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Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases.
MedLine Citation:
PMID:  20161290     Owner:  NLM     Status:  Publisher    
Inorganic arsenic that is ingested through drinking water or inhalation is metabolized by biological methylation pathways into organoarsenical metabolites. It is now becoming understood that this metabolism that was formerly considered to be detoxification may contribute as much or more to increasing the toxicity of arsenic. One proposed mode of the toxic action of arsenic and its organoarsenic metabolites is through its binding to proteins and inactivating their enzymatic activity. The classic case has been considered the affinity of the proximal 1,3 sulfhydryl groups of the lipoic acid cofactor of the pyruvate dehydrogenase complex for arsenic. A 2:1 stoichiometry of sulfhydryl to arsenic groups has been measured in proteins and arsenical complexes can be synthesized using free D,L-lipoic acid. The relative importance of this site for arsenic binding has come in to question through the use of methylating bifunctional arsenic complexes that suggested the methylation of an active site histidine may also be important, and the suggestion that arsenic inhibits the pyruvate dehydrogenase complex indirectly by elevating mitochondrial hydrogen peroxide generation. In order to separate the effects of direct trivalent arsenite toxicity from that of hydrogen peroxide and activated oxygen, we studied the inhibition of the PDH complex under conditions that did not generate hydrogen peroxide but did expose the lipoic acid group in its reduced state to arsenicals. We also studied the effects of arsenicals in the inhibition of the alpha-ketoglutarate dehydrogenase complex. We found that only trivalent arsenical compounds inhibited the activity of both dehydrogenase complexes and only when the lipoic acid was in its reduced form. Arsenite inhibited both enzyme complexes approximately equivalently while monomethylarsenite inhibited the PDH complex to a greater extent than the KGDH complex - although both complexes were very sensitive to inhibition by this complex. Dimethylarsenite inhibition of both complexes was only observed with longer pre-incubation periods. Cumulative inhibition by the reduced arsenical was observed for all complexes indicating a binding mode of inhibition that is dependent upon lipoic acid being in its reduced state.
Erik R Bergquist; Robert J Fischer; Kent D Sugden; Brooke D Martin
Publication Detail:
Journal Detail:
Title:  Journal of organometallic chemistry     Volume:  694     ISSN:  0022-328X     ISO Abbreviation:  -     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2010-7-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0053303     Medline TA:  J Organomet Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  973-980     Citation Subset:  -    
Department of Chemistry, University of Montana, 32 Campus Drive, Missoula, MT 59812, USA.
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Grant Support
P20 RR016455-01//NCRR NIH HHS; P20 RR017670-030010//NCRR NIH HHS; R01 ES010437-01//NIEHS NIH HHS; R01 ES010437-02//NIEHS NIH HHS; R01 ES010437-03//NIEHS NIH HHS; R01 ES010437-04//NIEHS NIH HHS; R01 ES010437-05//NIEHS NIH HHS; R01 ES014872-01//NIEHS NIH HHS; R01 ES014872-02//NIEHS NIH HHS; R01 ES014872-04//NIEHS NIH HHS

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