In Situ Generation of a Bisubstrate Analogue for Protein Arginine Methyltransferase 1

Osborne, Tanesha C.; Roska, Rachel L. Weller; Rajski, Scott R.; Thompson, Paul R.

doi:10.1021/ja077104v

Cited by 86 publications

(91 citation statements)

References 20 publications

(32 reference statements)

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“…There is an intensive ongoing effort to identify specific arginine methylation inhibitors (22)(23)(24). Small molecule inhibitors of protein function are powerful tools to probe the physiological roles of enzymes.…”

mentioning

confidence: 99%

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

Selvi

Batta

Kishore

et al. 2010

Journal of Biological Chemistry

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Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, "KAPRK," where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition. In a promoter-specific context, inhibition of H3R17 methylation represses expression of p21, a p53-responsive gene, thus implicating a possible role for H3 Arg-17 methylation in tumor suppressor function. These data establish TBBD as a novel specific inhibitor of arginine methylation and demonstrate substrate sequence-directed inhibition of enzyme activity by a small molecule and its physiological consequence.

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mentioning

confidence: 99%

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

Selvi

Batta

Kishore

et al. 2010

Journal of Biological Chemistry

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“…This was first observed by Osborne et al., who demonstrated the protein methyltransferase 1 (PRMT1)‐catalyzed transalkylation of a peptide using an N‐mustard‐based cofactor. The product of this reaction, essentially a peptide with a covalently bound cofactor analogue, is a potent inhibitor for the MTase 15. Hence, the reaction is self‐limiting.…”

Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

“…This was the first successful demonstration of the bump‐hole technique as a means to develop selective combinations of mutant methyltransferase enzymes and tailored AdoMet analogues 44. The aziridine‐based cofactor analogues and the PRMT1 protein methyltransferase have been successfully employed for protein transalkylation 15, 58. The doubly‐activated (mTAG) cofactors were first employed in protein transalkylation reactions by Peters et al 20e.…”

Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

et al. 2017

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Methyltransferases (MTases) form a large family of enzymes that methylate a diverse set of targets, ranging from the three major biopolymers to small molecules. Most of these MTases use the cofactor S‐adenosyl‐l‐Methionine (AdoMet) as a methyl source. In recent years, there have been significant efforts toward the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups. Two major classes of AdoMet analogues currently exist: doubly‐activated molecules and aziridine based molecules, each of which employs a different approach to achieve transalkylation rather than transmethylation. In this review, we discuss the various strategies for labelling and functionalizing biomolecules using AdoMet‐dependent MTases and AdoMet analogues. We cover the synthetic routes to AdoMet analogues, their stability in biological environments and their application in transalkylation reactions. Finally, some perspectives are presented for the potential use of AdoMet analogues in biology research, (epi)genetics and nanotechnology.

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“…that serves as inhibitor of PRMT1. 21 While the reaction is useful for generating PMT inhibitors, it does not allow characterization of novel PMT substrates.…”

Section: Protein/histone Methylationmentioning

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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In Situ Generation of a Bisubstrate Analogue for Protein Arginine Methyltransferase 1

Cited by 86 publications

References 20 publications

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

Probing Chromatin-modifying Enzymes with Chemical Tools

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