HDAC11, an emerging therapeutic target for metabolic disorders

Chen, Huizhen; Xie, Chunguang; Qiu, Chen; Zhuang, Songlin

doi:10.3389/fendo.2022.989305

Cited by 20 publications

(11 citation statements)

References 142 publications

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“…On the contrary, HDAC6 and HDAC10, which are representative of Class IIb, are expressed in the heart, skeletal muscle and brain [20], and in the liver, spleen, and kidney, respectively [21]. HDAC11, the only Class IV enzyme, shows a high catalytic efficiency as a fatty acid acylase and is present in the brain, heart, kidney, testis, and skeletal muscle [22].…”

Section: Hdac Structure and Functionmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

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Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

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Section: Hdac Structure and Functionmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…The only Class IV enzyme, HDAC11, is expressed in the brain, heart, kidney, testis, and skeletal muscle, and it is localized in the nucleus. HDAC11 is known for its high catalytic efficiency as a fatty acid acylase and possesses a catalytic activity center that is common to both Class I and Class II enzymes (Chen, Xie, et al, 2022).…”

Section: Histone Deacetylasementioning

confidence: 99%

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Han,

Feng,

et al. 2023

Chem Biol Drug Des

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Epigenetic regulation of genes through posttranslational regulation of proteins is a well‐explored approach for disease treatment, particularly in cancer chemotherapy. Histone deacetylases have shown significant potential as effective drug targets in therapeutic studies aiming to restore epigenetic normality in oncology. Besides their role in modifying histones, histone deacetylases can also catalyze the deacetylation of various nonhistone proteins and participate in the regulation of multiple biological processes. This paper provides a review of the classification, structure, and functional characteristics of the four classes of human histone deacetylases. The increasing abundance of structural information on HDACs has led to the gradual elucidation of structural differences among subgroups and subtypes. This has provided a reasonable explanation for the selectivity of certain HDAC inhibitors. Currently, the US FDA has approved a total of six HDAC inhibitors for marketing, primarily for the treatment of various hematological tumors and a few solid tumors. These inhibitors all have a common pharmacodynamic moiety consisting of three parts: CAP, ZBG, and Linker. In this paper, the structure–effect relationship of HDAC inhibitors is explored by classifying the six HDAC inhibitors into three main groups: isohydroxamic acids, benzamides, and cyclic peptides, based on the type of inhibitor ZBG. However, there are still many questions that need to be answered in this field. In this paper, the structure‐functional characteristics of HDACs and the structural information of the pharmacophore model and enzyme active region of HDAC is are considered, which can help to understand the inhibition mechanism of the compounds as well as the rational design of HDACs. This paper integrates the structural‐functional characteristics of HDACs as well as the pharmacophore model of HDAC is and the structural information of the enzymatic active region, which not only contributes to the understanding of the inhibition mechanism of the compounds, but also provides a basis for the rational design of HDAC inhibitors.

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“…There are four classes of HDACs, all of which are complexed with proteins that exhibit low substrate specificity ( 55 ). HDACs are classified into four major classes: HDAC class I (HDAC 1, 2, 3, and 8), HDAC class IIa (HDAC 4, 5, 7, and 9), HDAC class IIb (HDAC 6 and 10), HDAC class III (SIRT1-7), and HDAC class IV (HDAC11) ( 6 , 56 ). HDACs cause chromatin enrichment by deacetylating histones, blocking access to DNA, and inhibiting transcription ( 57 ).…”

Section: Histone Deacetylase In Heart Diseasementioning

confidence: 99%

Roles of histone acetylation sites in cardiac hypertrophy and heart failure

Funamoto

Imanishi

Tsuchiya

et al. 2023

Front. Cardiovasc. Med.

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Heart failure results from various physiological and pathological stimuli that lead to cardiac hypertrophy. This pathological process is common in several cardiovascular diseases and ultimately leads to heart failure. The development of cardiac hypertrophy and heart failure involves reprogramming of gene expression, a process that is highly dependent on epigenetic regulation. Histone acetylation is dynamically regulated by cardiac stress. Histone acetyltransferases play an important role in epigenetic remodeling in cardiac hypertrophy and heart failure. The regulation of histone acetyltransferases serves as a bridge between signal transduction and downstream gene reprogramming. Investigating the changes in histone acetyltransferases and histone modification sites in cardiac hypertrophy and heart failure will provide new therapeutic strategies to treat these diseases. This review summarizes the association of histone acetylation sites and histone acetylases with cardiac hypertrophy and heart failure, with emphasis on histone acetylation sites.

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HDAC11, an emerging therapeutic target for metabolic disorders

Cited by 20 publications

References 142 publications

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Roles of histone acetylation sites in cardiac hypertrophy and heart failure

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