Open Access Research article

Molecular evolution and the role of oxidative stress in the expansion and functional diversification of cytosolic glutathione transferases

Rute R da Fonseca1*, Warren E Johnson2, Stephen J O'Brien2, Vítor Vasconcelos13 and Agostinho Antunes12*

Author Affiliations

1 CIMAR/CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 177, 4050-123 Porto, Portugal

2 Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702-1201, USA

3 Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Portugal

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BMC Evolutionary Biology 2010, 10:281  doi:10.1186/1471-2148-10-281

Published: 15 September 2010



Cytosolic glutathione transferases (cGST) are a large group of ubiquitous enzymes involved in detoxification and are well known for their undesired side effects during chemotherapy. In this work we have performed thorough phylogenetic analyses to understand the various aspects of the evolution and functional diversification of cGSTs. Furthermore, we assessed plausible correlations between gene duplication and substrate specificity of gene paralogs in humans and selected species, notably in mammalian enzymes and their natural substrates.


We present a molecular phylogeny of cytosolic GSTs that shows that several classes of cGSTs are more ubiquitous and thus have an older ancestry than previously thought. Furthermore, we found that positive selection is implicated in the diversification of cGSTs. The number of duplicate genes per class is generally higher for groups of enzymes that metabolize products of oxidative damage.


1) Protection against oxidative stress seems to be the major driver of positive selection in mammalian cGSTs, explaining the overall expansion pattern of this subfamily;

2) Given the functional redundancy of GSTs that metabolize xenobiotic chemicals, we would expect the loss of gene duplicates, but by contrast we observed a gene expansion of this family, which likely has been favored by: i) the diversification of endogenous substrates; ii) differential tissue expression; and iii) increased specificity for a particular molecule;

3) The increased availability of sequence data from diversified taxa is likely to continue to improve our understanding of the early origin of the different cGST classes.