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169 results on '"Loidl, Peter"'

8. A new amidohydrolase from Bordetella or Alcaligenes strain FB188 with similarities to histone deacetylases

Author

Hildmann, Christian, Ninkovic, Milena, Dietrich, Rudiger, Wegener, Dennis, Riester, Daniel, Zimmermann, Thomas, Birch, Olwen M., Bernegger, Christine, Loidl, Peter, and Schwienhorst, Andreas

Subjects
Bacterial genetics -- Research, Microbial enzymes -- Research, Gram-negative bacteria -- Genetic aspects, Gram-negative bacteria -- Research, Biological sciences
Abstract

The full-length gene encoding the histone deacetylase (HDAC)-Iike amidohydrolase (HDAH) from Bordetella or Alcaligenes (Bordetella/Alcaligenes) strain FBI88 (DSM 11172) was cloned using degenerate primer PCR combined with inverse-PCR techniques and ultimately expressed in Escherichia coll. The expressed enzyme was biochemically characterized and found to be similar to the native enzyme for all properties examined. Nucleotide sequence analysis revealed an open reading frame of 1,110 bp which encodes a polypeptide with a theoretical molecular mass of 39 kDa. Interestingly, peptide sequencing disclosed that the N-terminal methionine is lacking in the mature wild-type enzyme, presumably due to the action of methionyl aminopeptidase. Sequence database searches suggest that the new amidohydrolase belongs to the HDAC superfamily, with the closest homologs being found in the subfamily assigned acetylpolyamine amidohydrolases (APAH). The APAH subfamily comprises enzymes or putative enzymes from such diverse microorganisms as Pseudomonas aeruginosa, Archaeoglobus fulgidus, and the actinomycete Mycoplana ramosa (formerly M. bullata). The FB188 HDAH, however, is only moderately active in catalyzing the deacetylation of acetylpolyamines. In fact, FB188 HDAH exhibits significant activity in standard HDAC assays and is inhibited by known HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA). Several lines of evidence indicate that the FB188 HDAH is very similar to class 1 and 2 HDACs and contains a [Zn.sup.2+] ion in the active site which contributes significantly to catalytic activity. Initial biotechnological applications demonstrated the extensive substrate spectrum and broad optimum pH range to be excellent criteria for using the new HDAH from Bordetella/ Alcaligenes strain FB188 as a biocatalyst in technical biotransformations, e.g., within the scope of human immunodeficiency virus reverse transcriptase inhibitor synthesis.

Published
2004

9. An inhibitor-resistant histone deacetylase in the plant pathogenic fungus Cochliobolus carbonum

Author

Brosch, Gerald, Dangl, Markus, Graessle, Stefan, Loidl, Adele, Trojer, Patrick, Brandtner, Eva-Maria, Mair, Karin, Walton, Jonathan D., Baidyaroy, Dipnath, and Loidl, Peter

Subjects
Fungi -- Physiological aspects, Enzymes -- Structure-activity relationship, Toxins -- Physiological aspects, Histones -- Physiological aspects, Biological sciences, Chemistry
Abstract

Results reveal that Cochliobolus carbonum produces two types of histone deacetylases, a toxin-resistant and other toxin-sensitive forms. Data indicate that inhibitor-resistant activity is displayed by the toxin-producing form.

Published
2001

10. RPD3-type histone deacetylases in maize embryos

Author

Lechner, Thomas, Lusser, Alexandra, Pipal, Alexandra, Brosch, Gerald, Loidl, Adele, Goralik-Schramel, Maria, Sendra, Ramon, Wegener, Sigrun, Walton, Jonathan D., and Loidl, Peter

Subjects
Biochemistry -- Research, Histones -- Research, Corn -- Analysis, DNA -- Research, Cloning -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on the posttranslational core histone acetylation. The identification of two maize histone deacetylase forms by purification and cDNA cloning is described.

Published
2000

11. Different types of maize histone deacetylases are distinguished by a highly complex substrate and site specificity

Author

Kolle, Doris, Brosch, Gerald, Lechner, Thomas, Pipal, Alexandra, Helliger, Wilfried, Taplick, Jan, and Loidl, Peter

Subjects
Histones -- Research, Corn -- Genetic aspects, Biological sciences, Chemistry
Abstract

A study was conducted to analyze the specificity of deacetylases for core histones, acetylased histone H4 subspecies and acetylated H4-lysine residues. Histone deacetylase was purified from germinating maize embryos at 72 h after the start of seed inhibition. Experimental results indicated that different kinds of deacetylases interaction with highly specific acetylation patterns on nucleosomes.

