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Peroxisomedb: a Database for the Peroxisomal Proteome, Functional Published online 28 November 2006 Nucleic Acids Research, 2007, Vol. 35, Database issue D815–D822 doi:10.1093/nar/gkl935 PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease Agatha Schlu¨ ter1, Ste´phane Fourcade1, Enric Dome`nech-Este´vez1, Toni Gabaldo´ n2, Jaime Huerta-Cepas2, Guillaume Berthommier3, Raymond Ripp3, Ronald J. A. Wanders4, Olivier Poch3 and Aurora Pujol1,5,* 1Centre de Gene`tica Me`dica i Molecular, Institut d’Investigacio´ Biome`dica de Bellvitge-Institut de Recerca Oncolo`gica (IDIBELL-IRO), Hospital Duran i Reynals, Granvia Km 2,7. 08907 Hospitalet de Llobregat, Barcelona, Spain, 2Bioinformatics Department, Centro de Investigacio´n Prı´ncipe Felipe, Avda. Autopista del Saler, 16 Valencia 46013, Spain, 3Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, CNRS/INSERM/ULP/Colle`ge de, France, 1 rue Laurent Fries, BP10142 67404 Illkirch Cedex, France, 4Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands and 5Institucio´ Catalana de Recerca i Estudis Avancats¸ (ICREA), Barcelona, Spain Received August 9, 2006; Revised October 11, 2006; Accepted October 12, 2006 ABSTRACT systematic characterization of the peroxisomal Peroxisomes are essential organelles of eukaryotic proteome and facilitate system biology approaches origin, ubiquitously distributed in cells and organ- on the organelle. isms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes INTRODUCTION causes more than 20 fatal inherited conditions. We Peroxisomes were first identified by de Duve in 1966 (1). have created a peroxisomal database (http://www. Only a few months ago, the open debate on its ontogenetic peroxisomeDB.org) that includes the complete as well as evolutionary origin has been settled: the organelle peroxisomal proteome of Homo sapiens and is derived from ER-membranes (2–4). This constitutes per- Saccharomyces cerevisiae, by gathering, updating haps, a modern illustration in an organelle context, of the and integrating the available genetic and functional ‘ontogeny recapitulates phylogeny’ principle. Peroxisomes information on peroxisomal genes. PeroxisomeDB are indispensable for development, morphogenesis and differ- is structured in interrelated sections ‘Genes’, entiation, and play roles of paramount importance in hydro- gen peroxide detoxification and fatty acid metabolism, ‘Functions’, ‘Metabolic pathways’ and ‘Diseases’, hallmark functions of the organelle. The plasticity of their that include hyperlinks to selected features of NCBI, protein composition and biochemical function is remarkable ENSEMBL and UCSC databases. We have designed and may vary according to the organism, cell type and/or graphical depictions of the main peroxisomal meta- environmental condition. Depending on species, peroxisomes bolic routes and have included updated flow charts are playing key roles on the degradation of amino acids, for diagnosis. Precomputed BLAST, PSI-BLAST, methanol and purines, or in the synthesis of bile acids, essen- multiple sequence alignment (MUSCLE) and phylo- tial polyunsaturated fatty acids or penicillin [see reviews genetic trees are provided to assist in direct (5–7)]. Peroxisomes belong to the microbody family jointly multispecies comparison to study evolutionary with glyoxysomes of plants and glycosomes of trypanosomes, conserved functions and pathways. Highlights of which are related peroxisomes specialized in glycolisis and the PeroxisomeDB include new tools developed glyoxylate pathways, respectively. In higher eukaryotes, peroxisomes play a key role in lipid homeostasis, adapting for facilitating (i) identification of novel peroxisomal its copy number to obey cellular requirements, such as cold proteins, by means of identifying proteins carrying exposure, nutrients or drugs. At a first glimpse, some peroxi- peroxisome targeting signal (PTS) motifs, (ii) detec- somal routes such as the b-oxidation of fatty acids could seem tion of peroxisomes in silico, particularly useful to be redundant with the mitochondria b-oxidation, but they for screening the deluge of newly sequenced are in fact complementary as there is substrate specificity genomes. PeroxisomeDB should contribute to the between the two organelles. The peroxisomal b-oxidation is *To whom correspondence should be addressed. Tel: +34 93 2607343; Fax: +34 93 2607414; Email: [email protected] Ó 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. D816 Nucleic Acids Research, 2007, Vol. 35, Database issue uncoupled of ATP synthesis thus leading to heat