Arsenic and antimony transporters in eukaryotes

Abstract

Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective metalloid tolerance systems in eukaryotes include downregulation of metalloid uptake, efflux out of the cell, and complexation with phytochelatin or glutathione followed by sequestration into the vacuole. Understanding of arsenic and antimony transport system is of high importance due to the increasing usage of arsenic-based drugs in the treatment of certain types of cancer and diseases caused by protozoan parasites as well as for the development of bio- and phytoremediation strategies for metalloid polluted areas. However, in contrast to prokaryotes, the knowledge about specific transporters of arsenic and antimony and the mechanisms of metalloid transport in eukaryotes has been very limited for a long time. Here, we review the recent advances in understanding of arsenic and antimony transport pathways in eukaryotes, including a dual role of aquaglyceroporins in uptake and efflux of metalloids, elucidation of arsenic transport mechanism by the yeast Acr3 transporter and its role in arsenic hyperaccumulation in ferns, identification of vacuolar transporters of arsenic-phytochelatin complexes in plants and forms of arsenic substrates recognized by mammalian ABC transporters.

Keywords: ABC transporters; Acr3 antiporter; antimony; aquaglyceroporins; arsenic; glucose transporters; glutathione; phytochelatin.

Figure 1

Pathways for arsenic uptake and detoxification in the yeast S.cerevisiae. In yeast cells uptake of As(III) is facilitated mainly via the aquaglyceroporin Fps1 but in the absence of glucose As(III) also enters the cell through the hexose permeases Hxt (Hxt1-Hxt17, Gal2). As(V) is taken up by the phosphate transporters (Pho), such as Pho84 and Pho87, followed by reduction to As(III) by the arsenate reductase Acr2 in the cytoplasm. Next, As(III) is transported out of the cell by the As(III)/H⁺ antiporter Acr3 against the concentration gradient or by the aquaglyceroporin Fps1, especially during As(V) exposure, when the internal concentration of As(III) is higher than the outside. In addition, As(III) is conjugated with glutathione (GSH) and sequestrated into the vacuole by the ABC transporters Ycf1 and Vmr1.

Figure 2

Routes for arsenic transport in higher plants. In plant cells As(III) is accumulated through the aquaporins of Nodulin26-like intrinsic protein subfamily (NIPs) and plasma membrane intrinsic protein subfamily (PIPs), while As(V) uptake is catalyzed by the phosphate transporters (PHT1). In the cytoplasm As(V) is rapidly reduced to As(III) by the arsenate reductase ACR2/CDC25. Upon binding to phytochelatins (PCs), PC₂-As(III) complexes are compartmentalized into the vacuole by two A. thaliana ABC transporters, ABCC1 and ABCC2. As(III) can also leak out of the plant root cell via the NIP and PIP channels down the concentration gradient to external medium. On the other hand, in rice the silicon transporter Lsi2 localizing to the proximal side of root cells extrudes As(III) to the xylem contributing to metalloid accumulation in shoots and grain.

Figure 3

Summary of arsenic transport pathways in mammalian cells. As(V) uptake is mediated by the high-affinity phosphate transporter NaPiIIb. Next, As(V) is reduced to As(III) by CDC25 phosphatases/arsenate reductases. As(III) is transported into the mammalian cells via multiple pathways: the aquaglyceroporins (AQP3, AQP7, AQP9, AQP10), the glucose permeases (GLUT1, GLUT2, GLUT5) or the organic anion transporting polypeptides (OATPB, OATPC). The AQP9 and GLUT2 transporters are also responsible for the transport of methylated species of As(III) out of the cells. The ABC transporters from the ABCB (MDR1/P-gp) and ABCC (MRP1 and MRP2) subfamilies are the major pathways of As(III) extrusion. Both MRP1 and MRP2 are able to transport inorganic and monomethylated forms of As(III) conjugated with glutathione. In addition, MRP2 mediates efflux of seleno-bis(S-glutathionyl) arsinium ion. The exact form of As(III) recognized by MDR1/P-gp is uncertain but it is not glutathione-S-conjugate.