucidation was accomplished utilizing high field nmr, amino acid analyses, and mass spectral techniques (fab, tandem ms/ms), followed by chiral gas chromatographic procedures for absolute configuration assignments (all S-amino acid units). By these methods phakellistatin 1 1 was found to be cyclo (Pro-Ile-Pro-Ile-Phe-Pro-Tyr), and this assignment was finally confirmed by an X-ray crystal structure determination.
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| 8477005 |
Chemical characterization and toxicity of dihydro derivatives of nodularin and microcystin-LR, potent cyanobacterial cyclic peptide hepatotoxins |
10.1021/tx00032a003. |
Chem Res Toxicol |
Chemical characterization and toxicity of dihydro derivatives of nodularin and microcystin-LR, potent cyanobacterial cyclic peptide hepatotoxins
Abstract
- Dihydro derivatives of nodularin (1) and microcystin-LR (4), potent cyclic peptide hepatotoxins isolated from Nodularia spumigena and Microcystis aeruginosa, respectively, were prepared by sodium borohydride reduction of the dehydroamino acid residues. The two stereoisomers of both dihydronodularin (2 and 3) and dihydromicrocystin-LR (5 and 6), isolated by reversed-phase HPLC, showed similar toxicity to each other ip in mice, LD50 = 150 (2), 150 (3), 85 (5), and 100 (6) micrograms/kg. The stereochemistries of the reduced amino acids obtained by acid hydrolysis of dihydronodularin and dihydromicrocystin-LR respectively, alpha-(methylamino)butyric acid and N-methylalanine were determined by GC on a permethylated beta-cyclodextrin capillary column as their trifluoroacetyl methyl ester derivatives. Authentic L- and DL-N-methylamino acids were prepared to compare directly with the natural amino acids. Deuterated derivatives were also prepared using sodium borodeuteride (98 atom % D), and the location (beta) and percentage (78-84%) of the deuterium incorporation were determined.
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| 8483934 |
Cloning and characterization of a fourth human somatostatin receptor. |
10.1073/pnas.90.9.4196 |
Proc. Natl. Acad. Sci. U.S.A. |
Cloning and characterization of a fourth human somatostatin receptor.
Abstract
- We have isolated a gene coding for a fourth human somatostatin (somatotropin release-inhibiting factor) receptor. This additional somatostatin receptor (hSSTR4) is specifically expressed in human fetal and adult brain and lung tissue. The deduced amino acid sequence of the receptor displays both sequence and structural homology to three cloned somatostatin receptors as well as to other members of the family of GTP-binding-protein-coupled seven-helix transmembrane-spanning receptors. Pharmacological characterization of the expressed receptor reveals specific, high-affinity binding of somatostatin 14 and somatostatin 28. Surprisingly, several well-characterized synthetic somatostatin analogs fail to exhibit high-affinity binding to hSSTR4, indicating the existence of pharmacologically different receptor subtypes. Our data suggest that the diverse biological effects exerted by somatostatin are mediated by a family of receptors with discrete patterns of expression and different pharmacological properties.
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| 8490053 |
A comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22 (Tyr5,12, Lys7-polyphemusin II), determined by nuclear magnetic resonance |
10.1016/0167-4838(93)90183-r. |
Biochim Biophys Acta |
A comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22 (Tyr5,12, Lys7-polyphemusin II), determined by nuclear magnetic resonance
Abstract
- The solution structure of tachyplesin I, which was isolated from membrane acid extracts of the hemocytes from the Japanese horseshoe crab (Tachypleus tridentatus), was determined by nuclear magnetic resonance (NMR) and distance geometry calculation. Tachyplesin I takes an antiparallel beta-sheet structure with a type-II beta-turn. Recently, among more than 20 synthetic peptides associated with tachyplesin and its isopeptide (polyphemusin), we found that a novel compound, which we designated as T22 (Tyr5,12, Lys7-polyphemusin II), strongly inhibited the human immunodeficiency virus (HIV)-1-induced cytopathic effect and viral antigen expression. The solution structure of T22 was investigated using NMR, and its secondary structure was confirmed to be similar to that of tachyplesin I. The anti-parallel beta-sheet structure and the several amino-acid side chains on the plane of the beta-sheet of T22 are thought to be associated with the expression of anti-HIV activity.
