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T Wieland

Publications and source records attributed to T Wieland.

At least 73 records · Page 4Linked to original sources
PubMed1989

Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. VI. Specificity: amino acids, their N-methyl-, N-acetyl- and N-benzoylderivatives; glutathione- and cysteine conjugates, di- and oligopeptides.

In order to evaluate the specificity of the renal contraluminal PAH transport system for amino acids, oligopeptides and their conjugates, the inhibitory potency of these substances against contraluminal [3H] PAH influx has been determined. For this, inhibition of 3H-PAH flux from the interstitium into cortical tubular cells of the rat kidney in situ has been measured. Apparent Ki values were evaluated by a computer program assuming competitive inhibition. Unconjugated amino acids (glycine, cysteine, alanine, leucine, phenylalanine, tyrosine, aspartate, glutamate, arginine, ornithine and lysine) do not inhibit [3H] PAH influx. The very hydrophobic tryptophan, however, does. N-alpha-methylation does not change this behaviour. N-alpha-acetylation does not evoke interaction with the PAH transporter when it occurs with glycine, cysteine (to yield mercapturic acid), arginine, ornithine and lysine. However, it renders alanine, leucine, phenylalanine, tryptophan, L-aspartate moderately, and L-glutamate strongly, inhibitory. The acetylated D-isomers of alanine, leucine and phenylalanine exert a higher inhibitory potency compared with the respective L-isomers. N-alpha-benzoylation of L-lysine is ineffective. N-alpha-benzoylation, however, evokes interaction with the PAH transporter, when it occurs with ornithine less than arginine less than histidine less than glycine = leucine less than alanine = phenylalanine = aspartate = glutamate. Dipeptides interact with the PAH transporter according to their hydrophobicity (Nozaki scale down to 0.9, Fauchère scale up to 1.0). N-acetylation does not change this behaviour. Hydrophobicity also renders oligopeptides, as angiotensin II, inhibitory against PAH transport. Similarly the anionic angiotensin I converting enzyme inhibitors Captopril, Enalapril and Ramipril inhibit contraluminal PAH influx.

Acetylation↗
PubMed1989

Conformational stability of antamanide and analogs. Crystal structure of perhydrosymmetric antamanide, cyclic (-Val-Pro-Pro-Cha-Cha-Val-Pro-Pro-Cha-Cha-).

The synthetic perhydrogenated symmetric analog of the cyclic decapeptide antamanide is biologically inactive, although the conformation of the molecule and the crystal packing are very similar to that of the active symmetric analog of antamanide. In fact, the same conformation for the molecule has now been found in six polymorphs of uncomplexed antamanide and its analogs. The differences between the active and inactive antamanide analogs are displayed dramatically in the conformations of their metal ion (Na+ or Li+) complexes, thus suggesting strongly that for physiological activity antamanide is not in the conformation assumed by the uncomplexed molecule, but rather in the conformation assumed by the complexed state of natural antamanide. The present structure crystallizes in space group P2(1)2(1)2(1) with a = 20.515(14) A, b = 21.316(16) A, c = 17.128(16) A and four peptide molecules in the unit cell. There are three cocrystallized water molecules at full occupancy intrinsic to the peptide, and several more water molecules or other solvent molecules at partial occupancy. The formula of the peptide is C66H106N10O10.4-H2O.2X.

Chemical Phenomena↗
PubMed1989

Structure-toxicity relationships in the amatoxin series. Synthesis of S-deoxy[gamma(R)-hydroxy-Ile3]-amaninamide, its crystal and molecular structure and inhibitory efficiency.

