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Trivalent arsenic inhibits the functions of chaperonin complex.

ABSTRACT: The exact molecular mechanisms by which the environmental pollutant arsenic works in biological systems are not completely understood. Using an unbiased chemogenomics approach in Saccharomyces cerevisiae, we found that mutants of the chaperonin complex TRiC and the functionally related prefoldin complex are all hypersensitive to arsenic compared to a wild-type strain. In contrast, mutants with impaired ribosome functions were highly arsenic resistant. These observations led us to hypothesize that arsenic might inhibit TRiC function, required for folding of actin, tubulin, and other proteins postsynthesis. Consistent with this hypothesis, we found that arsenic treatment distorted morphology of both actin and microtubule filaments. Moreover, arsenic impaired substrate folding by both bovine and archaeal TRiC complexes in vitro. These results together indicate that TRiC is a conserved target of arsenic inhibition in various biological systems.

SUBMITTER: Pan X

PROVIDER: S-EPMC2954479 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Trivalent arsenic inhibits the functions of chaperonin complex.

Pan Xuewen X Reissman Stefanie S Douglas Nick R NR Huang Zhiwei Z Yuan Daniel S DS Wang Xiaoling X McCaffery J Michael JM Frydman Judith J Boeke Jef D JD

Genetics 20100726 2

The exact molecular mechanisms by which the environmental pollutant arsenic works in biological systems are not completely understood. Using an unbiased chemogenomics approach in Saccharomyces cerevisiae, we found that mutants of the chaperonin complex TRiC and the functionally related prefoldin complex are all hypersensitive to arsenic compared to a wild-type strain. In contrast, mutants with impaired ribosome functions were highly arsenic resistant. These observations led us to hypothesize tha ...[more]

PMID: 20660648

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Project description:Chronic ingestion of water containing inorganic arsenic (iAs) has been linked to a variety of adverse health effects, including cancer, hypertension and diabetes. Current evidence suggests that the toxic methylated trivalent metabolites of iAs, methylarsonous acid (MAs(III)) and dimethylarsinous acid (DMAs(III)) play a key role in the etiology of these diseases. Both MAs(III) and DMAs(III) have been detected in urine of subjects exposed to iAs. However, the rapid oxidation of DMAs(III) and, to a lesser extent, MAs(III) in oxygen-rich environments leads to difficulties in the analysis of these metabolites in samples of urine collected in population studies. Results of our previous work indicate that MAs(III) and DMAs(III) are relatively stable in a reducing cellular environment and can be quantified in cells and tissues. In the present study, we used the oxidation state-specific hydride generation-cryotrapping-atomic absorption spectroscopy (HG-CT-AAS) to examine the presence and stability of these trivalent metabolites in the liver of mice and in UROtsa/F35 cells exposed to iAs. Tri- and pentavalent metabolites of iAs were analyzed directly (without chemical extraction or digestion). Liver homogenates prepared in cold deionized water and cell culture medium and lysates were stored at either 0 °C or -80 °C for up to 22 days. Both MAs(III) and DMAs(III) were stable in homogenates stored at -80 °C. In contrast, DMAs(III) in homogenates stored at 0 °C began to oxidize to its pentavalent counterpart after 1 day; MAs(III) remained stable for at least 3 weeks under these conditions. MAs(III) and DMAs(III) generated in UROtsa/F35 cultures were stable for 3 weeks when culture media and cell lysates were stored at -80 °C. These results suggest that samples of cells and tissues represent suitable material for the quantitative, oxidation state-specific analysis of As in laboratory and population studies examining the metabolism or toxic effects of this metalloid.

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Trivalent arsenic inhibits the functions of chaperonin complex.

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Trivalent arsenic inhibits the functions of chaperonin complex.

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