Arsenate and its mechanism of action

· TGI - Biomarkers, Uncategorized

Arsenic is a metalloid which is present in the environment both naturally and anthropogenically. As in the case of other metals and metalloids, such as cadmium and chromium, arsenic has been shown to be a health risk at low concentrations.

In nature, arsenic is presented in many different oxidation states, being the inorganic ones, arsenite, As (III), and arsenate, As (V), the two main forms. While arsenite is presented mainly in anaerobic and alkaline environments, arsenate is more typical of aerobic and acid environments [1].

According to the World Health Organization (WHO), arsenic poisoning is one of the major health problems in several undeveloped countries, although cases have occurred in countries with a higher level of development [2]. In some areas of countries such as India and Bangladesh, arsenic poisoning is especially worrying and is usually caused by groundwater contamination, reaching levels above 10 µg/L which is the limit established as safe by the United States Environmental Protection Agency (EPA). There is a clear evidence of an association between the intake of arsenic and an increased risk of several types of cancer, miscarriages [3], as well as problems in cognitive development in growth stages [4][5][6].

At intracellular level, both arsenate and arsenite work differently. For instance, arsenate can enter the cell via a phosphate transporter due to its structural similarity to phosphate. For the same reason, arsenate can also alter several biochemical reactions such as cellular respiration. On the other hand, several reports have described the capacity of arsenite to damage DNA since arsenite inhibits base- and nucleotide-excision repair mechanisms [7][8][9][10].

Throughout the evolution, several mechanisms of response have been developed by organisms against different stressors. For instance, in the fission yeast Schizosaccharomyces pombe, the stress response is mainly directed by MAPKs and more specifically by the Spc1/Sty1 pathway. Spc1 is analogous to mammalian p38, and is activated when different types of stress such as UV radiation, heat shock and hyperosmolarity are present. In addition, it has been described that p38-like pathways are activated in response to arsenic stress in both S. pombe and Saccharomyces cerevisiae[11][12].

Regarding arsenate, several reports have shown that MAPK pathway is not the only mechanism of response used by eukaryotic organisms against arsenate. Some organisms can reduce arsenate to arsenite through the activity of arsenate reductases. Arsenite resulting from this reduction is removed from the cell through specific transporters (Escherichia coli Arsb, S. cerevisiae Acr3p, etc). This reducing capacity has been described in unicellular organisms, such as Leishmania major and S. cerevisiae, and pluricellular organisms, such as the fern Pteris vittata and human [13][14][15][16]. In the latter, arsenic reduction is carried out by the cell cycle phosphatase Cdc25, which also regulates G2/M transition by activating dephosphorylation of CDKs (cyclin dependent kinases) [17].

The current study proposes that arsenate reduction and intracellular accumulation of arsenite are the key mechanisms of arsenate tolerance in fission yeast.





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