The amatoxins, highly toxic components of Amanita mushrooms, strongly inhibit the DNA-dependent RNA polymerase II (or B) in eukaryotic cell nuclei. For optimal binding to the enzyme a gamma-hydroxyisoleucine side chain in the 3-position is important as in gamma-amanitin (compound 1), where the OH-group is bound in the [S]-configuration. Amanullin, a non-toxic component, having an oxygen-free isoleucine side chain no. 3, exhibits an inhibitory effect on RNA polymerase II about two orders of magnitude smaller than that of gamma-amanitin. An equal, relatively weak, inhibitory effect has previously been found with the synthetically obtained Ile3-analog 7. In the present paper the synthesis of an analog (2) bearing a gamma-hydroxyl group in the isoleucine side chain is described. The compound was found to have about the same inhibitory effect on RNA polymerase II from Drosophila embryos as amanullin and the Ile3-analog 7. Structure analysis by X-ray diffraction revealed that the hydroxyl group at the -carbon atom of side chain-3 has the [R]-configuration, the new analog thus being -deoxo[( )-hydroxy-[Ile3]-amaninamide. It follows that the [S]-configuration of this chiral center is a prerequisite to maximal toxicity. Crystallographic data demonstrating great similarity between the peptide backbones of the new analog and those of natural amatoxins are given.

Amanitins↗
PubMed1988

[Severe complications during enalapril therapy for heart insufficiency].

In 3 patients with severe cardiac failure high dose therapy with the ACE inhibitor enalapril was instituted during a state of extracellular volume depletion. Severe arterial hypotension with reversible renal insufficiency developed in all the patients. In two the hypovolemia was induced by diuretic treatment and in one by an acute infection with diarrhea. The latter patient also developed life-threatening hyperkalemia with cardiac arrest since he was also receiving spironolactone and potassium supplements. These cases demonstrate that ACE inhibitors should not be instituted during extracellular volume depletion and their initial dosage should be low. The dangerous combination of ACE inhibitors with spironolactone and potassium supplements should be avoided wherever possible.

Acute Kidney Injury↗
PubMed1988

[Sternocostoclavicular hyperostosis. Association with pustular psoriasis and systemic vasculitis].

A female patient with sternocostoclavicular hyperostosis has been followed for 14 years. The case merits special attention because of its association with psoriasis and with an episode of systemic vasculitis. Although patients with sternocostoclavicular hyperostosis usually lack the tissue type antigen HLA-B27, there are grounds for suspicion that the disease is related to the group of seronegative spondylo-arthritides.

Female↗
PubMed1988

The role of nucleoside-diphosphate kinase reactions in G protein activation of NADPH oxidase by guanine and adenine nucleotides.

NADPH-oxidase-catalyzed superoxide (O2-) formation in membranes of HL-60 leukemic cells was activated by arachidonic acid in the presence of Mg2+ and HL-60 cytosol. The GTP analogues, guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S] and guanosine 5'-[beta,gamma-imido]triphosphate, being potent activators of guanine-nucleotide-binding proteins (G proteins), stimulated O2- formation up to 3.5-fold. The adenine analogue of GTP[gamma S], adenosine 5'-[gamma-thio]triphosphate (ATP[gamma S]), which can serve as donor of thiophosphoryl groups in kinase-mediated reactions, stimulated O2- formation up to 2.5-fold, whereas the non-phosphorylating adenosine 5'-[beta,gamma-imido]triphosphate was inactive. The effect of ATP[gamma S] was half-maximal at a concentration of 2 microM, was observed in the absence of added GDP and occurred with a lag period two times longer than the one with GTP[gamma S]. HL-60 membranes exhibited nucleoside-diphosphate kinase activity, catalyzing the thiophosphorylation of GDP to GTP[gamma S] by ATP[gamma S]. GTP[gamma S] formation was half-maximal at a concentration of 3-4 microM ATP[gamma S] and was suppressed by removal of GDP by creatine kinase/creatine phosphate (CK/CP). The stimulatory effect of ATP[gamma S] on O2- formation was abolished by the nucleoside-diphosphate kinase inhibitor UDP. Mg2+ chelation with EDTA and removal of endogenous GDP by CK/CP abolished NADPH oxidase activation by ATP[gamma S] and considerably diminished stimulation by GTP[gamma S]. GTP[gamma S] also served as a thiophosphoryl group donor to GDP, with an even higher efficiency than ATP[gamma S]. Transthiophosphorylation of GDP to GTP[gamma S] was only partially inhibited by CK/CP. Our results suggest that NADPH oxidase is regulated by a G protein, which may be activated either by exchange of bound GDP by guanosine triphosphate or by thiophosphoryl group transfer to endogenous GDP by nucleoside-diphosphate kinase.

