Structure and dynamics of a lipoic acid-arsenical adduct

Dill, Kilian; Adams, Earle; O’Connor, Richard J.; McGown, Evelyn L.

doi:10.1021/tx00009a010

Cited by 20 publications

(9 citation statements)

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“…This is a nuclear-encoded mitochondrial enzyme complex that contains a 1,3-dithiol complex, lipoic acid as a post-translational modification on one of its subunits - the acetyltransferase or E2 subunit. As this satisfied the contemporary ‘ring hypothesis’ of arsenic binding [18], as lipoic acid out-competed monothiols for arsenical chelation [19], and as free D,L - lipoic acid complexed arsenicals well enough for some products to be structurally characterized [18,20,21], the lipoic acid moiety was the proposed dithiol site of arsenic binding and enzyme inhibition.…”

Section: Introductionmentioning

confidence: 58%

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Bergquist

Fischer

Sugden

et al. 2009

Journal of Organometallic Chemistry

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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 α-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. KeywordsArsenic; pyruvate dehydrogenase; alpha ketoglutarate dehydrogenase; lipoic acid; methyl arsenic Fax. (406) 243-4227, E-mail address: brooke.d.martin@umontana.edu. Only reduced arsenic species were able to inhibit the enzymatic action of the pyruvate and α-ketoglutarate dehydrogenase complexes and only under condition that poised the enzyme complex in a catalytic state that contained reduced lipoic acid groups. Monomethylarsenite was by far the most potent compound toward enzyme inhibition.

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Section: Introductionmentioning

confidence: 58%

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Bergquist

Fischer

Sugden

et al. 2009

Journal of Organometallic Chemistry

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“…Thus, the conjecture that 1c is most likely the ume was reduced in vacuo until an oil remained. From this residue major isomer [18] could not be confirmed.…”

Section: -(2-phenyl-132-dithiarsinan-4-yl)pentanoic Acid (1): Methodsmentioning

confidence: 86%

“…Both compounds contain who obtained 1 from PhAsCl 2 and Hlip(SH) 2 in solution AsϪAs bonds. In Salvarsan these bonds are oxidatively but did not isolate the product [18] . The final proof of the cleaved under physiological conditions (see above).…”

Section: Methodsmentioning

confidence: 91%

“…However, the underlying molecular mechanisms of action are still far from clear. It is assumed that the electronically soft species RAs 2ϩ and R 2 As ϩ (R ϭ e. g. alkyl, examined; these were obtained from As III starting materials aryl) block biological sulphydryl groups; however, "the inhiin all cases [16] [17] [18] . In the present paper we show that such bition of thiol-enzymes by As III , although widely quoted, is models are also accessible from compounds of mono-and poorly understood" [4] .…”

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confidence: 99%

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Models for the Inhibition of Dithiol‐Containing Enzymes by Organoarsenic Compounds: Synthetic Routes and the Structure of [PhAs(HlipS ₂ )] (HlipS ₂ ²⁻ = Reduced Lipoic Acid)

Döllen

Strasdeit

1998

Euro J of Inorganic Chem

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“…The stability of these cyclic complexes drops with the ringsize, whereby a 5-membered ring in an envelope configuration displays the highest stability. Following the literature [23][24][25][26] the lone pair favours the structures where the substituent on the As-atom is in the axial position, similar to the anomeric effect in cyclic conformations of sugars.…”

Section: Introductionmentioning

confidence: 70%

Anti-Proliferative Effects of Novel Glyco-Lipid-Arsenicals (III) on MCF-7 Human Breast Cancer Cells

Wimmer¹,

Robinson²,

Gopisetty-Venkata³

et al. 2006

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Arsenic trioxide appears to be effective in the treatment of pro-myelocytic leukaemia. The substituted phenylarsen(III)oxides are highly polar, they have a high tendency to undergo oxidation to As (V) and to form oligomers, to prevent this we protected the As-(OH)(2) group as cyclic dithiaarsanes. To increase the compound's biological stability and passive diffusion we conjugated the compound of interest with lipoamino acids (Laas). Alternatively, we further conjugated the dithiaarsane derivative with a carbohydrate to utilize active transport systems and to target compound. We investigated two novel glyco-lipid arsenicals (III) (compounds 9 and 11) for their ability to initiate MCF-7 breast cancer cell death and characterized the mechanism by which death was initiated. A significant decrease in MCF-7 cell proliferation was observed using 1 microM and 10 microM compound (11) and 10 microM of compound (9). Treatment with compound (11) triggered apoptosis of MFC-7 cells while compound (9) induced inhibition of cellular proliferation was not via rapid induction of apoptosis and more likely reflected necrosis and/or alterations in the cell cycle. Differences in the anti-proliferative potency of the two compounds indicate that structural modifications influence effectiveness.

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Structure and dynamics of a lipoic acid-arsenical adduct

Cited by 20 publications

References 6 publications

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Models for the Inhibition of Dithiol‐Containing Enzymes by Organoarsenic Compounds: Synthetic Routes and the Structure of [PhAs(HlipS ₂ )] (HlipS ₂ ²⁻ = Reduced Lipoic Acid)

Anti-Proliferative Effects of Novel Glyco-Lipid-Arsenicals (III) on MCF-7 Human Breast Cancer Cells

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Structure and dynamics of a lipoic acid-arsenical adduct

Cited by 20 publications

References 6 publications

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases

Models for the Inhibition of Dithiol‐Containing Enzymes by Organoarsenic Compounds: Synthetic Routes and the Structure of [PhAs(HlipS 2 )] (HlipS 2 2− = Reduced Lipoic Acid)

Anti-Proliferative Effects of Novel Glyco-Lipid-Arsenicals (III) on MCF-7 Human Breast Cancer Cells

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Models for the Inhibition of Dithiol‐Containing Enzymes by Organoarsenic Compounds: Synthetic Routes and the Structure of [PhAs(HlipS ₂ )] (HlipS ₂ ²⁻ = Reduced Lipoic Acid)