Catalytic Activity and Inhibition of Human Histone Deacetylase 8 Is Dependent on the Identity of the Active Site Metal Ion

Gantt, Stephanie L.; Gattis, Samuel G.; Fierke, Carol A.

doi:10.1021/bi060212u

Cited by 139 publications

(270 citation statements)

References 65 publications

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“…The deacetylase reaction requires a transition metal ion and, although the HDACs are typically considered Zn 2+ -containing enzymes, the metal ion in the active site, as demonstrated by the X-ray structure of HDAC8, can be substituted by Fe 2+ , Co 2+ and Mn 2+ [244]. This is consistent with the hypothesis that HDAC8 could function as a Fe 2+ -catalyzing enzyme in vivo ( Table 1) [245]. The overall fold of other recently crystallized HDACs is similar to the previously reported structures, even if several key features distinguish the various classes.…”

Section: Class I Ii and Iv Deacetylasessupporting

confidence: 78%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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Section: Class I Ii and Iv Deacetylasessupporting

confidence: 78%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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“…An alternative twostate ensemble model for binding was also used to assess catalytic efficacy ( Figure S2), which agreed qualitatively with the current simple model for a reasonable range of binding affinities. This model qualitatively predicts the trend seen in catalytic activity for these metals in experiment, though the trend is slightly perturbed, 37 either due to experimental errors or inaccuracies of our model. Co 2+ is predicted as the most active, followed by Zn 2+ and Fe 2+ .…”

Section: +supporting

confidence: 57%

Histone Deacetylase 8: Characterization of Physiological Divalent Metal Catalysis

et al. 2016

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Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from histones, resulting in gene silencing. Overexpression of HDACs is associated with cancer, and their inhibitors are of particular interest as chemotherapeutics. However, HDACs remain a target of mechanistic debate. HDAC class 8 is the most studied HDAC, and of particular importance due to its human oncological relevance. HDAC8 has traditionally been considered to be a Zn-dependent enzyme. However, recent experimental assays have challenged this assumption and shown that HDAC8 is catalytically active with a variety of different metals, and that it may be a Fedependent enzyme in vivo. We studied two opposing mechanisms utilizing a series of divalent metal ions in physiological abundance (Zn ). Extensive sampling of the entire protein with different bound metals was done with the mixed quantum-classical QM/DMD method. Density functional theory (DFT) on an unusually large cluster model was used to describe the active site and reaction mechanism. We have found that the reaction profile of HDAC8 is similar among all metals tested, and follows one of the previously published mechanisms, but the rate-determining step is different from the one previously claimed. We further provide a scheme for estimating the metal binding affinities to the protein. We use the quantum theory of atoms in molecules (QTAIM) to understand the different binding affinities for each metal in HDAC8 as well as the ability of each metal to bind and properly orient the substrate for deacetylation. The combination of this data with the catalytic rate constants is required to reproduce the experimentally observed trend in metal-depending performance. We predict Co 2+ and Zn 2+ to be the most active metals in HDAC8, followed by Fe 2+ , and Mn 2+ and Mg 2+ to be the least active. ■ INTRODUCTIONThe acetylation of lysine residues is an important reversible post-translational modification that modulates protein function, affecting a variety of cellular processes. 1−5 Proteomic surveys 6−8 have identified acetyl-lysine residues in diverse groups of proteins, including transcription factors, 9,10 cell signaling proteins, 11 metabolic enzymes (most prominently acetyl-CoA synthase 12−14 ), structural proteins in the cytoskeleton, 15,16 and HIV viral proteins. 17,18 One of the first discovered examples of lysine acetylation was that occurring in histones, 19,20 the predominant protein components of chromatin. Acetylation of histones has been linked to gene regulation: the addition of an acetyl moiety to histone lysine residues gives rise to an open chromatin structure that facilitates DNA transcription, while the removal of acetyl from histone acetyl-lysine residues is associated with a closed chromatin structure, transcriptional repression, and gene silencing. 21 The enzymes responsible for the addition and removal of acetyl groups are known as histone acetyltransferases (HATs) and histone deacetylases (HDACs) 22−26 for historical reasons, although it is now recog...

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“…Class I, II, and IV HDACs share a similar catalytic mechanism that involves the coordination of a divalent metal ion. Initial studies suggested that the catalytic metal was Zn(II), but recent findings have indicated that Fe(II) may play a more significant role (86). Regardless of the nature of the divalent ion, mechanistic studies indicate that the enzyme-coordinated metal and a conserved tyrosine (for Class I, IIb, and IV) or histidine (Class IIa) polarizes the carbonyl oxygen, priming the carbonyl carbon of the acetyl group.…”

Section: B Histone Acetylationmentioning

confidence: 99%

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Cyr

Domann

2011

Antioxidants & Redox Signaling

246

168

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Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD + , S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551-589.

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Catalytic Activity and Inhibition of Human Histone Deacetylase 8 Is Dependent on the Identity of the Active Site Metal Ion

Cited by 139 publications

References 65 publications

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Histone Deacetylase 8: Characterization of Physiological Divalent Metal Catalysis

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

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