Adenine Nucleotides↗
PubMed1987

Antamanide antagonizes the phalloidin-induced negative inotropic effect and blocks voltage dependently the fast outward K+ current in voltage-clamped frog muscle fibres.

The effects of antamanide (10(-14)-10(-5) M) and N-acetyl-secophalloidin (10(-7)-5 X 10(-3) M) a neutral non-toxic derivative of phalloidin, were tested on voltage-clamped single frog muscle fibres. Antamanide protected muscle fibres against the negative inotropic effect of phalloidin but blocked the fast potassium permeability in the same concentration range and the same voltage-dependent manner as did phalloidin. N-Acetyl-secophalloidin exhibited a strongly attenuated blocking effect on K+ permeability in a 1,000-fold higher concentration range than phalloidin. Neither antamanide nor N-acetyl-secophalloidin affected the contractile properties. These results suggest the existence in the frog muscle membrane of a receptor with two sites for phalloidin and antamanide which acts on potassium conductance.

Animals↗
PubMed1987

[50 years of phalloidine: its discovery, characterization and current and future applications in cell research].

Phalloidin, like the later-detected phallotoxins, consists of a cyclic heptapeptide backbone, the ring being crosslinked by a 2'-indolylthioether moiety (tryptathionine). After intraperitoneal administration--not per os--it will, after a short time, damage the liver specifically, presumably in consequence of its very tight binding to F-actin preventing its dissociation. This affinity can be utilized for a sensitive visual identification of F-actin by using fluorescent derivatives.

Actins↗
PubMed1987

Synthesis of cyclic tryptathionine peptides.

The helicity of the tryptathionine moiety of the phallotoxins has been recognized by comparison with cyclic tryptathionine tripeptides. In order to investigate the influence of the configuration of the component amino acids on the conformation of the cyclic peptides, six analogue thioether tripeptides containing L- and D-alanine and L- and D-cysteine, respectively, have been synthesized. The CD spectra of the peptides are very similar to each other, showing mirror images of the CD of phalloidin and, therefore, negative helicity. The spectra of the D-cysteine containing compounds differ from the L-cysteine containing compounds by their weakly positive ellipticity values around 270 nm. The cyclization reaction of Boc-Hpi-D-Ala-D-Cys(STrt)OCH3, along with the cyclic tripeptide, afforded a cyclic hexapeptide by dimerization. The CD spectrum of the dimer is very similar to that of phalloidin, thus pointing to a positive helicity of its two tryptathionine moieties. The dimeric thioether peptide forms a rather strong complex with Cu2+ ions.

Amanitins↗
PubMed1987

Synthesis of analogues of amaninamide, an amatoxin from the white Amanita virosa mushroom.

Analogs of amaninamide, due to the absence of a 6-hydroxy group in the tryptophan moiety, are more easily accessible by synthesis than derivatives of alpha-amanitin. Syntheses of bicyclic octapeptide thioethers 1f-1m have been carried out starting from linear Hpi-S-trityl-octapeptides (3), cyclization by intramolecular 2'-indolylthioether formation yielding monocyclic peptides (2) and final cyclization by DCCI. One of the bicyclic thioethers was oxidized to yield the corresponding chromatographically separated (R)- and (S)-sulfoxides, respectively. The products were characterized by RF-values, u.v. and CD spectra as well as by mass (FAB) spectroscopy. The widely differing inhibitory activities on RNA polymerase II (or B) from calf thymus are listed.

