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At least 847 records · Page 47Linked to original sources
PubMed1981

Protein topography of the 40 S ribosomal subunit from rabbit reticulocytes shown by cross-linking with 2-iminothiolane.

The small ribosomal subunit from rabbit reticulocytes was allowed to react with 2-iminothiolane under conditions that minimize the formation of 40 S subunit dimers. Reaction with 2-iminothiolane results in the formation of amidine-linked sulfhydryl derivatives of protein amino groups. Cross-linking between proximal sulfhydryl groups was promoted by mild oxidation of the modified ribosomal subunits. Protein extracted from cross-linked ribosomes was fractionated on the basis of charge by polyacrylamide-urea gel electrophoresis at pH 5.5. Cross-linked protein dimers in sequential slices of this gel were analyzed by diagonal polyacrylamide-sodium dodecyl sulfate gel electrophoresis. Constituent proteins of cross-linked pairs were located by their common mobility in the first dimension and by comparison of the sum of their molecular weights with that of the parent cross-linked species. They were unambiguously identified by extraction, radioiodination, two-dimensional polyacrylamide-urea gel electrophoresis and radioautography and comparison with nonradioactive markers. Thirty-six protein dimers were identified. Many proteins were found to occur in several cross-linked dimers and this facilitated representation of the results in a model showing the network of crosslinks. The results are discussed in relation to other structural and functional data on the 40 S ribosomal subunit.

Animals↗
PubMed1981

Acetylation of bovine growth hormone by N-acetylimidazole.

Bovine growth hormone was chemically modified with N-acetylimidazole and the acetylated tyrosine residues were identified. Tyrosine 42 was the most reactive followed by tyrosines 158, 35 and 109 and to a lesser degree by tyrosines 141 and 174. Several lysine residues were also acetylated. The modified hormone retained the native alpha-helix content but showed a weak growth promoting activity and was unable to complete in vivo with 125I-labeled bovine growth hormone for the liver binding sites. The loss in growth promoting activity induced by acetylation was prevented by the amidination of lysine residues. These findings combined with results already published suggest that tyrosine residues are not important in the manifestation of the hormone growth promoting activity.

Acetylation↗
PubMed1976

Effect of chemical modification by (di)imidoesters on cells and cell envelope components of Escherichia coli and Salmonella typhimurium.

Cells and cell envelope components of Escherichia coli and Salmonella typhimurium were treated with mono- and bifunctional imidates like methylbutyrimidate, methyl-4-mercaptobutyrimidate and dimethylsuberimidate, and after determination of the appropriate conditions, the effects on structure and function were investigated. Within 10 min after treatment of the bacteria with 5 mM of the (di)imidoesters, active transport, DNA-, RNA-, protein- and lipid-synthesis were severely inhibited. After crosslinking, cell envelope components, e.g. phospholipids, lipopolysaccharide, and periplasmic proteins, became partly inextractable. Crosslinked cells showed increased resistance to ultrasonic treatment and osmotic or detergent induced lysis. By the reaction of (di)imidoesters with phospholipids containing no amino groups, it could be demonstrated that non-amidine products were also formed. In addition, freeze-fracturing and freeze-etching demonstrated distinct crosslinked areas in the cell envelope of E. coli B.

Bacterial Proteins↗
PubMed1994

Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.

Footprinting experiments using both DNase I and methidium propyl-EDTA.Fe(II) have been used to investigate the sequence selectivity in binding to DNA of pentamidine and four butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with acquired immunodeficiency syndrome. In common with pentamidine, the butamidine drugs, which contain cis- or trans-1,4-but-2-ene linkers and either bis(amidine) or bis(imidazolidine) terminal groups, bind selectively to DNA sequences composed of at least 4 consecutive A.T base pairs. None of the drugs tolerates the presence of a G.C base pair within the binding site. Consistently in the DNase I and methidium propyl-EDTA.Fe(II) footprinting experiments, the cis-isomers produce stronger footprints than do the trans-isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that the conformation of the drug plays a determining role in the binding reaction. Starting from the known structure of a pentamidine-oligonucleotide complex, it is possible to rationalize the different capacities of the cis- and trans-butamidine analogues to recognize defined DNA sequences in terms of the radius of curvature of the molecule and the distance between the positively charged terminal groups. Together, these features constitute critical factors favoring (cis-conformation) or hampering (trans-conformation) the fitting of the drugs into the minor groove of DNA. In terms of structure-activity relationships, the AT-specific recognition of DNA by this series of butamidine derivatives cannot be directly correlated with their potencies against Pneumocystis carinii pneumonia.

