Background The toxic effects of many simple organic compounds stem from

Background The toxic effects of many simple organic compounds stem from their biotransformation to chemically reactive metabolites which bind covalently to cellular proteins. more technical searches by choosing chemical compound, pet species, target cells and protein titles/synonyms from draw-straight down menus, and iii) commonality queries over multiple chemical substances. Tabulated serp’s provide info, references and links to additional databases. Summary The TPDB can be a distinctive on-range compilation of information on the covalent modification of cellular proteins by reactive metabolites of chemicals and drugs. Its comprehensiveness and searchability should facilitate the elucidation of mechanisms of reactive metabolite toxicity. The database is freely available at Background The toxic effects of many simple organic chemicals, pollutants and even drugs are associated with their biotransformation to chemically reactive intermediates [1,2]. The latter in turn react covalently with cellular macromolecules, thus modifying their structure and potentially their function. Whereas modification of DNA can cause mutations or even cancer, protein modification is often associated with direct, acute cytotoxic effects. Protein covalent binding is usually detected by administering radioactive precursors to animals (or cell-based systems in vitro) and measuring the amount of radioactivity that becomes LY2157299 distributor covalently attached to the macromolecules (i.e., not removable by dialysis, extraction or chromatography) [3]. The extent, time course and anatomical distribution of protein covalent binding generally correlate very well with similar measures of target organ toxicity in whole animals or cellular systems. However, a few prominent exceptions to this pattern are also known. For example, whereas bromobenzene and p-acetamidophenol (acetaminophen) are “textbook” pro-toxins, p-bromophenol [4] and m-acetamidophenol [5,6] are essentially nontoxic despite the fact that they undergo metabolic activation LY2157299 distributor and covalent binding much like their toxic congeners. These and other examples indicate that while covalent binding is usually apparently em necessary /em for toxicity, not all covalent binding is usually em sufficient /em to cause toxicity. Since most biological responses to chemicals are highly structurally specific, to understand the mechanisms of cytotoxic responses it is imperative to understand the structural chemistry of protein covalent binding. The enzymes of xenobiotic metabolism generally have a rather broad substrate specificity that appears to be governed primarily by the functional group chemistry of potential substrates [7]. Since the early 1970s, considerable progress has been made in identifying the reactive metabolites formed from a large number of chemical functional groupings [8]. In the vast majority of cases they are electrophilic in nature. For example, epoxides, quinones and Michael acceptors generally react with cysteine sulfhydryl groups but also react with lysine, histidine and, to a lesser extent, methionine or even carboxylic acid side chains in proteins [9-11]. On the other hand metabolites such as acyl- and thioacyl halides and iminosulfinic acids show a strong tendency to acylate the epsilon-amino group of lysine side chains (Physique ?(Figure1)1) [12-14]. Open in a IL6 antibody separate window Figure 1 Formation of chemically reactive metabolites from steady pro-toxins. As opposed to the prosperity of structural information regarding cytotoxic metabolites, understanding of their proteins targets provides been very much slower to build up. The initial identifications of reactive metabolite focus on proteins were predicated on classical isolation and N-terminal sequencing of radioactive proteins from pets treated with radiolabeled pro-toxins [15,16]. Subsequent reviews have made an appearance sporadically and therefore are scattered through the entire literature, producing global comparisons or analyses challenging. Since the arrival of contemporary mass spectrometry-based strategies, much longer lists of focus on proteins have already been identified [17-20] however the literature still continues to be fragmented. Our laboratory provides been thinking about exploring the chance that different pro-harmful toxins focus on a common subset of proteins whose covalent modification may be mechanistically significant to cytotoxicity [17,21,22]. To check this hypothesis needed that we gather, organize and evaluate essentially em all /em of the publicly offered information regarding well-identified focus on proteins that become adducted by reactive metabolites of organic chemical substance pro-harmful toxins. The Reactive Metabolite Focus on Protein Data source (TPDB) and the linked analysis software program described herein had been intended to facilitate this. Construction and articles The Reactive Metabolite Focus on Protein Data source (TPDB) was applied as an Oracle 9i relational data source. An interactive internet interface was made using Java Server Web pages (JSP) and the Java Database Online connectivity (JDBC) API was utilized to user interface with the LY2157299 distributor Oracle data source. Presently our server works on the LINUX operating-system (RedHat AS3). The database is openly available on the internet and the schema of the data source design is on the website. Populating the database Computerized literature searches for “protein adducts” and similar terms yield more than 1500 references. However, the vast majority of LY2157299 distributor these simply report occurrences of protein covalent binding detected in model systems, in occupational health screenings based.

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