1,721,065 research outputs found
Tranylcypromine Derivatives Useful as Inhibitors Demethylases LSD1 and LSD2
No full textThe present invention relates to tranylcypromine derivatives and to their use as therapeutic
agents, particularly for the prevention and/or treatment of diseases and conditions associated
with the activity of histone demethylases LSD1 and LSD2, such as the diseases characterized by
deregulation of gene transcription, cell differentiation and proliferation, e.g. tumors, viral
infections. The invention also relates to the preparation of these compounds, as well as to
compositions containing them and to therapeutic use thereof
Alternative splicing in the mammalian nervous system endows the histone demethylase LSD1-KDM1 of the ability to induce neurite morphogenesis
No full textBiochemical and structural analysis of peroxisomal enzymes involved in ether phospholipid synthesis
No full textEther phospholipids are essential components of eukaryotic cell membrane and are involved in many fundamental functions such as bone development, signal transduction and intracellular transport. They are characterised by an alkyl or alkenyl substituent at sn-1 position of the glycerol backbone. Dihydroxyacetone-phosphate acyltransferase (DHAPAT) and the flavoenzyme alkyldihydroxyacetone-phosphate synthase (ADPS) work in complex to introduce an ether linkage into a phospholipid-precursor molecule. Deficit in ether phospholipids has very serious pathological consequences as observed in patients affected by genetic diseases such as Zellweger syndrome and rhizomelic chondrodysplasia punctata (RCDP). Here, we present the crystal structure of the mammalian Cavia porcellus ADPS, which reveals a dimeric organization. ADPS consists of a FAD-binding domain, a cap domain, and a substrate-binding domain. This third domain exhibits a beta-sheet and a gating alpha-helix, which is involved in the closure of a substrate tunnel specific for aliphatic chains of 16 carbon atoms. Superposition of C. porcellus and Dictyostelium discoideum ADPS structures shows that the FAD-binding domain is highly conserved between the two species whereas the substrate-binding domain is rotated by 20 degrees. Mutations in the amino acids Arg419, Tyr515, and Tyr578 have been found in patients affected by RCDP. Mutagenesis studies indicate that each of these mutations lead to the complete inactivation of the enzyme. Structural data confirmed the role of these side chains as they are located in the active site and are likely to directly take part in catalysis. Our data are discussed in the context of a proposed catalytic mechanism that involves formation of a covalent adduct between the flavin and the substrate, which enables the enzyme to catalyze the acyl-alkyl exchange reaction through a most unusual non-redox mechanism
Structure of FAD-bound L-aspartate oxidase: insight into substrate specificity and catalysis
No full textL-Aspartate oxidase (Laspo) catalyzes the conversion of L-Asp to iminoaspartate, the first step in the de novo biosynthesis of NAD +. This bacterial pathway represents a potential drug target since it is absent in mammals. The Laspo R386L mutant was crystallized in the FAD-bound catalytically competent form and its three-dimensional structure determined at 2.5 Å resolution in both the native state and in complex with succinate. Comparison of the R386L holoprotein with the wild-type apoenzyme [Mattevi, A., Tedeschi, G., Bacchella, L., Coda, A., Negri, A., and Ronchi, S. (1999) Structure 7, 745-756] reveals that cofactor incorporation leads to the ordering of two polypeptide segments (residues 44-53 and 104-141) and to a 27° rotation of the capping domain. This motion results in the formation of the active site cavity, located at the interface between the capping domain and the FAD-binding domain. The structure of the succinate complex indicates that the cavity surface is decorated by two clusters of H-bond donors that anchor the ligand carboxylates. Moreover, Glu121, which is strictly conserved among Laspo sequences, is positioned to interact with the L-Asp α-amino group. The architecture of the active site of the Laspo holoenzyme is remarkably similar to that of respiratory fumarate reductases, providing strong evidence for a common mechanism of catalysis in Laspo and flavoproteins of the succinate dehydrogenase/fumarate reductase family. This implies that Laspo is mechanistically distinct from other flavin-dependent amino acid oxidases, such as the prototypical D-amino acid oxidase
Structural characterization of L-aspartate oxidase and identification of an interdomain loop by limited proteolysis
No full textL-Aspartate oxidase is the first enzyme in the de novo biosynthesis of pyridinic coenzymes in facultative aerobic organisms. The enzyme is FAD dependent and it shares common features with both the oxidase and the fumarate reductase classes of flavoproteins. In this report we focused our attention on the supersecondary structure of the molecule by means of limited proteolysis studies. Moreover the polymerization state of the protein at different pH and the interactions with NAD and its analogues are described. The results suggest that L-aspartate oxidase is a monomer at pH values lower than 4.5 and a dimer at pH values higher than 6.5. The protein is organized in two major domains connected by a flexible loop located in the 120-140 region. The data obtained by limited proteolysis of the holo and the apo form in the presence and in the absence of substrates (fumarate and menadione), inhibitors (succinate) and NAD allows the proposition that both domains are involved in the binding of the flavin coenzyme. Moreover the data reported in this manuscript suggest that NAD inhibits L-aspartate oxidase activity by competing with the flavin for the binding to the enzyme
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
- …