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| 8491186 |
The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling |
10.1002/j.1460-2075.1993.tb05842.x. |
EMBO J |
The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling
Abstract
- GRB2, a small protein comprising one SH2 domain and two SH3 domains, represents the human homologue of the Caenorhabditis elegans protein, sem-5. Both GRB2 and sem-5 have been implicated in a highly conserved mechanism that regulates p21ras signalling by receptor tyrosine kinases. In this report we show that in response to insulin, GRB2 forms a stable complex with two tyrosine-phosphorylated proteins. One protein is the major insulin receptor substrate IRS-1 and the second is the SH2 domain-containing oncogenic protein, Shc. The interactions between GRB2 and these two proteins require ligand activation of the insulin receptor and are mediated by the binding of the SH2 domain of GRB2 to phosphotyrosines on both IRS-1 and Shc. Although GRB2 associates with IRS-1 and Shc, it is not tyrosine-phosphorylated after insulin stimulation, implying that GRB2 is not a substrate for the insulin receptor. Furthermore, we have identified a short sequence motif (YV/IN) present in IRS-1, EGFR and Shc, which specifically binds the SH2 domain of GRB2 with high affinity. Interestingly, both GRB2 and phosphatidylinositol-3 (PI-3) kinase can simultaneously bind distinct tyrosine phosphorylated regions on the same IRS-1 molecule, suggesting a mechanism whereby IRS-1 could provide the core for a large signalling complex. We propose a model whereby insulin stimulation leads to formation of multiple protein--protein interactions between GRB2 and the two targets IRS-1 and Shc. These interactions may play a crucial role in activation of p21ras and the control of downstream effector molecules.
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| 8508481 |
Conformational recognition of RA-XII by 80S ribosomes: a differential line broadening study in 1H NMR spectroscopy |
10.1248/cpb.41.781. |
Chem Pharm Bull (Tokyo) |
Conformational recognition of RA-XII by 80S ribosomes: a differential line broadening study in 1H NMR spectroscopy
Abstract
- 1H NMR spectroscopy has been used to demonstrate specific binding of rat 80S ribosomes to the major conformer of an antitumor bicyclic hexapeptidic glucoside, RA-XII, isolated from Rubia cordifolia, in a fast exchange process.
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| 8508915 |
Novel antimicrobial peptides from skin secretion of the European frog Rana esculenta |
10.1016/0014-5793(93)81384-c. |
FEBS Lett |
Novel antimicrobial peptides from skin secretion of the European frog Rana esculenta
Abstract
- Three antimicrobial peptides were isolated from skin secretion of the European frog, Rana esculenta. Two of them show similarity to brevinin-1 and brevinin-2, respectively, two antimicrobial peptides recently isolated from a Japanese frog Morikawa, N., Hagiwara, K. and Nakajima, T. (1992) Biochem. Biophys. Res. Commun. 189, 184-190. The third one, named esculentin, is 46 residues long and represents a different type of peptide. All these peptides have as a common motif an intramolecular disulfide bridge located at the COOH-terminal end. The peptides from R. esculenta show distinctive antibacterial activity against representative Gram-negative and Gram-positive bacterial species. In particular, esculentin is the most active against Staphylococcus aureus, and has a much lower hemolytic activity.
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| 8512564 |
Molecular cloning and sequencing of a human somatostatin receptor, hSSTR4. |
10.1006/bbrc.1993.1673 |
Biochem. Biophys. Res. Commun. |
Molecular cloning and sequencing of a human somatostatin receptor, hSSTR4.
Abstract
- We recently reported the cloning of a somatostatin receptor (SSTR) subtype from a rat genomic library designated rSSTR4. In the present study, we report the cloning of the human SSTR4 gene. A human genomic library was screened with a 1.2 kb fragment of rSSTR4 containing the full open reading frame and a genomic clone, hSSTR4, was isolated. The deduced amino acid sequence of this clone encoded a protein of 388 amino acids and is a member of the G-protein coupled receptor superfamily. Comparison of rat and human SSTR4 sequences demonstrated 89% identity. In addition, the sequence of hSSTR4 shows 61%, 46%, and 47% sequence identity with previously identified isoforms hSSTR1, hSSTR2, and hSSTR3, respectively.
