Biochemical Journal

Review

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

David SHEEHAN, Gerardene MEADE, Vivienne M. FOLEY, Catriona A. DOWD

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.

  • detoxification
  • GST
  • polymorphism
  • protein
  • xenobiotic

Footnotes

  • Abbreviations used: CDNB, 1-chloro-2,4-dinitrobenzene; Dnp-SG, dinitrophenol–glutathione conjugate; EST, expressed sequence tag; GST, glutathione transferase; MAPEG, membrane-associated proteins in eicosanoid and glutathione metabolism; MIF, migration inhibitory factor; MOAT, multispecific organic ion transporter; MRP, multidrug-resistance-associated protein; single-letter prefixes denote species of origin (r, rat; m, mouse; h, human).