Substituting Nε-thioacetyl-lysine for Nε-acetyl-lysine in Peptide Substrates as a General Approach to Inhibiting Human NAD+-dependent Protein Deacetylases

Fatkins, David G.; Zheng, Wei

doi:10.3390/ijms9010001

Cited by 41 publications

(50 citation statements)

References 36 publications

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“…The 1’-thiol of the 1’- SH - O AADPr product could be detected with thiol reactive reagents ( e.g. Ellman’s reagent) similar to an existing HDAC8 assay that detects thioacetate formed from dethioacetylation (Fatkins et al, 2008). To develop activity-based probes, addition of a tag ( e.g.…”

Section: Small-molecule Modulation Of Sirtuin Activitymentioning

confidence: 99%

Mechanisms and Molecular Probes of Sirtuins

Smith

Hallows

Denu

2008

Chemistry & Biology

128

129

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Summary Sirtuins are critical regulators of many cellular processes including insulin secretion, the cell cycle, and apoptosis. Sirtuins are associated with a variety of age-associated diseases such as type II diabetes, obesity, and Alzheimer’s disease. A thorough understanding of sirtuin chemical mechanisms will aid toward developing novel therapeutics that regulate metabolic disorders and combat associated diseases. In this review, we discuss the unique deacetylase mechanism of sirtuins and how this information might be employed to develop inhibitors and other molecular probes for therapeutic and basic research applications. We also cover physiological regulation of sirtuin activity and how these modes of regulation may be exploited to manipulate sirtuin activity in live cells. Development of molecular probes and drugs that specifically target sirtuins will further understanding of sirtuin biology and potentially afford new treatments of several human diseases.

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Section: Small-molecule Modulation Of Sirtuin Activitymentioning

confidence: 99%

Mechanisms and Molecular Probes of Sirtuins

Smith

Hallows

Denu

2008

Chemistry & Biology

128

129

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show abstract

“…The mode of action of sirtuin (Class III) inhibitors (i.e indoles, hydroxynaphthaldehyde derivatives, splitomicins, suramins and kinase inhibitors) is not fully understood, and much less is known about their biological consequences. 49, 50, 51 In fact, sirtuin inhibitors shown to be effective in lower organisms do not work on human subtypes. 42 Nevertheless, Sirtuin I and 2 specific inhibitors (SEN96 and COMPOUND 6J) are in clinical trials (Table 4) 52, 53 .…”

Section: Introductionmentioning

confidence: 99%

The promise and failures of epigenetic therapies for cancer treatment

Bojang

Ramos

2014

Cancer Treatment Reviews

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Genetic mutations and gross structural defects in the DNA sequence permanently alter genetic loci in ways that significantly disrupt gene function. In sharp contrast, genes modified by aberrant epigenetic modifications remain structurally intact and are subject to partial or complete reversal of modifications that restore the original (i.e. non-diseased) state. Such reversibility makes epigenetic modifications ideal targets for therapeutic intervention. The epigenome of cancer cells is extensively modified by specific hypermethylation of the promoters of tumor suppressor genes relative to the extensive hypomethylation of repetitive sequences, overall loss of acetylation, and loss of repressive marks at microsatellite/repeat regions. In this review, we discuss emerging therapies targeting specific epigenetic modifications or epigenetic modifying enzymes either alone or in combination with other treatment regimens. The limitations posed by cancer treatments that elicit unintended epigenetic modifications that result in exacerbation of tumor progression are also discussed. Lastly, a brief discussion of the specificity restrictions posed by epigenetic therapies and ways to address such limitations is presented.

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“…Two of the zinc-dependent HDAC inhibitors (HDACi) (vorinostat and romidespin) have been approved for cutaneous T-cell lymphoma in the USA. 65 The biological response to HDACi includes the upregulation of p21 in a p53-independent fashion, which causes cell cycle arrest in the G 1 phase. 66 The HDACi butyrate and trichostatin A (TSA) have been shown to stabilize p21 mRNA, repress cyclins A and D, and activate p16 and p27, causing cell cycle arrest.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Targeting chromatin to improve radiation response

Olcina

O'Dell²,

Hammond³

2015

BJR

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Chromatin, the structure formed by the wrapping of approximately 146 base pairs of DNA around an octamer of histones, has a profound impact on numerous DNA-based processes. Chromatin modifications and chromatin remodellers have recently been implicated in important aspects of the DNA damage response including facilitating the initial sensing of the damage as well as subsequent recruitment of repair factors. Radiation is an effective cancer therapy for a large number of tumours, and there is considerable interest in finding approaches that might further increase the efficacy of radiotherapy. The use of radiation leads to the generation of DNA damage and, therefore, agents that can affect the sensing and repair of DNA damage may have an impact on overall radiation efficacy. The chromatin modifications as well as chromatin modifiers that have been associated with the DNA damage response will be summarized in this review. An emphasis will be placed on those processes that can be pharmacologically manipulated with currently available inhibitors. The rationale for the use of these inhibitors in combination with radiation will also be described.

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Substituting Nε-thioacetyl-lysine for Nε-acetyl-lysine in Peptide Substrates as a General Approach to Inhibiting Human NAD+-dependent Protein Deacetylases

Cited by 41 publications

References 36 publications

Mechanisms and Molecular Probes of Sirtuins

Mechanisms and Molecular Probes of Sirtuins

The promise and failures of epigenetic therapies for cancer treatment

Targeting chromatin to improve radiation response

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