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| 8524402 |
Crystal structures of human calcineurin and the human FKBP12-FK506- calcineurin complex. |
10.1038/378641a0 |
Nature |
Crystal structures of human calcineurin and the human FKBP12-FK506- calcineurin complex.
Abstract
- Calcineurin (CaN) is a calcium- and calmodulin-dependent protein serine/threonine phosphate which is critical for several important cellular processes, including T-cell activation. CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cytoplasmic binding proteins (cyclophilin and FKBP12, respectively). We report here the crystal structures of full-length human CaN at 2.1 A resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 A resolution. In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule. In the FKBP12-FK506-CaN complex, the auto-inhibitory element is displaced from the active site. The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcineurin, including a natural anchoring protein.
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| 8531090 |
Pharmacological evaluation of 1229U91, a novel high-affinity and selective neuropeptide Y-Y1 receptor antagonist |
None |
J Pharmacol Exp Ther |
Pharmacological evaluation of 1229U91, a novel high-affinity and selective neuropeptide Y-Y1 receptor antagonist
Abstract
- The physiological role of neuropeptide Y (NPY), peptide YY (PYY) and their receptors (Y1 and Y2) has been difficult to elucidate mainly due to the lack of selective and high-affinity antagonists. Recently, Burroughs Wellcome disclosed a series of cyclic peptides, including the compound 1229U91, which were reported to be selective NPY receptor antagonists (PCT Publication No. WO 94/00486). The objective of this study was to evaluate the pharmacological properties of 1229U91. In radioligand binding studies, 1229U91 displaced specifically bound 125IPYY from SK-N-MC cells (Y1 receptors) and SK-N-BE(2) cells (Y2 receptors) yielding pKi +/- S.E.M. estimates of 10.9 +/- 0.2 and 7.9 +/- 0.2, respectively. In the isolated perfused kidney of rat (Y1 receptor assay), NPY (10-1000 ng, bolus injection) evoked concentration-dependent increases in perfusion pressure (EC50 = 54.5 ng). In this assay, 1229U91 (1, 10 and 100 nM) produced concentration-dependent dextral displacement of the concentration-effect curve to NPY. The antagonism was surmountable at 1 nM 1229U91 (apparent pA2 estimate +/- S.E.M. = 9.3 +/- 0.4). At concentrations of 10 and 100 nM, 1229U91 produced significant depression of the maximum response to NPY (36 and 67%, respectively). In the vas deferens of rat (Y2 receptor assay), 1229U91 (3 microM) had no effect on NPY-induced inhibition of electrically evoked twitch response. In pithed rats, 1229U91 (0.3, 1 and 3 micrograms/kg/min i.v.) produced dose-dependent dextral displacement of the pressor dose-response curve to NPY yielding dose-ratio estimates of 2.4, 25.4 and 57.5, respectively. 1229U91 (3 micrograms/kg/min i.v.) had no effect on the pressor responses to norepinephrine or angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 8543019 |
Interaction of cryptophycin 1 with tubulin and microtubules |
10.1016/0014-5793(95)01271-0. |
FEBS Lett |
Interaction of cryptophycin 1 with tubulin and microtubules
Abstract
- The cryptophycins are newly discovered antimitotic agents isolated from the cyanobacterium Nostoc. Previous studies using cultured cells demonstrated that microtubules are the target of these compounds. We have studied the interaction of cryptophycin 1 with tubulin and microtubules in vitro. Cryptophycin 1 is an effective inhibitor of tubulin polymerization, causes tubulin to aggregate, and depolymerizes microtubules to linear polymers somewhat similar to the spiral-like structures produced by the Vinca alkaloids. Cryptophycin 1 also inhibits vinblastine binding to tubulin but not colchicine binding. Thus, it appears that the cryptophycins may bind to the Vinca site in tubulin or to a site that overlaps with the Vinca site.
