Nε-Thioacetyl-lysine: A multi-facet functional probe for enzymatic protein lysine Nε-deacetylation

Fatkins, David G.; Monnot, Andrew D.; Zheng, Wei

doi:10.1016/j.bmcl.2006.04.075

Cited by 103 publications

(141 citation statements)

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“…Previously, our laboratory 18,19 and that of Denu 20 established N e -thioacetyl-lysine as a powerful and general catalytic mechanism-based sirtuin inhibitory warhead, thus starting the field of developing sirtuin inhibitors with a variety of different catalytic mechanism-based inhibitory warheads. 21 The key to the working of such an inhibitor is the sirtuin-catalyzed formation of one or more stalled intermediates along a catalytic coordinate.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 However, our current functional and especially pharmacological understanding of the sirtuin-catalyzed deacylation reaction is still limited. One attributing factor to this is the lack of sufficient potency, selectivity, or cell permeability for the sirtuin chemical modulators that have been used in the functional and pharmacological interrogation of the sirtuin deacylation reaction.Previously, our laboratory 18,19 and that of Denu 20 established N e -thioacetyl-lysine as a powerful and general catalytic mechanism-based sirtuin inhibitory warhead, thus starting the field of developing sirtuin inhibitors with a variety of different catalytic mechanism-based inhibitory warheads. 21 The key to the working of such an inhibitor is the sirtuin-catalyzed formation of one or more stalled intermediates along a catalytic coordinate.…”

mentioning

confidence: 99%

“…2). 18,20,22 Based on two tripeptidic lead compounds (1 and 2, Fig. 3) with a central N e -thioacetyl-lysine that were found previously by our laboratory to be potent yet nearly non-selective human SIRT1/2/3 inhibitors, 23 in the current study we prepared 20 derivatives with http://dx.…”

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confidence: 99%

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Human SIRT3 tripeptidic inhibitors containing Nε-thioacetyl-lysine

Chen

Wang

Huang

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Human SIRT3 tripeptidic inhibitors containing Nε-thioacetyl-lysine

Chen

Wang

Huang

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…100,110 It was shown that thioacetyl-lysine interferes with this reaction pathway and constitutes a mechanism-based sirtuin inhibitor. 100,111 The sulfur of the thioacetyl group attacks the C1' carbon of NAD + , but forms the thioimidate product 28, which cannot be processed by the enzyme (Figure 4h) …”

Section: -105mentioning

confidence: 99%

Probing Chromatin-modifying Enzymes with Chemical Tools

Fischle

Schwarzer

2016

ACS Chem. Biol.

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2 Glossary section/Key words:Epigenetics: Inheritance of gene expression profiles independent of changes in DNA sequence or content.Histones: Small, basic proteins that package eukaryotic DNA into chromatin.Nucleosomes: Nucleosome core particles consist of an octamer of histone proteins (2x H2A, H2B, H3, H4) around which 147 bp of DNA are wrapped. Addition of linker DNA of various length and linker histones (H1) makes up the nucleosome as the basic, repeating unit of chromatin. DNA-Methylation:Enzymatic and none-enzymatic modification of DNA bases with methyl-groups.The methylation of C5 of cytosine is most relevant for gene regulation.Histone modifications: Chemical, posttranslational modifications of specific amino acids of histone proteins. The most abundant modifications are acetylation and methylation of the ε-amino group of lysines, methylation of the guanidino group of arginines and phosphorylation of hydroxyl groups in serines and threonines.Chemical probes: Synthetic molecules designed to interact with a protein of interest in order to study its function and activity.Cosubstrate probes: Chemical probes that are derived from the cellular small molecules that donate modifying groups to DNA and histones such as Adenosine triphosphate (ATP), Acetyl coenzyme A (acetyl-CoA) and S-adenosyl methionine (SAM).Substrate profiling: Proteomic approach to define the pool of target proteins of specific modifying enzymes using cosubstrate probes and mass spectrometry. 3 AbstractChromatin is the universal template of genetic information of all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins and the DNA bases are crucial signaling events in directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Therefore, these so called epigenetic regulators are intensively studied and represent promising drug targets in modern medicine. We summarize and discuss recent advances in the field of chemical biology that have provided chromatin research with sophisticated tools for investigating the composition, activity and target sites of chromatin modifying enzymes and reader proteins. 4In all eukaryotic cells chromatin, the complex of DNA and histone proteins regulates the functional state of the genome by altering condensation states and active recruitment of regulatory factors. The basic structural unit of chromatin is the nucleosome core particle. It consists of a protein core formed by two copies each of the histone proteins H2A, H2B, H3 and H4 with 147 base pairs of DNA wrapped around.1 Nucleosome core particles are connected by linker DNA, which can bind linker histones thereby giving rise to the fundamental repeating unit of chromatin, the nucleosome. Control of different chromatin states is mediated by a multitude of posttranslational modifications (PTMs) of the histone proteins, including methylation, acetylation and phosphorylatio...

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“…Although various other mechanism-based inhibitors of SIRTs, such as peptides containing ε-N-thioacetyl-K (K Tac ), 73,75 have been reported, these peptide-based molecules exhibit neither high potency nor isoform-selectivity. To overcome this problem, we performed a RaPID selection for peptide inhibitors of SIRT2 containing a K Tfa residue as a "warhead" targeted to the catalytic pocket of SIRT2.…”

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confidence: 99%

Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

Terasaka

Suga

2013

Chemistry Letters

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Flexizymes are a family of aminoacylation ribozymes devised by in vitro selection in our research group. They charge a wide variety of nonproteinogenic amino acids onto virtually any kind of tRNAs, enabling us to reprogram the genetic code in a custom-made cell-free translation system. This genetic code reprogramming method was integrated with a mRNA display method, which not only expresses nonstandard peptides such as macrocyclic peptides but also selects ligands specifically binding to target proteins. This system is referred to as random nonstandard peptide integrated discovery (RaPID) system, which has yielded inhibitors against disease-related target proteins. In this review, we summarize the evolutionary history and recent applications of the flexizymes and RaPID system.

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Nε-Thioacetyl-lysine: A multi-facet functional probe for enzymatic protein lysine Nε-deacetylation

Cited by 103 publications

References 37 publications

Human SIRT3 tripeptidic inhibitors containing Nε-thioacetyl-lysine

Human SIRT3 tripeptidic inhibitors containing Nε-thioacetyl-lysine

Probing Chromatin-modifying Enzymes with Chemical Tools

Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

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