ArticlePloS one2013
The interaction of the chemotherapeutic drug chlorambucil with human glutathione transferase A1-1: kinetic and structural analysis.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 36 citations in OpenAlex.
- Functional Characterization and Inhibition Analysis of a Glutathione Transferase fromPharmaceuticals (Basel, Switzerland) · 2026Article
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Biochemical characterization and gene structure analysis of the 24-kDa glutathione transferase sigma from Taenia solium.FEBS open bio · 2024Article
- The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates.Antioxidants (Basel, Switzerland) · 2023Review
- Glutathione: Lights and Shadows in Cancer Patients.Biomedicines · 2023Review
- A Key Role in Catalysis and Enzyme Thermostability of a Conserved Helix H5 Motif of Human Glutathione Transferase A1-1.International journal of molecular sciences · 2023Article
- Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1.Antioxidants (Basel, Switzerland) · 2022Article
- Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect.Clinical pharmacokinetics · 2022Review
- Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1-1.Biomolecules · 2022Article
- Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation.Molecules (Basel, Switzerland) · 2022Review
- Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies.PloS one · 2022Article
- The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes.Molecules (Basel, Switzerland) · 2021Article
- The analysis of GSTA1 promoter genetic and functional diversity of human populations.Scientific reports · 2021Article
- ESR Resolves the C Terminus Structure of the Ligand-free Human Glutathione S-Transferase A1-1.Biophysical journal · 2018Article
- On the Inhibition Mechanism of Glutathione Transferase P1 by Piperlongumine. Insight From Theory.Frontiers in chemistry · 2018Article
- Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity.Monatshefte fur chemie · 2018Article
- SilencingOncology letters · 2017Article
- Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 Å resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated.
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