scholarly journals A Novel Motif in Fungal Class 1 Histone Deacetylases Is Essential for Growth and Development ofAspergillus

2010 ◽  
Vol 21 (2) ◽  
pp. 345-353 ◽  
Author(s):  
Martin Tribus ◽  
Ingo Bauer ◽  
Johannes Galehr ◽  
Gudrun Rieser ◽  
Patrick Trojer ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Filamentous Fungi ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
C Terminus ◽  
Promising Target ◽  
Class 1 ◽  
Core Histones ◽  
Agricultural Applications ◽  
Eukaryotic Organisms

Acetylation of the N-terminal tails of core histones is an important regulatory mechanism in eukaryotic organisms. In filamentous fungi, little is known about the enzymes that modify histone tails. However, it is increasingly evident that histone deacetylases and histone acetyltransferases are critical factors for the regulation of genes involved in fungal pathogenicity, stress response, and production of secondary metabolites such as antibiotics or fungal toxins. Here, we show that depletion of RpdA, an RPD3-type histone deacetylase of Aspergillus nidulans, leads to a pronounced reduction of growth and sporulation of the fungus. We demonstrate that a so far unnoticed motif in the C terminus of fungal RpdA histone deacetylases is required for the catalytic activity of the enzyme and consequently is essential for the viability of A. nidulans. Moreover, we provide evidence that this motif is also crucial for the survival of other, if not all, filamentous fungi, including pathogens such as Aspergillus fumigatus or Cochliobolus carbonum. Thus, the extended C terminus of RpdA-type enzymes represents a promising target for fungal-specific histone deacetylase-inhibitors that may have potential as novel antifungal compounds with medical and agricultural applications.

scholarly journals Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

2018 ◽  
Vol 92 (6) ◽  
Author(s):  
Thomas D. Zaikos ◽  
Mark M. Painter ◽  
Nadia T. Sebastian Kettinger ◽  
Valeri H. Terry ◽  
Kathleen L. Collins
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Hiv Latency ◽  
Bryostatin 1 ◽  
Hiv Reservoir ◽  
Class 1

ABSTRACTCombinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of protein kinase C (PKC) agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of proviral factors regulated by non-class 1 histone deacetylases. Here, we show that class 1-selective agents used alone or with the PKC agonist bryostatin-1 induced more HIV protein expression per infected cell. In addition, the combination of entinostat and bryostatin-1 induced viral outgrowth, whereas bryostatin-1 combinations with pan-HDIs did not. When class 1-selective HDIs were used in combination with pan-HDIs, the amount of viral protein expression and virus outgrowth resembled that of pan-HDIs alone, suggesting that pan-HDIs inhibit robust gene expression induced by class 1-selective HDIs. Consistent with this, pan-HDI-containing combinations reduced the activity of NF-κB and Hsp90, two cellular factors necessary for potent HIV protein expression, but did not significantly reduce overall cell viability. An assessment of viral clearance fromin vitrocultures indicated that maximal protein expression induced by class 1-selective HDI treatment was crucial for reservoir clearance. These findings elucidate the limitations of current approaches and provide a path toward more effective strategies to eliminate the HIV reservoir.IMPORTANCEDespite effective antiretroviral therapy, HIV evades eradication in a latent form that is not affected by currently available drug regimens. Pharmacologic latency reversal that leads to death of cellular reservoirs has been proposed as a strategy for reservoir elimination. Because histone deacetylases (HDACs) promote HIV latency, HDAC inhibitors have been a focus of HIV cure research. However, many of these inhibitors broadly affect multiple classes of HDACs, including those that promote HIV gene expression (class 1 HDACs). Here, we demonstrate that targeted treatment with class 1-selective HDAC inhibitors induced more potent HIV latency reversal than broadly acting agents. Additionally, we provide evidence that broadly acting HDIs are limited by inhibitory effects on non-class 1 HDACs that support the activity of proviral factors. Thus, our work demonstrates that the use of targeted approaches to induce maximum latency reversal affords the greatest likelihood of reservoir elimination.

