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Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast
Author(s) -
Talemi Soheil Rastgou,
Jacobson Therese,
Garla Vijay,
Navarrete Clara,
Wagner Annemarie,
Tamás Markus J.,
Schaber Jörg
Publication year - 2014
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12631
Subject(s) - arsenic , detoxification (alternative medicine) , arsenic toxicity , biology , glutathione , toxicity , yeast , arsenite , biochemistry , intracellular , enzyme , chemistry , pathology , medicine , alternative medicine , organic chemistry
Summary 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) Fps 1 is controlled by Hog 1‐dependent and Hog 1‐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.