Versatility of Glutathione Transferase Proteins

Mannervik, Bengt

doi:10.3390/biom13121749

Biomolecules

2023

DOI: 10.3390/biom13121749

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Versatility of Glutathione Transferase Proteins

Bengt Mannervik

Abstract: For more than 60 years, glutathione transferases (GSTs) have attracted attention, but the research field of the GSTome [...]

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2024

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Cited by 5 publications

References 28 publications

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The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation

Boeglin,

Stec,

Noguchi

et al. 2024

Journal of Biological Chemistry

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The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation

Boeglin,

Stec,

Noguchi

et al. 2024

Journal of Biological Chemistry

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Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors

Sabt,

Kitsos,

Ebaid

et al. 2024

PLoS ONE

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Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.

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Structural Analysis of the Drosophila melanogaster GSTome

Petiot,

Schwartz,

Delarue

et al. 2024

Biomolecules

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Glutathione transferase (GST) is a superfamily of ubiquitous enzymes, multigenic in numerous organisms and which generally present homodimeric structures. GSTs are involved in numerous biological functions such as chemical detoxification as well as chemoperception in mammals and insects. GSTs catalyze the conjugation of their cofactor, reduced glutathione (GSH), to xenobiotic electrophilic centers. To achieve this catalytic function, GSTs are comprised of a ligand binding site and a GSH binding site per subunit, which is very specific and highly conserved; the hydrophobic substrate binding site enables the binding of diverse substrates. In this work, we focus our interest in a model organism, the fruit fly Drosophila melanogaster (D. mel), which comprises 42 GST sequences distributed in six classes and composing its GSTome. The goal of this study is to describe the complete structural GSTome of D. mel to determine how changes in the amino acid sequence modify the structural characteristics of GST, particularly in the GSH binding sites and in the dimerization interface. First, we predicted the 3D atomic structures of each GST using the AlphaFold (AF) program and compared them with X-ray crystallography structures, when they exist. We also characterized and compared their global and local folds. Second, we used multiple sequence alignment coupled with AF-predicted structures to characterize the relationship between the conservation of amino acids in the sequence and their structural features. Finally, we applied normal mode analysis to estimate thermal B-factors of all GST structures of D. mel. Particularly, we extracted flexibility profiles of GST and identify key residues and motifs that are systematically involved in the ligand binding/dimerization processes and thus playing a crucial role in the catalytic function. This methodology will be extended to guide the in silico design of synthetic GST with new/optimal catalytic properties for detoxification applications.

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Versatility of Glutathione Transferase Proteins

Abstract: For more than 60 years, glutathione transferases (GSTs) have attracted attention, but the research field of the GSTome [...]

Cited by 5 publications

References 28 publications

The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation

The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation

Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors

Structural Analysis of the Drosophila melanogaster GSTome

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