Published
1999

15. Purification and characterization of a high molecular weight histone deacetylase complex (HD2) of maize embryos

Author

Brosch, Gerald, Lusser, Alexandra, Goralik-Schramel, Maria, and Loidl, Peter

Subjects
Enzymes -- Research, Histones -- Research, Biological sciences, Chemistry
Abstract

The purification of an enzymatically active high molecular weight protein complex was attained employing a series of chromatographic steps. The purified enzyme was characterized in terms of enzymatic and kinetic characteristics, and sensitivity to various histone deacetylase inhibitors. All three protein components of the HD2 complex were found to be enzymatically active. Polyclonal antibodies against each of the three polypeptides were raised in rabbits. Each antiserum reacted with all three polypeptides on Western blots, indicating that p45, p42 and p39 are highly homologous.

Published
1996

20. Histone methyltransferases in Aspergillus nidulans: evidence for a novel enzyme with a unique substrate specificity

Author

Trojer, Patrick, Dangl, Markus, Bauer, Ingo, Graessle, Stefan, Loidl, Peter, and Brosch, Gerald

Subjects
Histones -- Chemical properties, Protein biosynthesis -- Analysis, Enzymes -- Synthesis, Enzymes -- Analysis, Biological sciences, Chemistry
Abstract

Enzymes involved in histone arginine methylation in the filamentous fungus Aspergillus nidulans are studied. The existence of in vivo arginine methylation on histones as demonstrated by site-specific antibodies and the high level and specificity of protein arginine N-methyltransferases (PRMTs) for individual core histones in A. nidulans suggests an important role of these enzymes for chromatin modulating activities.

Published
2004

23. 3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 2. Effect of Pyrrole C2 and/or C4 Substitutions on Biological Activity

Author

Mai, Antonello, Massa, Silvio, Cerbara, Ilaria, Valente, Sergio, Ragno, Rino, Bottoni, Patrizia, Scatena, Roberto, Loidl, Peter, Brosch, Gunther, Scatena, Roberto (ORCID:0000-0002-9425-8293), Mai, Antonello, Massa, Silvio, Cerbara, Ilaria, Valente, Sergio, Ragno, Rino, Bottoni, Patrizia, Scatena, Roberto, Loidl, Peter, Brosch, Gunther, and Scatena, Roberto (ORCID:0000-0002-9425-8293)

Abstract

Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in inhibiting maize HD2 activity in vitro. In the present paper, we investigated the effect on anti-HD2 activity of chemical substitutions performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f) = 0.77 microM; IC50(1a) = 3.8 microM). IC50 values of compounds 3, prepared as 1b homologues, revealed that between benzene and carbonyl groups at the pyrrole-C(4) position a hydrocarbon spacer length ranging from two to five methylenes is well accepted by the APHA template, being that 3a (two methylenes) and 3d (five methylenes) are more potent (2.3- and 1.4-fold, respectively) than 1b, while the introduction of a higher number of methylene units (see 3e,f) decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 = 0.043 microM) showed the same potency as SAHA in inhibiting HD2 in vitro, and it was 3000- and 2.6-fold more potent than sodium valproate and HC-toxin and was 4.3- and 6-fold less potent than trapoxin and TSA, respectively. Finally, conformationally constrained forms of 1b,c (compounds 4), prepared with the aim to obtain some information potentially useful for a future 3D-QSAR study, showed the same (4a,b) or higher (4c,d) HD2 inhibiting activities in comparison with those of the reference drugs. Molecular modeling and docking calculations on the designed compounds perfo

Published
2004

24. 3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 3. Discovery of Novel Lead Compounds Through Structure-Based Drug Design and Docking Studies

Author

Ragno, Rino, Mai, Antonello, Massa, Silvio, Cerbara, Ilaria, Valente, Sergio, Bottoni, Patrizia, Scatena, Roberto, Jesacher, Fredrik, Loidl, Peter, Brosch, Gunther, Scatena, Roberto (ORCID:0000-0002-9425-8293), Ragno, Rino, Mai, Antonello, Massa, Silvio, Cerbara, Ilaria, Valente, Sergio, Bottoni, Patrizia, Scatena, Roberto, Jesacher, Fredrik, Loidl, Peter, Brosch, Gunther, and Scatena, Roberto (ORCID:0000-0002-9425-8293)

