Review
Glutathione transporters

https://doi.org/10.1016/j.bbagen.2012.11.018 Get rights and content

Abstract

Background

Glutathione (GSH) is synthesized in the cytoplasm but there is a requirement for glutathione not only in the cytoplasm, but in the other organelles and the extracellular milieu. GSH is also imported into the cytoplasm. The transports of glutathione across these different membranes in different systems have been biochemically demonstrated. However the molecular identity of the transporters has been established only in a few cases.

Scope of review

An attempt has been made to present the current state of knowledge of glutathione transporters from different organisms as well as different organelles. These include the most well characterized transporters, the yeast high-affinity, high-specificity glutathione transporters involved in import into the cytoplasm, and the mammalian MRP proteins involved in low affinity glutathione efflux from the cytoplasm. Other glutathione transporters that have been described either with direct or indirect evidences are also discussed.

Major conclusions

The molecular identity of a few glutathione transporters has been unambiguously established but there is a need to identify the transporters of other systems and organelles. There is a lack of direct evidence establishing transport by suggested transporters in many cases. Studies with the high affinity transporters have led to important structure-function insights.

General significance

An understanding of glutathione transporters is critical to our understanding of redox homeostasis in living cells. By presenting our current state of understanding and the gaps in our knowledge the review hopes to stimulate research in these fields. This article is part of a Special Issue entitled Cellular functions of glutathione.

Highlights

► Glutathione transporters described in different organisms and different organelles. ► Eukaryotic cells have multiple glutathione transporters. ► Glutathione transporters have evolved from different protein families. ► Low and high affinity transporters are described. ► Yeast high affinity transporters have facilitated structure function studies.

Section snippets

Introduction and historical perspective

Glutathione (GSH) is the most abundant small molecular weight thiol present in living cells. It is synthesized in the cytoplasm (although in plants part of the synthesis is in the chloroplasts) [1], but carries out a variety of functions both in the cytoplasm and other organelles. The roles of glutathione include its role as a redox buffer [2], [3], [4], in the cellular response to oxidative stress, biosynthesis of iron–sulfur proteins in the mitochondria [5], [6], [7], [8], detoxification of

The yeast high affinity glutathione transporters are members of the oligopeptide transporter family

Biochemical studies with yeasts had revealed the presence of glutathione uptake systems in S. cerevisiae [14]. Subsequent studies with this yeast led to the identification of the first high affinity glutathione transporter, Hgt1p [38] that was required for the uptake of glutathione from the extracellular medium. Deleting the gene for this transporter led to an almost complete loss in uptake of radioactive glutathione. Knockout of the gene was also synthetically lethal with a knockout of the

The MRP/CFTR family in low affinity glutathione efflux

The multidrug resistance associated protein (MRP) family is a subclass of the ABC superfamily (ABCC). In humans, this family includes a total of nine MRP genes (MRP1 to MRP9) and the cystic fibrosis transmembrane regulator (CFTR). These proteins are plasma membrane localized. ATP-binding and hydrolysis provide the driving force for pumping substrates out of the cell. These proteins are known to be involved in multidrug resistance and function as multispecific organic anion transporters, but

Concluding remarks

Glutathione transporters play a key role in glutathione homeostasis of living cells. Despite their importance, the identification and characterization of glutathione transporters have been difficult, progress slow, and at times controversial. The differing requirements in the cell and the organelles have led to the evolution of glutathione transporters from different protein families with widely differing kinetic parameters, and substrate specificities. Some of the glutathione transporters such

Acknowledgements

AT and MZ acknowledge receipt of fellowship from CSIR, India. This work was supported in part by Grant-in-Aid projects to A.K.B. from the Departments of Science and Technology and Department of Biotechnology, Government of India.

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