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| 8556152 |
Mass spectral analyses of microcystins from toxic cyanobacteria using on-line chromatographic and electrophoretic separations |
10.1016/0021-9673(95)00438-s. |
J Chromatogr A |
Mass spectral analyses of microcystins from toxic cyanobacteria using on-line chromatographic and electrophoretic separations
Abstract
- The application of capillary electrophoresis and of reversed-phase liquid chromatography coupled to electrospray mass spectrometry is presented for the analysis of microcystins isolated from toxic strains of Microcystis aeruginosa. The separation performance of these two techniques is compared in terms of both sensitivity and of resolution of closely related microcystins. Quantitation of microcystin-LR present at low micrograms/ml concentrations in cell extracts is demonstrated using both techniques. A marked advantage of capillary electrophoresis over liquid chromatography was its ability to resolve different desmethyl microcystin-LR analogues. Identification of these positional isomers was facilitated using capillary electrophoresis combined with tandem mass spectrometry (MS-MS). Rationalization of fragment ions observed in MS-MS spectra of microcystins was made possible through comparison with 15N labelled microcystins obtained from stable isotope feeding experiments. The potential of tandem mass spectrometry in providing selective detection of microcystins in cell extracts, and in structural characterization of novel microcystins, was also investigated.
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| 8557559 |
RES-701-2, -3 and -4, novel and selective endothelin type B receptor antagonists produced by Streptomyces sp. I. Taxonomy of producing strains, fermentation, isolation, and biochemical properties |
10.7164/antibiotics.48.1213. |
J Antibiot (Tokyo) |
RES-701-2, -3 and -4, novel and selective endothelin type B receptor antagonists produced by Streptomyces sp. I. Taxonomy of producing strains, fermentation, isolation, and biochemical properties
Abstract
- RES-701-2, -3 and -4, novel cyclic peptide endothelin antagonists, were isolated from the culture broths of Streptomyces sp. RE-701 and RE-896, RES-701s selectively inhibited the ET-1 binding to endothelin type B receptor (ETB receptor) with IC50 values ranging from 5 to 20 nM. Taxonomy of the producing strains, fermentation, isolation and biochemical properties of RES-701s are described.
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| 8557566 |
Chondramides A approximately D, new antifungal and cytostatic depsipeptides from Chondromyces crocatus (myxobacteria). Production, physico-chemical and biological properties |
10.7164/antibiotics.48.1262. |
J Antibiot (Tokyo) |
Chondramides A approximately D, new antifungal and cytostatic depsipeptides from Chondromyces crocatus (myxobacteria). Production, physico-chemical and biological properties
Abstract
- Novel depsipeptides, named chondramides were produced at levels up to 4.3 mg/liter by several myxobacteria of the genus Chondromyces. The compounds are structurally closely related to jaspamide/jasplakinolide from marine sponges of the genus Jaspis. Initially the chondramides were detected in acetone extracts of the biomass of Chondromyces crocatus, strain Cm c2. So far, four structural variants could be characterized, the chondramides A approximately D. They inhibited the growth of a few yeasts and showed high cytostatic activity against cultivated human and animal cells.
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| 8557597 |
Inhibition of acyl-CoA: cholesterol acyltransferase by isohalobacillin, a complex of novel cyclic acylpeptides produced by Bacillus sp. A1238 |
10.7164/antibiotics.48.1419. |
J Antibiot (Tokyo) |
Inhibition of acyl-CoA: cholesterol acyltransferase by isohalobacillin, a complex of novel cyclic acylpeptides produced by Bacillus sp. A1238
Abstract
- A complex of metabolites consisting of two isomeric cyclic acylpeptides was isolated from a culture of Bacillus sp. A1238 by successive chromatographies on Amberlite XAD-7, silica gel and silica ODS columns. By a combination of spectroscopic and chemical analyses, the two subcomponents were identified as isomers of halobacillin, and the complex was designated isohalobacillin. Each molecule of isohalobacillin subcomponents contains either a 3-hydroxy-1-oxo-13-methyltetradecyl or a 3-hydroxy-1-oxo-12 methyltetradecyl moiety in place of a 3-hydroxy-1-oxopentadecyl moiety that is found in the halobacillin molecule. In a cell-free assay, isohalobacillin inhibited acyl-CoA: cholesterol acyltransferase by 50% at a concentration of 50 microM. When added to a culture of macrophage J774, the agent inhibited oxidized low density lipoprotein-induced synthesis of cholesteryl ester from 14Coleate without affecting surface binding, internalization and degradation of the lipoprotein in the cells.
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