Amanitins↗
PubMed1987

Fourth polymorph of [Phe4 Val6] antamanide (pentahydrate).

The cyclic decapeptide antamanide and the synthetic, biologically active analog [Phe4 Val6]antamanide (cyclic[ValProProPhePhe]2) crystallize in various crystal forms as a function of the solvent. The present crystalline polymorph obtained from acetone/water (also from ethanol/water and DMSO/water) crystallizes in space group P2(1)2(1)2(1) with a = 20.194 (30) A, b = 21.118 (31) A, c = 16,132 (25) A and four molecules of peptide in the unit cell. There are five cocrystallized water molecules per peptide molecule, of which four water molecules are intrinsic to the peptide molecule. Although the molecular packing is entirely different in each of the polymorphs, the conformation of the peptide molecule, including the intrinsic water molecules, is very similar in all the polymorphs.

Models, Molecular↗
PubMed1986

alpha-Amanitin uptake into hepatocytes. Identification of hepatic membrane transport systems used by amatoxins.

Hepatic transport studies with amatoxins, toxic bicyclic octapeptides from poisonous mushrooms of the genus Amanita were performed, using [(6'-O,1'-N-di[3H]methyl)trp4]-alpha-amanitin and [(6'-O,1'-N-di-methyl)trp4]-[4-[3H]desmethyl)hyi3]-gamma-ama nitin. Uptake into hepatocytes from rat liver was inhibited by taurocholate and antamanide. Photoaffinity labeling studies with isolated hepatocytes and basolateral plasma membranes, using the sodium salt of (7,7-azo-3 alpha, 12 alpha-dihydroxy-5 beta-[3 beta-3H]cholan-24-oyl)-2- aminoethanesulfonic acid demonstrated that the presence of alpha-amanitin decreased the labeling of the two sinusoidal bile salt-binding membrane polypeptides with the apparent molecular weights of 54,000 and 48,000. In basolateral plasma membrane vesicles amanitin uptake was temperature-dependent and could be stimulated 1.5 to 2-fold by an out to in Na+ gradient as compared to a K+ gradient or sucrose and 2 to 2.5-fold as compared to amanitin equilibration (overshoot). Kinetic studies proved saturability of amanitin uptake in the presence and absence of a Na+ gradient. Membrane transport could be inhibited by taurocholate, antamanide, phalloidin, prednisolone, and silybin, but not by penicillin G or thioctic acid. Hepatic uptake of amatoxins is mediated by the sinusoidal bile salt-transport systems which are also involved in the uptake of antamanide and phalloidin. This supports the concept of a multispecificity of hepatic transport systems for a wide variety of amphipathic molecules.

Affinity Labels↗
PubMed1985

A study on the pharmacokinetics in mouse of adenine-9-beta-D-arabinofuranoside 5-monophosphate conjugated with lactosaminated albumin.

In plasma of mice injected with adenine-9-beta-D-arabinofuranoside monophosphate (ara-AMP) coupled to human lactosaminated serum albumin (L-HSA) some of the ara-AMP molecules are enzymatically released, whereas others remain linked to L-HSA. Evidence has been obtained that ara-AMP is not deaminated when it is conjugated to L-HSA, in contrast to the free drug which is rapidly metabolized to its hypoxanthine derivative.

Animals↗
PubMed1985

The phalloidin binding site of F-actin.

Tritium-containing affinity-labelling derivatives of phalloidin, an alkylating iodoacetyl compound (EAL) and a photolabile, carbene generating diazirine (PAL), have been reacted with rabbit muscle actin, the former after protection of thiol groups with N-ethylmaleimide. Labelled peptides generated by tryptic and/or thermolysin digestion were isolated by paper peptide mapping and characterized by determination of their amino acid sequences. EAL binds to methionine-119 and methionine-355; PAL binds to glutamic acid-117. These residues are located in regions with extremely conserved amino acid sequences. The cleft between the two domains of the actin monomer is suggested as the possible binding site for phalloidin.