Base Sequence↗
PubMed1976

Primary structure of human carbonic anhydrase C.

The primary structure of human erythrocyte carbonic anhydrase C has been determined. The single polypeptide chain contains 259 amino acid residues devoid of disulfide bridges. The experimental approach has involved restriction of the action of trypsin to arginyl bonds by amidination of the lysyl side chains. The six tryptic fragments obtained have been separated and sequenced by manual techniques. During the sequence work on human carbonic anhydrase C, 3 very easily deamidated asparagine residues were noted, all occurring in -Asn-Gly- sequences. The deamidation which takes place even under normal conditions of peptide preparation seems to be associated with a beta-aspartyl shift. A few minor differences existing between our structure and the results from another laboratory are discussed. A brief comparison is made with the primary structures of other carbonic anhydrases with regard to the function of some amino acid residues in the active site of the enzymes.

Amino Acid Sequence↗
PubMed1998

Metabolism and excretion of a new anxiolytic drug candidate, CP-93, 393, in healthy male volunteers.

CP-93,393 [(7S,9aS)-1-(2-pyrimidin-2-yloctahydropyrido[1,2-a] pyrazin-7-ylmethyl)pyrrolidine-2,5-dione] is a new anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. The excretion, biotransformation, and pharmacokinetics of CP-93,393 were investigated in six healthy male volunteers after oral administration of a 5-mg dose of [14C]CP-93,393. The administered radioactivity was excreted predominantly in the urine. One week after administration of the dose, cumulative excretion amounted to 67.8 +/- 2.5% in the urine and 22.0 +/- 5.6% in the feces. In total, 89.8 +/- 5.7% of the radioactive dose was recovered in urine and feces. Mean maximum plasma concentration values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorphan, respectively. AUC0-infinity values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma concentration and AUC0-infinity values for total radioactivity were similar for the two phenotypes. Less than 0.5% of the dose was excreted in urine as unchanged drug for both EMs and PMs, suggesting extensive metabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-position of the pyrimidine ring was identified as the main metabolic pathway. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjugates (M-7 and M-13, respectively) accounted for approximately 51% of the administered dose in excreta of both PMs and EMs. Hydrolysis of the succinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for approximately 9% of the dose. A novel metabolite, apparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18. M-15 (47-62%), its sulfate conjugate (M-13, approximately 9%), and the pyrimidine ring-cleaved product (M-18, 7-13%) were identified as the major circulating metabolites for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, i.e. 1) aromatic hydroxylation followed by conjugation with glucuronic acid and sulfuric acid, 2) oxidative degradation of the pyrimidine ring, and 3) hydrolysis of the succinimide ring. The identified metabolites accounted for approximately 90, 91, and 92% of the total radioactivity present in urine, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with human liver microsomes.

Administration, Oral↗
PubMed1998

Chemotherapy for onchocerciasis: results of in vitro experiments with promising new compounds.

An improved short-term in vitro culture system was used for the routine screening of hundreds of promising new compounds with the target organism, the filarial nematode Onchocerca volvulus. The most active leads were identified among the pyrimidinylguanidines, amidine derivatives, the imidazolinylhydrazones, thiosemicarbazone derivatives and thiadiazole derivatives. Single compounds of these leads demonstrated strong macrofilaricidal efficacy in minimum effective dose trials down to 0.1 microM and in experiments evaluating the minimum time of exposure after less than 6 h exposure. In the group of the pyrimidinylguanidines we found a significant correlation of structure and activity: change of a single side-group in the molecules had dramatic influence on compound activity. Most of the new compounds that were active on the macrofilariae did not show significant activity on microfilariae (mf) in in vitro trials. Only one compound with significant activity against female O. volvulus worms killed mf at very low concentrations. Some of the promising leads will be processed in further trials on a preclinical level with predictive cattle models.

Animals↗