Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast.
Artikel i vetenskaplig tidskrift, 2014

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.

Arsenic

Microbiology

Molecular microbiology

Författare

Soheil Rastgou Talemi

Otto von Guericke Universitaet Magdeburg

Therese Jacobson

Göteborgs universitet

Vijay Garla

Yale University

Clara Navarrete Roman

Göteborgs universitet

Annemarie Wagner

Chalmers, Teknisk fysik

Markus J. Tamás

Göteborgs universitet

J. Schaber

Otto von Guericke Universitaet Magdeburg

Molecular Microbiology

0950-382X (ISSN) 1365-2958 (eISSN)

Vol. 92 6 1343-56

Ämneskategorier

Biokemi och molekylärbiologi

Mikrobiologi

Bioinformatik och systembiologi

DOI

10.1111/mmi.12631

PubMed

24798644