Actins↗
PubMed1984

Analogs of viroidin. Synthesis of four virotoxin-like F-actin binding heptapeptides with one less hydroxyl group in the dihydroxy-proline ring.

The vitroxins, toxic cyclic heptapeptides from Amanita virosa fungi, contain a 3,4-dihydroxy-L-proline, an imino acid scarcely accessible in greater amounts. Therefore in the syntheses of the analogs described this imino acid was replaced by 4-cis-hydroxy-L-proline, a component of the analogously toxic phallotoxins. The following syntheses are described: 1a = cyclo (L-alanyl-D-threonyl-D-seryl-L-4-cis-hydroxy-L-prolyl-L-alanyl-2- methylthio-L-tryptophyl-L-leucyl), 1b = 1a but with 2-methylsulfonyl-L-tryptophan in position 6, 2a = cyclic (L-valyl-D-threonyl-D-seryl-4-cis-hydroxy-L-prolyl-L-alanyl-2- methylthio-L-tryptophyl-hydroxyl-L-leucyl), and 2b = 2a, but with 2-methylsulfonyl-L-tryptophan in position 6. In a test for binding strength to rabbit muscle F-actin 2b and 2a exhibited about 40% of that of demethylphalloin. Analogs 1a and 2b have not been tested.

Actins↗
PubMed1984

Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling.

Phalloidin, a bicyclic heptapeptide, and antamanide, a monocyclic decapeptide from the poisonous mushroom Amanita phalloides, interact with bile-salt-binding polypeptides of the hepatocyte membrane, as demonstrated by photoaffinity labeling using the photolabile bile salt derivative 7,7,-azo-3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid, either unconjugated or taurine conjugated. With the photolabile derivatives of phalloidin, N-delta-(4-[(1-azi-2,2,2-trifluoroethyl) benzoyl]-beta-alanyl)-delta-aminophalloin, (N epsilon-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]lys6)-anta manide, the same membrane polypeptides with apparent MrS of 54,000 and 48,000 were labeled as with the photolabile derivatives of unconjugated and conjugated bile salts. The presence of bile salts decreased markedly the extent of labeling of these phalloidin- and antamanide-binding polypeptides. These results indicate that hepatic uptake systems for bile salts, phallotoxins, and the cycloamanide antamanide are identical, thus explaining the organotropism of phallotoxins.

Affinity Labels↗
PubMed1983

A carbene-generating photoaffinity probe for beta-adrenergic receptors.

A new radioiodinated (2.2 Ci/mumol) iodocyanopindolol derivative carrying a 4-(3-trifluoromethyldiazirino)benzoyl residue has been synthesized. The long-wavelength absorption of the diazirine permits formation of the carbene by photolysis under very mild conditions. [125I]ICYP-diazirine binds with high affinity (Kd = 60 pM) to beta-receptors from turkey erythrocyte membranes. Upon irradiation, [125I]ICYP-diazirine is covalently incorporated in a Mr 40 000 protein. Stereoselective inhibition of photolabeling by the (-)enantiomers of alprenolol and isoproterenol indicated that the Mr 40 000 protein contains a beta-adrenergic binding site. The yield of specific labeling was up to 8.2% of total beta-receptor binding sites. The Mr 40 000 protein photolabeled in the membrane could be solubilized at comparable yield with either digitonin or Triton X-100. Irradiation of digitonin-solubilized turkey erythrocyte membranes with [125I]ICYP-diazirine resulted in specific labeling of two proteins with Mr 40 000 and 50 000. In guinea-pig lung membranes, at least five proteins were photolabeled, of which one (with approximately Mr 67 000) was labeled specifically.

Affinity Labels↗