Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily

Abstract

The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions. They have peroxidase and isomerase activities, they can inhibit the Jun N-terminal kinase (thus protecting cells against H2O2-induced cell death), and they are able to bind non-catalytically a wide range of endogenous and exogenous ligands. Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi and Theta classes on the basis of a combination of criteria such as substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity. Non-mammalian GSTs have been much less well characterized, but have provided a disproportionately large number of three-dimensional structures, thus extending our structure–function knowledge of the superfamily as a whole. Moreover, several novel classes identified in non-mammalian species have been subsequently identified in mammals, sometimes carrying out functions not previously associated with GSTs. These studies have revealed that the GSTs comprise a widespread and highly versatile superfamily which show similarities to non-GST stress-related proteins. Independent classification systems have arisen for groups of organisms such as plants and insects. This review surveys the classification of GSTs in non-mammalian sources, such as bacteria, fungi, plants, insects and helminths, and attempts to relate them to the more mainstream classification system for mammalian enzymes. The implications of this classification with regard to the evolution of GSTs are discussed.

Dietary low or excess levels of lipids reduced growth performance, and impaired immune function and structure of head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella) under the infection of Aeromonas hydrophila

“…Dietary lipids levels do not impact the amount of GSH in the head kidney significantly, either. In animals, GST can catalyse the conjugation of reactive oxygen species to GSH, which is then excreted outside the cell to combat oxidative damage [96]. Thus, the lack of effect of dietary lipids levels on the activity of GSH may be partly due to the unchanged activity of GST in the head kidney of young grass carp.…”

A glutathione S-transferase from Proteus mirabilis involved in heavy metal resistance and its potential application in removal of Hg2+

“…GSTs are widely distributed in natural organisms and are found in both eukaryotes and prokaryotes. GSTs play important roles in higher eukaryotes in cellular detoxification against a large number of harmful xenobiotics and endobiotics [1,[3][4][5]. In bacteria, GST activity is very low and failed to attract the interest of microbiologists and molecular biologists until fairly recently.…”

“…Bacterial GSTs are mainly referred as four different classes: beta, chi, theta and zeta [1,2,4,6,7]. Beta class of cytoplasmic GSTs (cGSTs), characterized by the presence of a cysteine residue at the GSH site, is able to conjugate the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) and bind to the GSH-affinity matrix [6].…”

Proteomic identification, cDNA cloning and enzymatic activity of glutathione S-transferases from the generalist marine gastropod, Cyphoma gibbosum

“…Glutathione S-transferases (GST, EC 2.5.1.18) form a large superfamily of multifunctional enzymes capable of conjugating a broad range of toxic electrophilic xenobiotics with glutathione [1]. GSTs function primarily as detoxification enzymes, generally rendering the resultant products more water soluble (nonreactive conjugate), thereby facilitating excretion.…”

“…The catalytic versatility and diversity of GSTs can be attributed to the nonspecific nature of the hydrophobic substrate binding site (H-site), and the extensive gene duplication and divergence that has occurred in this superfamily [2,3]. The soluble GSTs in metazoans are divided into eight classes (alpha, kappa, mu, pi, sigma, theta, omega and zeta) based on sequence identity, immunological and kinetic properties [1,4,5]. While the majority of GST enzymatic characterization has focused on mammalian forms, non-vertebrate models offer an exciting opportunity to examine the evolution of GSTs and their adaptive responses to environmental chemicals, including natural products.…”