Tocopherol esters inhibit human glutathione S-transferase omega.

Sampayo-Reyes, Adriana; Zakharyan, Roksana

doi:10.18388/abp.2006_3326

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…Interestingly, α-tocopherol (vitamin E), including several esterified tocopherols, such as (+)-α-tocopherol phosphate and (+)-α-tocopherol succinate are also potent inhibitors of both GSTP1-1 [126] and GSTO1-1 [127]. Among them, alpha tocopheryl succinate (α-TOS) is the most effective form of vitamin E analogues, affecting cancer cell death.…”

Section: The Role Of Glutathione Transferases In Chemoresistance: mentioning

confidence: 99%

Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

Plješa-Ercegovac

Savić-Radojević

Matić

et al. 2018

IJMS

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Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same time regulating signaling pathways involved in cell proliferation and apoptosis. In addition to upregulated GST expression, different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro-drugs. As a result of extensive research, certain GST inhibitors are already tested in clinical trials. Catalytic properties of GST isoenzymes are also exploited in bio-activation of specific pro-drugs, enabling their targeted accumulation in cancer cells with upregulated expression of the appropriate GST isoenzyme. Moreover, the latest approach to increase specificity in treatment of solid tumors is development of GST pro-drugs that are derivatives of conventional anti-cancer drugs. A future perspective is based on the design of new drugs, which would selectively target GST overexpressing cancers more prone to developing chemoresistance, while decreasing side effects in off-target cells.

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Section: The Role Of Glutathione Transferases In Chemoresistance: mentioning

confidence: 99%

Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

Plješa-Ercegovac

Savić-Radojević

Matić

et al. 2018

IJMS

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“…The reservoir consisted 2.2 M (NH 4 ) 2 SO 4 and 100 mM Sodium Acetate, pH 4.75. 1 l of protein was mixed with 1 l L-ascorbate (100 mM), 1 l of a saturated solution of tocopherol succinate (an uncompetitive inhibitor 30 ) and 1 l of reservoir solution.…”

Section: Site-directed Mutagenesis Purification and Crystallization Of Gsto1-1mentioning

confidence: 99%

Structural Insights into the Dehydroascorbate Reductase Activity of Human Omega-Class Glutathione Transferases

Zhou¹,

Brock²,

Liú³

et al. 2012

Journal of Molecular Biology

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The reduction of dehydroascorbate (DHA) to ascorbic acid (AA) is a vital cellular function. The omega-class glutathione transferases (GSTs) catalyze several reductive reactions in cellular biochemistry, including DHA reduction. In humans, two isozymes (GSTO1-1 and GSTO2-2) with significant DHA reductase (DHAR) activity are found, sharing 64% sequence identity. While the activity of GSTO2-2 is higher, it is significantly more unstable in vitro. We report the first crystal structures of human GSTO2-2, stabilized through site-directed mutagenesis and determined at 1.9 Å resolution in the presence and absence of glutathione (GSH). The structure of a human GSTO1-1 has been determined at 1.7 Å resolution in complex with the reaction product AA, which unexpectedly binds in the G-site, where the glutamyl moiety of GSH binds. The structure suggests a similar mode of ascorbate binding in GSTO2-2. This is the first time that a non-GSH-based reaction product has been observed in the G-site of any GST. AA stacks against a conserved aromatic residue, F34 (equivalent to Y34 in GSTO2-2). Mutation of Y34 to alanine in GSTO2-2 eliminates DHAR activity. From these structures and other biochemical data, we propose a mechanism of substrate binding and catalysis of DHAR activity.

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“… The data representing turnover numbers in min −1 have been extracted from the following references: a (Dixon et al, 2002 ); b (Dixon and Edwards, 2010b ); c (Lallement et al, 2014 ); d (Tang and Yang, 2013 ); e (Meux et al, 2011 ); f (Lam et al, 2012 ); g (Meux et al, 2013 ); h (Yamada and Takusagawa, 2007 ); i (Allocati et al, 2000 ); j (Allocati et al, 2008 ); k (Perito et al, 1996 ); l (Allocati et al, 2009 ); m (Board et al, 2000 ); n (Board and Anders, 2007 ); o (Brock et al, 2013 ); p (Sampayo-Reyes and Zakharyan, 2006 ). Nd, not detected; ?…”

Section: Introductionmentioning

confidence: 99%

The still mysterious roles of cysteine-containing glutathione transferases in plants

et al. 2014

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Glutathione transferases (GSTs) represent a widespread multigenic enzyme family able to modify a broad range of molecules. These notably include secondary metabolites and exogenous substrates often referred to as xenobiotics, usually for their detoxification, subsequent transport or export. To achieve this, these enzymes can bind non-substrate ligands (ligandin function) and/or catalyze the conjugation of glutathione onto the targeted molecules, the latter activity being exhibited by GSTs having a serine or a tyrosine as catalytic residues. Besides, other GST members possess a catalytic cysteine residue, a substitution that radically changes enzyme properties. Instead of promoting GSH-conjugation reactions, cysteine-containing GSTs (Cys-GSTs) are able to perform deglutathionylation reactions similarly to glutaredoxins but the targets are usually different since glutaredoxin substrates are mostly oxidized proteins and Cys-GST substrates are metabolites. The Cys-GSTs are found in most organisms and form several classes. While Beta and Omega GSTs and chloride intracellular channel proteins (CLICs) are not found in plants, these organisms possess microsomal ProstaGlandin E-Synthase type 2, glutathionyl hydroquinone reductases, Lambda, Iota and Hemerythrin GSTs and dehydroascorbate reductases (DHARs); the four last classes being restricted to the green lineage. In plants, whereas the role of DHARs is clearly associated to the reduction of dehydroascorbate to ascorbate, the physiological roles of other Cys-GSTs remain largely unknown. In this context, a genomic and phylogenetic analysis of Cys-GSTs in photosynthetic organisms provides an updated classification that is discussed in the light of the recent literature about the functional and structural properties of Cys-GSTs. Considering the antioxidant potencies of phenolic compounds and more generally of secondary metabolites, the connection of GSTs with secondary metabolism may be interesting from a pharmacological perspective.

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Tocopherol esters inhibit human glutathione S-transferase omega.

Cited by 11 publications

References 27 publications

Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

Structural Insights into the Dehydroascorbate Reductase Activity of Human Omega-Class Glutathione Transferases

The still mysterious roles of cysteine-containing glutathione transferases in plants

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