The reactive metabolite target protein database (TPDB) – a web-accessible resource

Hanzlik, Robert P.; Koen, Yakov M.; Theertham, Bhargav; Dong, Yanfeng; Fang, Jianwen

doi:10.1186/1471-2105-8-95

Cited by 37 publications

(32 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is therefore necessary to identify the subset of targets, i.e., covalently modified macromolecules, that are critical to the toxicological process. Unfortunately, although some liver proteins have been identified which are modified covalently by several xenobiotics (Hanzlik et al 2007), there are currently no techniques to predict the target macromolecule(s) for a particular chemically reactive metabolite let alone the biological consequences of a particular modification. However, from a simple chemical perspective, it is known that hard electrophiles generally react with hard nucleophiles, such as functional groups in DNA and lysine residues in proteins, whereas soft electrophiles react with soft nucleophiles, which include cysteine residues in proteins and in glutathione (Table 2), which has a concentration of approximately 10 mM in the liver.…”

Section: Relationship Between Metabolic Activation and Hepatotoxicitymentioning

confidence: 99%

“…The extent to which a particular loss of activity in vivo is due to adduction by a reactive metabolite or drug-induced oxidative modifications of amino acid residues is a complex analytical problem (Andringa et al 2008). Despite these difficulties, the expectation is that a comprehensive database of cellular proteins modified covalently by reactive metabolites in vivo should ultimately facilitate elucidation of the mechanisms of associated toxicities (Hanzlik et al 2007). It is already apparent that, although each bioactivated xenobiotic may modify a unique set of hepatic proteins, there is a partial commonality with the proteins modified by other compounds .…”

Section: Model Hepatotoxins: Role Of Reactive Metabolite Formationmentioning

confidence: 99%

See 1 more Smart Citation

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Srivastava¹,

Maggs²,

Antoine³

et al. 2009

Handbook of Experimental Pharmacology

133

117

View full text Add to dashboard Cite

Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.

show abstract

Section: Relationship Between Metabolic Activation and Hepatotoxicitymentioning

confidence: 99%

Section: Model Hepatotoxins: Role Of Reactive Metabolite Formationmentioning

confidence: 99%

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Srivastava¹,

Maggs²,

Antoine³

et al. 2009

Handbook of Experimental Pharmacology

133

117

View full text Add to dashboard Cite

show abstract

“…Users can access the TPDB and conduct custom searches by chemical, target tissue, species, protein name, or combinations of these criteria. Since these search functions have been described previously (50) and are illustrated in the help function on the website, only one will be mentioned here, and that is the Commonality Matrix function (Table 2). On its diagonal this matrix shows the number of target proteins known for any given chemical (listed alphabetically on the row and column headings).…”

Section: The Reactive Metabolite Target Protein Databasementioning

confidence: 99%

Filling and mining the reactive metabolite target protein database

Hanzlik¹,

Fang²,

Koen³

2009

Chemico-Biological Interactions

Self Cite

View full text Add to dashboard Cite

The post-translational modification of proteins is a well-known endogenous mechanism for regulating protein function and activity. Cellular proteins are also susceptible to post-translational modification by xenobiotic agents that possess, or whose metabolites possess, significant electrophilic character. Such non-physiological modifications to endogenous proteins are sometimes benign, but in other cases they are strongly associated with, and are presumed to cause, lethal cytotoxic consequences via necrosis and/or apoptosis. The Reactive Metabolite Target Protein Database (TPDB) is a searchable, freely web-accessible (http://tpdb.medchem.ku.edu:8080/protein_database/) resource that attempts to provide a comprehensive, up-to-date listing of known reactive metabolite target proteins. In this report we characterize the TPDB by reviewing briefly how the information it contains came to be known. We also compare its information to that provided by other types of "-omics" studies relevant to toxicology, and we illustrate how bioinformatic analysis of target proteins may help to elucidate mechanisms of cytotoxic responses to reactive metabolites.The post-translational modification of proteins is a well-known endogenous mechanism for regulating protein function and activity (1,2). Modifications such as disulfide bond formation, acylation, phosphorylation, glycosylation, metal ion binding and others can affect enzymatic activity, intracellular signaling via protein-protein interactions (PPIs), subcellular trafficking and localization, or even protein degradation. Cellular proteins are also susceptible to posttranslational modification by xenobiotic agents that possess, or whose metabolites possess, significant electrophilic character (e.g., epoxides, Michael acceptors, aldehydes, acylating agents, benzylic sulfate esters, etc.). Such non-physiological modifications to endogenous proteins are sometimes benign, but in other cases they are strongly associated with (and presumed to cause) lethal cytotoxic consequences via necrosis and/or apoptosis. Understanding the mechanisms by which protein covalent binding leads to cytotoxicity has been a major concern in Toxicology for nearly 40 years.During this time, as technology evolved, peak interest progressed from identifying the structures of reactive metabolites and the chemistry and enzymology of their formation, to elucidating the nature of the adducts formed with proteins and biological nucleophiles, to the identification of the target proteins modified by particular reactive metabolites. With information on the latter becoming more readily available, interest is now turning to the elucidation of mechanisms connecting protein covalent binding events to downstream cytotoxic events and cell death. Although our knowledge about reactive metabolite target Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo...

show abstract

“…Eighteen of the 25 proteins have known drug interactions in the Target Protein Database (38) (Supplemental File 8). An independent Gene Ontology (39) analysis also confirmed that a majority of the oxidized cysteines were located in mitochondrial and cytoplasmic proteins that are known to metabolize drugs and lipids (Supplemental File 8).…”

Section: Resultsmentioning

confidence: 99%

Sequence Tagging Reveals Unexpected Modifications in Toxicoproteomics

Dasari

Chambers

Codreanu

et al. 2011

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Toxicoproteomic samples are rich in posttranslational modifications (PTMs) of proteins. Identifying these modifications via standard database searching can incur significant performance penalties. Here we describe the latest developments in TagRecon, an algorithm that leverages inferred sequence tags to identify modified peptides in toxicoproteomic data sets. TagRecon identifies known modifications more effectively than the MyriMatch database search engine. TagRecon outperformed state of the art software in recognizing unanticipated modifications from LTQ, Orbitrap, and QTOF data sets. We developed user-friendly software for detecting persistent mass shifts from samples. We follow a three-step strategy for detecting unanticipated PTMs in samples. First, we identify the proteins present in the sample with a standard database search. Next, identified proteins are interrogated for unexpected PTMs with a sequence tag-based search. Finally, additional evidence is gathered for the detected mass shifts with a refinement search. Application of this technology on toxicoproteomic data sets revealed unintended cross-reactions between proteins and sample processing reagents. Twenty five proteins in rat liver showed signs of oxidative stress when exposed to potentially toxic drugs. These results demonstrate the value of mining toxicoproteomic data sets for modifications.

show abstract

The reactive metabolite target protein database (TPDB) – a web-accessible resource

Cited by 37 publications

References 21 publications

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Filling and mining the reactive metabolite target protein database

Sequence Tagging Reveals Unexpected Modifications in Toxicoproteomics

Contact Info

Product

Resources

About