ArticleBiochemistry2016
General Base-General Acid Catalysis in Human Histone Deacetylase 8.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- HDAC11 Deacetylates BRAF to Regulate Kinase Activity and Cell Proliferation.ACS chemical biology · 2025Article
- Review
- Identification of SIRT3 as an eraser of H4K16la.iScience · 2023Article
- Lysine Deacetylase Substrate Selectivity: Distinct Interaction Surfaces Drive Positive and Negative Selection for Residues Following Acetyllysine.Biochemistry · 2023Article
- Endogenous expression of inactive lysine deacetylases reveals deacetylation-dependent cellular mechanisms.PloS one · 2023Article
- Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations.ACS omega · 2022Article
- Computational Analysis of Histone Deacetylase 10 Mechanism by the ONIOM Method: A Complementary Approach to X-ray and Kinetics Studies.ACS omega · 2022Article
- Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.Science advances · 2022Article
- Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Aromatic side-chain flips orchestrate the conformational sampling of functional loops in human histone deacetylase 8.Chemical science · 2021Article
- How enzymes harness highly unfavorable proton transfer reactions.Protein science : a publication of the Protein Society · 2021Review
- Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders.Journal of structural biology · 2021Article
- X-ray Crystallographic Snapshots of Substrate Binding in the Active Site of Histone Deacetylase 10.Biochemistry · 2021Article
- Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine.Epigenetics insights · 2021Article
- Bifunctional HDAC Therapeutics: One Drug to Rule Them All?Molecules (Basel, Switzerland) · 2020Review
- Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics.Frontiers in molecular biosciences · 2020Article
- Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases.Current opinion in structural biology · 2019Review
- HDAC3 and HDAC8 are required for cilia assembly and elongation.Biology open · 2019Article
- Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview.Molecules (Basel, Switzerland) · 2019Review
- Preparation of a new construct of human histone deacetylase 8 for the crystallization of enzyme-inhibitor complexes.Methods in enzymology · 2019Article
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7 authors.
Funding
Abstract
Histone deacetylases (HDACs) regulate cellular processes such as differentiation and apoptosis and are targeted by anticancer therapeutics in development and in the clinic. HDAC8 is a metal-dependent class I HDAC and is proposed to use a general acid-base catalytic pair in the mechanism of amide bond hydrolysis. Here, we report site-directed mutagenesis and enzymological measurements to elucidate the catalytic mechanism of HDAC8. Specifically, we focus on the catalytic function of Y306 and the histidine-aspartate dyads H142-D176 and H143-D183. Additionally, we report X-ray crystal structures of four representative HDAC8 mutants: D176N, D176N/Y306F, D176A/Y306F, and H142A/Y306F. These structures provide a useful framework for understanding enzymological measurements. The pH dependence of kcat/KM for wild-type Co(II)-HDAC8 is bell-shaped with two pKa values of 7.4 and 10.0. The upper pKa reflects the ionization of the metal-bound water molecule and shifts to 9.1 in Zn(II)-HDAC8. The H142A mutant has activity 230-fold lower than that of wild-type HDAC8, but the pKa1 value is not altered. Y306F HDAC8 is 150-fold less active than the wild-type enzyme; crystal structures show that Y306 hydrogen bonds with the zinc-bound substrate carbonyl, poised for transition state stabilization. The H143A and H142A/H143A mutants exhibit activity that is >80000-fold lower than that of wild-type HDAC8; the buried D176N and D176A mutants have significant catalytic effects, with more subtle effects caused by D183N and D183A. These enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization.
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