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Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

ABSTRACT: The exposure of cells to several metal ions stabilizes HIF-1 alpha protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases. Here we provide evidence supporting the latter mechanism. We show that HIF-1 alpha stabilization in human lung epithelial cells occurred following exposure to various metal and metalloid ions, including those that cannot substitute for iron in the hydroxylases. In each case addition of the reducing agent ascorbic acid (AA)* abolished HIF-1 alpha protein stabilization. To better understand the role of iron oxidation in hydroxylase inhibition and to define the role of AA in the enzyme recovery we applied molecular modeling techniques. Our results indicate that the energy required for iron substitution by Ni(II) in the enzyme is high and unlikely to be achieved in a biological system. Additionally, computer modeling allowed us to identify a tridentate coordination of AA with the enzyme-bound iron, which explains the specific demand for AA as the iron reductant. Thus, the stabilization of HIF-1 alpha by numerous metal ions that cannot substitute for iron in the enzyme, the alleviation of this effect by AA, and our computer modeling data support the hypothesis of iron oxidation in the hydroxylases following exposure to metal ions.

SUBMITTER: Kaczmarek M

PROVIDER: S-EPMC2639755 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

Kaczmarek Monika M Cachau Raul E RE Topol Igor A IA Kasprzak Kazimierz S KS Ghio Andy A Salnikow Konstantin K

Toxicological sciences : an official journal of the Society of Toxicology 20081213 2

The exposure of cells to several metal ions stabilizes HIF-1 alpha protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases. Here we provide evidence supporting the latter mechanism. We show that HIF-1 alpha stabilization in human lung epithelial cells occurred following exposure to various metal and metalloid ions, including those that cannot substi ...[more]

PMID: 19074761

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Project description:Redox-inactive metal ions that function as Lewis acids play pivotal roles in modulating reactivities of oxygen-containing metal complexes in a variety of biological and biomimetic reactions, including dioxygen activation/formation and functionalization of organic substrates. Mononuclear nonheme iron(III)-peroxo species are invoked as active oxygen intermediates in the catalytic cycles of dioxygen activation by nonheme iron enzymes and their biomimetic compounds. Here, we report mononuclear nonheme iron(III)-peroxo complexes binding redox-inactive metal ions, [(TMC)FeIII(O2)]+-M3+ (M3+ = Sc3+ and Y3+; TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), which are characterized spectroscopically as a 'side-on' iron(III)-peroxo complex binding a redox-inactive metal ion, (TMC)FeIII-(?,?2:?2-O2)-M3+ (2-M). While an iron(III)-peroxo complex, [(TMC)FeIII(O2)]+, does not react with electron donors (e.g., ferrocene), one-electron reduction of the iron(III)-peroxo complexes binding redox-inactive metal ions occurs readily upon addition of electron donors, resulting in the generation of an iron(IV)-oxo complex, [(TMC)FeIV(O)]2+ (4), via heterolytic O-O bond cleavage of the peroxide ligand. The rates of the conversion of 2-M to 4 are found to depend on the Lewis acidity of the redox-inactive metal ions and the oxidation potential of the electron donors. We have also determined the fundamental electron-transfer properties of 2-M, such as the reduction potential and the reorganization energy in electron-transfer reaction. Based on the results presented herein, we have proposed a mechanism for the reactions of 2-M and electron donors; the reduction of 2-M to the reduced species, (TMC)FeII-(O2)-M3+ (2'-M), is the rate-determining step, followed by heterolytic O-O bond cleavage of the reduced species to form 4. The present results provide a biomimetic example demonstrating that redox-inactive metal ions bound to an iron(III)-peroxo intermediate play a significant role in activating the peroxide O-O bond to form a high-valent iron(IV)-oxo species.

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Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

Publications

Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

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