Abstract

Aroyl-pyrrole-hydroxy-amides (APHAs) are a new class of synthetic HDAC inhibitors recently described by us. Through three different docking procedures we designed, synthesized, and tested two new isomers of APHA lead compound 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1), compounds 3 and 4, characterized by different insertions of benzoyl and propenoylhydroxamate groups onto the pyrrole ring. Biological activities of 3 and 4 were predicted by computational tools up to 617-fold more potent than that of 1 against HDAC1; thus, 3 and 4 were synthesized and tested against both mouse HDAC1 and maize HD2 enzymes. Predictions of biological affinities (K(i) values) of 3 and 4, performed by a VALIDATE model (applied on either SAD or automatic DOCK or Autodock results) and by the Autodock internal scoring function, were in good agreement with experimental activities. Ligand/receptor positive interactions made by 3 and 4 into the catalytic pocket, in addition to those showed by 1, could at least in part account for their higher HDAC1 inhibitory activities. In particular, in mouse HDAC1 inhibitory assay 3 and 4 were 19- and 6-times more potent than 1, respectively, and 3 and 4 antimaize HD2 activities were 16- and 76-times higher than that of 1, 4 being as potent as SAHA in this assay. Compound 4, tested as antiproliferative and cytodifferentiating agent on MEL cells, showed dose-dependent growth inhibition and hemoglobin accumulation effects.

Published
2004

27. Binding mode analysis of 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide: a new synthetic histone deacetylase inhibitor inducing histone hyperacetylation growth inhibition and terminal cell differentiation

Author

Mai, Antonello, Massa, Silvio, Ragno, Rino, Esposito, Marco, Sbardella, Giovanni, Nocca, Giuseppina, Scatena, Roberto, Jesacher, Frederic, Loidl, Peter, Brosch, Gunther, Nocca, Giuseppina (ORCID:0000-0002-2799-4557), Scatena, Roberto (ORCID:0000-0002-9425-8293), Mai, Antonello, Massa, Silvio, Ragno, Rino, Esposito, Marco, Sbardella, Giovanni, Nocca, Giuseppina, Scatena, Roberto, Jesacher, Frederic, Loidl, Peter, Brosch, Gunther, Nocca, Giuseppina (ORCID:0000-0002-2799-4557), and Scatena, Roberto (ORCID:0000-0002-9425-8293)

Abstract

The binding mode of 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides 1a-c, belonging to a recently reported class of synthetic histone deacetylase (HDAC) inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072), into the new modeled HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. HDAC1 X-ray coordinates were obtained by virtual "mutation" of those of histone deacetylase-like protein, a bacterial HDAC homologue. In in vitro antimaize HD2 as well as antimouse HDAC1 assay, compounds 1a-c showed inhibitory activities in the low micromolar range. Similarly, 1a-c are endowed with anti-HDAC activity in vivo: on mouse A20 cells, 1a-c induced histone hyperacetylation leading to a highly increased acetylation level of H4 as compared to control histones. Results obtained with acid-urea-triton polyacrylamide gel electrophoresis have been confirmed by Western Blot experiments. Finally, compound 1a, chosen as a representative member of this class of HDAC inhibitors, resulted endowed with antiproliferative (45 and 85% cell growth inhibition at 40 and 80 microM, respectively) and cellular differentiation (18 and 21% of benzidine positive cells at the same concentrations) activities in murine erythroleukemic cells.

Published
2002

33. 3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 3. Discovery of Novel Lead Compounds through Structure-Based Drug Design and Docking Studies,

Author

Ragno, Rino, primary, Mai, Antonello, additional, Massa, Silvio, additional, Cerbara, Ilaria, additional, Valente, Sergio, additional, Bottoni, Patrizia, additional, Scatena, Roberto, additional, Jesacher, Florian, additional, Loidl, Peter, additional, and Brosch, Gerald, additional

Published
2004
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40. Binding Mode Analysis of 3-(4-Benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide: A New Synthetic Histone Deacetylase Inhibitor Inducing Histone Hyperacetylation, Growth Inhibition, and Terminal Cell Differentiation

Author

Mai, Antonello, primary, Massa, Silvio, additional, Ragno, Rino, additional, Esposito, Monica, additional, Sbardella, Gianluca, additional, Nocca, Giuseppina, additional, Scatena, Roberto, additional, Jesacher, Florian, additional, Loidl, Peter, additional, and Brosch, Gerald, additional

Published
2002
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