scholarly journals Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 717 ◽  
Author(s):  
Na Zhao ◽  
Feifei Yang ◽  
Lina Han ◽  
Yuhua Qu ◽  
Di Ge ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Immunoblot Analysis ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Human Cancer Cell Lines

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

scholarly journals Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

2015 ◽  
Vol 22 (2) ◽  
pp. 273-284 ◽  
Author(s):  
Yunfei Wang ◽  
Ryan L. Stowe ◽  
Christie E. Pinello ◽  
Guimei Tian ◽  
Franck Madoux ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Class I

scholarly journals Design and Synthesis of Small Molecules Based on a Substructural Analysis of the Histone Deacetylase Inhibitors TSA and SAHA

2011 ◽  
Vol 8 (3) ◽  
pp. 1394-1400
Author(s):  
Lynda Ekou ◽  
Tchirioua Ekou ◽  
Javier Garcia ◽  
Isabelle Opalinski ◽  
Jean Pierre Gesson
Keyword(s):  
Small Molecules ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Suberoylanilide Hydroxamic Acid ◽  
Considerable Potential ◽  
Design And Synthesis

Inhibitors of histone deacetylases (HDACs) are patent inducers of differentiation and bear considerable potential as drugs for chemoprevention and treatment of cancer. In this paper, we have investigated three synthetic, inhibitors A1a,b, A2a. Analogue hybrid trichostatine A (TSA), suberoylanilide hydroxamic acid SAHA, in order to seek new histone deacetylases (HDACs) inhibitors.

scholarly journals Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine

2021 ◽  
Vol 14 ◽  
pp. 251686572110656
Author(s):  
Harrison Yoo ◽  
Gregory A Polsinelli
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Decanoic Acid ◽  
Fatty Acyl ◽  
Peptide Substrate ◽  
Medium Chain ◽  
Histone Deacetylase 8 ◽  
Lysine Residues

Histone deacetylases (HDACs) catalyze the removal of Ɛ-acetyl-lysine residues of histones via hydrolysis. Removal of acetyl groups results in condensation of chromatin structure and alteration of gene expression by repression. HDACs are considered targets for the treatment of cancer due to their role in regulating transcription. HDAC8 inhibition may be an important anti-proliferative factor for histone deacetylase inhibitors on cancer cells and may give rise to the progression of apoptosis. HDAC8 activity was analyzed with various peptides where the target lysine is modified with medium-chain fatty acyl group. Kinetic data were determined for each p53 peptide substrate. The results suggest that there was HDAC8 deacetylase activity on peptide substrate as well as deacylase activity with acylated peptide substrate variants. HDAC8 inhibition by hexanoic and decanoic acid was also examined. The Ki for hexanoic and decanoic acid were determined to be 2.35 ± 0.341 and 4.48 ± 0.221 mM, respectively.

scholarly journals Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

2019 ◽  
Vol 5 (2) ◽  
pp. 235-253
Author(s):  
Kajal Thapa ◽  
Savir Kumar ◽  
Anurag Sharma ◽  
Sandeep Arora ◽  
Amarjot Kaur Grewal ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Epigenetic Modification ◽  
Histone Acetyltransferases ◽  
Lysine Acetylation ◽  
Histone Deacetylases Inhibitors ◽  
Nucleosomal Array ◽  
Key Factor

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.

scholarly journals An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme

2007 ◽  
Vol 401 (3) ◽  
pp. 659-665 ◽  
Author(s):  
Kristin Moreth ◽  
Daniel Riester ◽  
Christian Hildmann ◽  
René Hempel ◽  
Dennis Wegener ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Esterase Activity ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Hdac Inhibitors ◽  
Porcine Liver ◽  
Drug Candidates ◽  
Core Histones ◽  
Ic50 Values

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of ϵ-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration.

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