ArticleJournal of the American Chemical Society2017
Enzyme Architecture: Modeling the Operation of a Hydrophobic Clamp in Catalysis by Triosephosphate Isomerase.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Hydrophobic interactions of a substrate with L193 on the flexible substrate-binding loop contribute to 3α-hydroxysteroid dehydrogenase/carbonyl reductase catalytic efficiency.Protein science : a publication of the Protein Society · 2026Article
- WatCon: A Python Tool for Analysis of Conserved Water Networks Across Protein Families.JACS Au · 2025Article
- The Role of Protein Side Chains in Enzyme-Activating Conformational Changes: Lessons from Studies on Variant Enzymes.Chemical reviews · 2025Review
- Glycerol 3-Phosphate Dehydrogenase Catalyzed Hydride Transfer: Enzyme Activation by Cofactor Pieces.Biochemistry · 2024Article
- Glycerol 3-Phosphate Dehydrogenase: Role of the Protein Conformational Change in Activation of a Readily Reversible Enzyme-Catalyzed Hydride Transfer Reaction.Biochemistry · 2024Article
- The Role of Asn11 in Catalysis by Triosephosphate Isomerase.Biochemistry · 2023Article
- Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1.Antioxidants (Basel, Switzerland) · 2022Article
- Evolution of Enzyme Function and the Development of Catalytic Efficiency: Triosephosphate Isomerase, Jeremy R. Knowles, and W. John Albery.Biochemistry · 2021Article
- How enzymes harness highly unfavorable proton transfer reactions.Protein science : a publication of the Protein Society · 2021Review
- Insight into Inhibitory Mechanism of PDE4D by Dietary Polyphenols Using Molecular Dynamics Simulations and Free Energy Calculations.Biomolecules · 2021Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Ground-State Destabilization by Active-Site Hydrophobicity Controls the Selectivity of a Cofactor-Free Decarboxylase.Journal of the American Chemical Society · 2020Article
- Master curve of boosted diffusion for 10 catalytic enzymes.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-phosphate Dehydrogenase.ACS catalysis · 2020Article
- Enhancing aChemical science · 2020Article
- The role of ligand-gated conformational changes in enzyme catalysis.Biochemical Society transactions · 2019Review
- Uncovering the Role of Key Active-Site Side Chains in Catalysis: An Extended Brønsted Relationship for Substrate Deprotonation Catalyzed by Wild-Type and Variants of Triosephosphate Isomerase.Journal of the American Chemical Society · 2019Article
- Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis.Journal of the American Chemical Society · 2019Article
- Enzyme Architecture: Breaking Down the Catalytic Cage that Activates Orotidine 5'-Monophosphate Decarboxylase for Catalysis.Journal of the American Chemical Society · 2018Article
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Authors and funding
8 authors.
Funding
Abstract
Triosephosphate isomerase (TIM) is a proficient catalyst of the reversible isomerization of dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde phosphate (GAP), via general base catalysis by E165. Historically, this enzyme has been an extremely important model system for understanding the fundamentals of biological catalysis. TIM is activated through an energetically demanding conformational change, which helps position the side chains of two key hydrophobic residues (I170 and L230), over the carboxylate side chain of E165. This is critical both for creating a hydrophobic pocket for the catalytic base and for maintaining correct active site architecture. Truncation of these residues to alanine causes significant falloffs in TIM's catalytic activity, but experiments have failed to provide a full description of the action of this clamp in promoting substrate deprotonation. We perform here detailed empirical valence bond calculations of the TIM-catalyzed deprotonation of DHAP and GAP by both wild-type TIM and its I170A, L230A, and I170A/L230A mutants, obtaining exceptional quantitative agreement with experiment. Our calculations provide a linear free energy relationship, with slope 0.8, between the activation barriers and Gibbs free energies for these TIM-catalyzed reactions. We conclude that these clamping side chains minimize the Gibbs free energy for substrate deprotonation, and that the effects on reaction driving force are largely expressed at the transition state for proton transfer. Our combined analysis of previous experimental and current computational results allows us to provide an overview of the breakdown of ground-state and transition state effects in enzyme catalysis in unprecedented detail, providing a molecular description of the operation of a hydrophobic clamp in triosephosphate isomerase.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.