Dataset Information

Large-scale chemical dissection of mitochondrial function.

ABSTRACT: Mitochondrial oxidative phosphorylation (OXPHOS) is under the control of both mitochondrial (mtDNA) and nuclear genomes and is central to energy homeostasis. To investigate how its function and regulation are integrated within cells, we systematically combined four cell-based assays of OXPHOS physiology with multiplexed measurements of nuclear and mtDNA gene expression across 2,490 small-molecule perturbations in cultured muscle. Mining the resulting compendium revealed, first, that protein synthesis inhibitors can decouple coordination of nuclear and mtDNA transcription; second, that a subset of HMG-CoA reductase inhibitors, combined with propranolol, can cause mitochondrial toxicity, yielding potential clues about the etiology of statin myopathy; and, third, that structurally diverse microtubule inhibitors stimulate OXPHOS transcription while suppressing reactive oxygen species, via a transcriptional mechanism involving PGC-1alpha and ERRalpha, and thus may be useful in treating age-associated degenerative disorders. Our screening compendium can be used as a discovery tool both for understanding mitochondrial biology and toxicity and for identifying novel therapeutics.

SUBMITTER: Wagner BK

PROVIDER: S-EPMC2715872 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Large-scale chemical dissection of mitochondrial function.

Wagner Bridget K BK Kitami Toshimori T Gilbert Tamara J TJ Peck David D Ramanathan Arvind A Schreiber Stuart L SL Golub Todd R TR Mootha Vamsi K VK

Nature biotechnology 20080224 3

Mitochondrial oxidative phosphorylation (OXPHOS) is under the control of both mitochondrial (mtDNA) and nuclear genomes and is central to energy homeostasis. To investigate how its function and regulation are integrated within cells, we systematically combined four cell-based assays of OXPHOS physiology with multiplexed measurements of nuclear and mtDNA gene expression across 2,490 small-molecule perturbations in cultured muscle. Mining the resulting compendium revealed, first, that protein synt ...[more]

PMID: 18297058

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Project description:BackgroundThere are presently hundreds of online databases hosting millions of chemical compounds and associated data. As a result of the number of cheminformatics software tools that can be used to produce the data, subtle differences between the various cheminformatics platforms, as well as the naivety of the software users, there are a myriad of issues that can exist with chemical structure representations online. In order to help facilitate validation and standardization of chemical structure datasets from various sources we have delivered a freely available internet-based platform to the community for the processing of chemical compound datasets.ResultsThe chemical validation and standardization platform (CVSP) both validates and standardizes chemical structure representations according to sets of systematic rules. The chemical validation algorithms detect issues with submitted molecular representations using pre-defined or user-defined dictionary-based molecular patterns that are chemically suspicious or potentially requiring manual review. Each identified issue is assigned one of three levels of severity - Information, Warning, and Error - in order to conveniently inform the user of the need to browse and review subsets of their data. The validation process includes validation of atoms and bonds (e.g., making aware of query atoms and bonds), valences, and stereo. The standard form of submission of collections of data, the SDF file, allows the user to map the data fields to predefined CVSP fields for the purpose of cross-validating associated SMILES and InChIs with the connection tables contained within the SDF file. This platform has been applied to the analysis of a large number of data sets prepared for deposition to our ChemSpider database and in preparation of data for the Open PHACTS project. In this work we review the results of the automated validation of the DrugBank dataset, a popular drug and drug target database utilized by the community, and ChEMBL 17 data set. CVSP web site is located at http://cvsp.chemspider.com/.ConclusionA platform for the validation and standardization of chemical structure representations of various formats has been developed and made available to the community to assist and encourage the processing of chemical structure files to produce more homogeneous compound representations for exchange and interchange between online databases. While the CVSP platform is designed with flexibility inherent to the rules that can be used for processing the data we have produced a recommended rule set based on our own experiences with the large data sets such as DrugBank, ChEMBL, and data sets from ChemSpider.

Dataset Information

Large-scale chemical dissection of mitochondrial function.

Publications

Large-scale chemical dissection of mitochondrial function.

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