ArticleThe Journal of biological chemistry2013
Enzymatic detoxication, conformational selection, and the role of molten globule active sites.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- The Ensemble Basis of Allostery and Function: Insights from Models of Local Unfolding.Journal of molecular biology · 2025Review
- Protein structure-function continuum model: Emerging nexuses between specificity, evolution, and structure.Protein science : a publication of the Protein Society · 2024Review
- Direct observation of negative cooperativity in a detoxification enzyme at the atomic level by Electron Paramagnetic Resonance spectroscopy and simulation.Protein science : a publication of the Protein Society · 2023Article
- Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4.Biomolecules · 2023Article
- Pre-Molten, Wet, and Dry Molten Globules en Route to the Functional State of Proteins.International journal of molecular sciences · 2023Review
- Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1-1.Biomolecules · 2022Article
- Loosely-packed dynamical structures with partially-melted surface being the key for thermophilic argonaute proteins achieving high DNA-cleavage activity.Nucleic acids research · 2022Article
- Mechanisms of ligand binding.Biophysics reviews · 2020Review
- Promiscuous Ribozymes and Their Proposed Role in Prebiotic Evolution.Chemical reviews · 2020Review
- Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters.The FEBS journal · 2020Review
- Conformational selection turns on phenylalanine hydroxylase.The Journal of biological chemistry · 2018Article
- Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale.The Journal of biological chemistry · 2018Article
- ESR Resolves the C Terminus Structure of the Ligand-free Human Glutathione S-Transferase A1-1.Biophysical journal · 2018Article
- Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation.Biochemistry · 2017Article
- Polysaccharides fromBioMed research international · 2017Article
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
- Comparison of epsilon- and delta-class glutathione S-transferases: the crystal structures of the glutathione S-transferases DmGSTE6 and DmGSTE7 from Drosophila melanogaster.Acta crystallographica. Section D, Biological crystallography · 2015Article
- Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity.The Journal of steroid biochemistry and molecular biology · 2015Review
- An evolutionary biochemist's perspective on promiscuity.Trends in biochemical sciences · 2015Article
- Multiple conformational selection and induced fit events take place in allosteric propagation.Biophysical chemistry · 2014Review
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Authors and funding
5 authors.
Funding
Abstract
The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning "induced fit" versus "conformational selection" has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1-1 (GSTA1-1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1-1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that "local" molten globule behavior optimizes detoxication enzymes.
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