Kinetics and Comparative Reactivity of Human Class I and Class IIb Histone Deacetylases
Abstract
Histone deacetylase (HDAC) enzymes modulate gene expression through the deacetylation of acetylated lysine residues on histone proteins. They operate in biological systems as part of multiprotein corepressor complexes. To understand the reactivity of isolated HDACs and the contribution of cofactor binding to reactivity, the reaction kinetics of isolated, recombinant human HDACs 1, 2, 3, 6, 8, and 10 were measured using a novel, continuous protease-coupled enzyme assay. Values of k(cat) and k(cat)/K(m) and the pH dependence of these values were determined for the reactions of each isozyme with acetyl-Gly-Ala-(N(epsilon)-acetyl-Lys)-AMC. Values of k(cat) spanned the range of 0.006-2.8 s(-1), and k(cat)/K(m) values ranged from 60 to 110000 M(-1) s(-1). The pH profiles for both k(cat) and k(cat)/K(m) were bell-shaped for all of the HDAC isozymes, with pH optima at approximately pH 8. Values of K(i) for the inhibitor trichostatin A were determined for each isozyme. The inhibition constants were generally similar for all HDAC isozymes, except that the value for HDAC8 was significantly higher than that for the other isozymes. The reaction of HDAC8 with an alternative substrate was performed to assess the steric requirements of the HDAC8 active site, and the effect of phosphorylation on HDAC1 activity was examined. The results are discussed in terms of the biological roles of the HDAC enzymes and the proposed reaction mechanism of acetyllysine hydrolysis by these enzymes.
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HDAC8 has the lowest kcat/Km value on acetyl lysine peptides (~60±7 M−1S−1) when compared to other HDACs tested.
“Overall, HDAC8 has lowest kcat/Km value on acetyl lysine peptides (~60±7 M−1S−1) when compared to other HDACs tested.11”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [11]
Previous kinetics studies show that all HDACs have Km values between 20-40 μM, except HDAC8 which has a significantly higher Km (>200 μM).
“Previous kinetics studies of different HDACs (HDAC1, 2, 3, 6, 8 and 10)11 show that all of the HDACs have Km values between 20-40 μM, except for HDAC8 which has a significantly higher Km (>200 μM).”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [11]
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- Authors
- Schultz, B. E., Misialek, S., Wu, J., Tang, J., Conn, M. T., Tahilramani, R., & Wong, L.
- Affiliations
- Celera, 180 Kimball Way, South San Francisco, California 94080
- Corresponding author
- Schultz, Brian E.
- ORCID
- Schultz, Brian E.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2004-08-01
- Volume
- 43
- Issue
- 34
- Pages
- 11083-11091
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2044216740
- Cited by
- 88
- References
- 13
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 4
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone deacetylase, HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, HDAC10, enzyme kinetics, catalytic efficiency, pH dependence, corepressor complex, histone deacetylation
- MeSH terms
- Histone Deacetylase 6, Histone Deacetylase 3, Binding Sites, Binding, Competitive, Coumarins, Enzyme Activation, Enzyme Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Isoenzymes, Kinetics, Lysine, Phosphorylation, Recombinant Proteins, Repressor Proteins, Substrate Specificity, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors
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