ArticleJournal of the American Chemical Society2010
A proton-shuttle reaction mechanism for histone deacetylase 8 and the catalytic role of metal ions.
Article in Journal of the American Chemical Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 131 citations in OpenAlex.
- Structure-guided identification of histone deacetylase 11 inhibitors for targeted chemotherapy through long-timescale molecular dynamics simulation.Journal of molecular modeling · 2026Article
- Preclinical Characterization of SDFZ-8, a Highly Potent HDAC1 Inhibitor, for Cancer Immunotherapy.MedComm · 2025Article
- Unraveling the Catalytic Mechanism and Substrate Selectivity of HDAC10: A Dual-Filter Approach for Polyamine Deacetylation.JACS Au · 2025Article
- Crucial Structural Understanding for Selective HDAC8 Inhibition: Common Pharmacophores, Molecular Docking, Molecular Dynamics, and Zinc Binder Analysis of Selective HDAC8 Inhibitors.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2025Review
- The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Enzymatic-related network of catalysis, polyamine, and tumors for acetylpolyamine oxidase: from calculation to experiment.Chemical science · 2024Article
- In the quest for histone deacetylase inhibitors: current trends in the application of multilayered computational methods.Amino acids · 2023Review
- Intrinsic structural dynamics dictate enzymatic activity and inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Understanding catalytic synergy in dinuclear polymerization catalysts for sustainable polymers.Nature communications · 2023Article
- Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6).ACS chemical biology · 2023Article
- AcceleratingThe journal of physical chemistry. B · 2022Article
- Computational Analysis of Histone Deacetylase 10 Mechanism by the ONIOM Method: A Complementary Approach to X-ray and Kinetics Studies.ACS omega · 2022Article
- Electric Fields in Catalysis: From Enzymes to Molecular Catalysts.ACS catalysis · 2021Article
- Aromatic side-chain flips orchestrate the conformational sampling of functional loops in human histone deacetylase 8.Chemical science · 2021Article
- An in silico mechanistic insight into HDAC8 activation facilitates the discovery of new small-molecule activators.Bioorganic & medicinal chemistry · 2020Article
- A distal regulatory region of a class I human histone deacetylase.Nature communications · 2020Article
- Accelerated computation of free energy profile at ab initio quantum mechanical/molecular mechanical accuracy via a semi-empirical reference potential. II. Recalibrating semi-empirical parameters with force matching.Physical chemistry chemical physics : PCCP · 2019Article
- Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview.Molecules (Basel, Switzerland) · 2019Review
- Insights into the stereoselectivity of human SETD7 methyltransferase.RSC advances · 2019Article
- Two symmetric arginine residues play distinct roles inProceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Zinc-dependent histone deacetylase 8 (HDAC8) catalyzes the removal of acetyl moieties from histone tails, and is critically involved in regulating chromatin structure and gene expression. The detailed knowledge of its catalytic process is of high importance since it has been established as a most promising target for the development of new antitumor drugs. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations and umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have provided further evidence against the originally proposed general acid-base catalytic pair mechanism for Zinc-dependent histone deacetylases. Instead, our results indicated that HDAC8 employs a proton-shuttle catalytic mechanism, in which a neutral His143 first serves as the general base to accept a proton from the zinc-bound water molecule in the initial rate-determining nucleophilic attack step, and then shuttles it to the amide nitrogen atom to facilitate the cleavage of the amide bond. During the deacetylation process, the Zn(2+) ion changes its coordination mode and plays multiple catalytic roles. For the K(+) ion, which is located about 7 A from the catalytic Zn(2+) ion and conserved in class I and II HDACs, our simulations indicated that its removal would lead to the different transition state structure and a higher free energy reaction barrier for the rate-determining step. It is found that the existence of this conserved K(+) ion would enhance the substrate binding, increase the basicity of His143, strengthen the catalytic role of zinc ion, and improve the transition state stabilization by the enzyme environment.
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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.