Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
Mol Microbiol. 2014 Jun;92(6):1343-56. doi: 10.1111/mmi.12631. Epub 2014 May 23.
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.
砷在人类疾病的病因和治疗中都具有双重作用。因此，人们对阐明砷的毒性和解毒机制非常感兴趣。通过集成建模方法，我们确定了一个最佳的简约数学模型，该模型可以重现和预测不同条件和突变体的细胞内砷动力学，从而为酵母中的砷毒性和解毒机制提供了新的见解，这些见解部分可以通过专门的实验来证实。具体来说，我们的分析表明：(i) 砷在短期（急性）暴露期间主要与蛋白质结合，而在长期（慢性）暴露期间则主要与谷胱甘肽结合的砷结合，(ii) 砷不稳定地保留，而是可以通过一种出口机制离开液泡，以及 (iii) 在亚砷酸盐胁迫下，Fps1 受到 Hog1 依赖性和非 Hog1 依赖性机制的控制。我们的结果挑战了谷胱甘肽耗竭作为砷毒性的关键机制，而是表明 (iv) 增加谷胱甘肽生物合成可保护蛋白质组免受砷的破坏作用，以及 (v) 广泛的蛋白质失活导致这种类金属的毒性。我们在酵母中的工作可能有助于阐明高等真核生物中的类似机制，并对砷在医学治疗中的应用具有重要意义。