production helpful in this regard, because we integrate the different routes in thermogenesis. specifying which steps take place in peroxisomes. Further, cur- Gaining knowledge on peroxisome components, metabolic rent annotation of peroxisomal proteins in the databases is functions in the different organisms and their key players frequently incomplete and often does not distinguish between remains an important challenge. We wish to contribute to proteins, which have a confirmed peroxisomal sublocalization the field with PeroxisomeDB (http://www.peroxisomeDB. and those which are only candidates according to in silico org). This relational database has been created joining exper- predictions. Using annotated data derived from one of the tise from peroxisome biologists and bioinformaticians, and most broadly used bio-ontology resources, Gene Ontology provides a comprehensive and exhaustive reference list of (GO), supplemented with curated experimental literature peroxisomal proteins of human and Saccharomyces cerevisiae with extensive hyperlinks to databases, which we believe to Table 1. PeroxisomeDB contents be among the most useful currently available. In addition to combining these links on a single location, we have included Database contents Number of entries useful tools for in silico detection of the organelle, based on the presence of four peroxins that we had recently found Peroxisomal genes 157 Homo sapiens [GO:77(6)] 85 to be peroxisomal markers (2); and also for detection of Saccharomyces cerevisiae (GO:51) 61 peroxisome targeting signals (PTS) motifs for PTS1, PTS2 Present in M.musculus and not in human 7 and for Pex19 binding sites, facilitating thereof the identifi- Present in Y.lipolytica and not in human 4 cation of novel candidate peroxisomal proteins. Functions and metabolic pathways 50 Diseases 22 Interactive metabolic pathway schemes 6 Peroxisomal tools 2 Peroxisome identification tool RESULTS Target signal predictor The peroxisomal proteome Number of entries refers to the number of genes manually annotated in peroxisomeDB. Gene Ontology (GO) followed by number indicates the The available metabolic databases (i.e. Kegg) use to depict number of peroxisomal entries previously annotated as such in GO; the number metabolic pathways regardless of the subcellular compartmen- in brackets indicates misannotated entries identified in GO and not included talization of the different enzymatic steps. PeroxisomeDB is in peroxisomeDB. Figure 1. One of the six interactive schemes displayed in PeroxisomeDB: ‘Peroxins and other PMPs (peroxisome membrane proteins)’. Nucleic Acids Research, 2007, Vol. 35, Database issue D817 Figure 2. Gene Page for a given peroxisomal gene, including a brief description, localization, functional role, disease caused by malfunction if any, tools for functional genomics and selected links to reference databases (Gene Info). searches, we have built a complete peroxisomal proteome of additional schemes are focused on the Peroxins and other Homo sapiens (encoded by 85 genes) and S.cerevisiae peroxisomal membrane proteins (PMP) (Figure 1), and on (encoded by 61 genes). To this core ensemble, we have added Peroxisomal Disease. the peroxisomal proteins from the model organisms Mus In the ‘Genes’ section, we have included: (i) a description musculus or Yarrowia lipolytica which lack their human and localization of the individual protein, (ii) its functional orthologues, for instance the mouse urate oxidase or the several roles, (iii) the corresponding disease caused by protein Pex that are mostly restricted to Y.lipolytica (Table 1). malfunction, (iv) selected links to reference databases (Gene Info). Of particular relevance, we found the following sec- tions: (i) from NCBI, the gene summary, the chromosomal From gene to pathway, from metabolite to disease localization, the predicted intron/exon structure at ACE The proteomes are organized in interrelated sections: VIEW, the Single Nucleotide Polymorphism (SNP) collec- ‘Genes’, ‘Functions’, ‘Diseases’ and ‘Metabolic pathways’. tion, the ortholog prediction and the conserved domains The information is integrated in a section called ‘The Peroxi- section; (ii) from ENSEMBL, the gene summary page that some at a Glance’, which includes four interactive schemes includes information on regions of syntheny; (iii) from the depicting the main peroxisomal functions: Lipid Metabolism, UCSC, the Proteome and Genome Browser with extensive Glyoxylate and Dicarboxylate Metabolism, Amino acid expression data derived from microarray experiments;
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