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Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast.

Soheil Rastgou Talemi ; Therese Jacobson ; Vijay Garla ; Clara Navarrete ; Annemarie Wagner (Institutionen för teknisk fysik) ; Markus J. Tamás ; Jörg Schaber
Molecular Microbiology (0950-382X). Vol. 92 (2014), 6, p. 1343-56.
[Artikel, refereegranskad vetenskaplig]

Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein-bound during short-term (acute) exposure, whereas glutathione-conjugated arsenic dominates during long-term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1-dependent and Hog1-independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy.

Nyckelord: Molecular microbiology, Microbiology, Arsenic



Denna post skapades 2014-06-10. Senast ändrad 2016-10-04.
CPL Pubid: 199039

 

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Institutioner (Chalmers)

Institutionen för kemi och molekylärbiologi (GU)
Institutionen för teknisk fysik (1900-2015)

Ämnesområden

Biokemi och molekylärbiologi
Mikrobiologi
Bioinformatik och systembiologi

Chalmers infrastruktur