A5101538508- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Acute Myeloid Leukemia Research
- Sirtuins and Resveratrol in Medicine
- Click Chemistry and Applications
- Synthetic Organic Chemistry Methods
- Genomics and Chromatin Dynamics
- Autophagy in Disease and Therapy
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- Genetics and Neurodevelopmental Disorders
- Calcium signaling and nucleotide metabolism
- Marine Sponges and Natural Products
- Amino Acid Enzymes and Metabolism
- Electron Spin Resonance Studies
- Polyamine Metabolism and Applications
- Plant Molecular Biology Research
- Bone and Joint Diseases
- Signaling Pathways in Disease
Tokyo University of Pharmacy and Life Sciences
2018-2025
RIKEN Center for Sustainable Resource Science
2015-2024
Kyushu University
1994-2023
Genomics (United Kingdom)
2012-2022
Tohoku University
2020-2022
NTT (Japan)
2019
Nara Medical University
2018
RIKEN
2008-2017
Life University
2017
The University of Tokyo
2011-2016
The first total synthesis of (+)-chaetocin has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction diketopiperazine 10 and Co(I)-mediated reductive dimerization 12 as key reactions. enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogues without the sulfur functionality are inactive.
Acylation of lysine is an important protein modification regulating diverse biological processes. It was recently demonstrated that members the human Sirtuin family are capable catalyzing long chain deacylation, in addition to well-known NAD(+)-dependent deacetylation activity [Feldman, J. L., Baeza, J., and Denu, M. (2013) Biol. Chem. 288, 31350-31356]. Here we provide a detailed kinetic structural analysis describes interdependence NAD(+)-binding acyl-group selectivity for series Sirtuins,...
Although heat-shock protein 70 (HSP70), an evolutionarily highly conserved molecular chaperone, is known to be post-translationally modified in various ways such as phosphorylation, ubiquitination and glycosylation, physiological significance of lysine methylation has never been elucidated. Here we identify dimethylation HSP70 at Lys-561 by SETD1A. Enhanced was detected types human cancer immunohistochemical analysis, although the barely detectable corresponding non-neoplastic tissues....
Histone acetylation is an essential process in the epigenetic regulation of diverse biological processes, including environmental stress responses plants. Previously, our research group identified a histone deacetylase (HDAC) inhibitor (HDI) that confers salt tolerance Arabidopsis (Arabidopsis thaliana). In this study, we demonstrate class I HDAC (HDA19) and II HDACs (HDA5/14/15/18) control to through different pathways. The screening 12 selective HDIs indicated seven newly reported enhance...
Abstract Sickle cell disease (SCD) is a heritable disorder caused by β-globin gene mutations. Induction of fetal γ-globin an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as agents. However, the molecular mechanisms whereby these small molecules reactivate remain unclear. Here we report development highly selective and non-genotoxic inhibitor, RK-701. RK-701 treatment induces globin expression both in human erythroid cells...
<title>Abstract</title> Reversible histone acylation is crucial for epigenetic gene expression regulation. Histone typically mediated by lysine acyltransferases (KATs), which use acyl-CoAs as acyl donors. Here, we revealed the novel role of deacetylases HDAC1 and HDAC2 in catalysis. Notably, show that directly catalyze sorbylation using sorbic acid, a common food preservative, addition to facilitating desorbylation. This newly discovered HDAC1/2-driven function distinctive active mark leads...
In C2C12 myoblasts, endogenous histone deacetylase HDAC4 shuttles between cytoplasmic and nuclear compartments, supporting the hypothesis that its subcellular localization is dynamically regulated. However, upon differentiation, this dynamic equilibrium disturbed we find accumulates in nuclei of myotubes, suggesting a positive role muscle differentiation. Consistent with notion regulation intracellular trafficking, reveal contains modular structure consisting C-terminal autonomous export...
Conjugation of small ubiquitin-like modifier (SUMO) to protein (SUMOylation) regulates multiple biological systems by changing the functions and fates a large number proteins. Consequently, abnormalities in SUMOylation have been linked diseases, including breast cancer. Using an situ cell-based screening system, we identified spectomycin B1 related natural products as novel inhibitors. Unlike known inhibitors such ginkgolic acid, directly binds E2 (Ubc9) selectively blocks formation E2-SUMO...
Eukaryotic translation initiation factor 5A (eIF5A) is a protein subject to hypusination, which essential for its function. eIF5A also acetylated, but the role of that modification unknown. Here, we report acetylation regulates subcellular localization eIF5A. We identified PCAF as major cellular acetyltransferase eIF5A, and HDAC6 SIRT2 deacetylases. Inhibition deacetylases or impaired hypusination increased leading nuclear accumulation. As constitutively hypusinated under physiological...
Abstract DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S -adenosyl- l -methionine. Methylation regulates gene expression, serving a variety physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation cysteine residue in DNMT3B attenuates activity consequent aberrant upregulation expression. These genes include Cyclin D2 ( Ccnd2 ),...
SIRT2 is a member of the human sirtuin family proteins and possesses NAD + -dependent lysine deacetylase/deacylase activity. has been implicated in carcinogenesis various cancers including leukaemia considered an attractive target for cancer therapy. Here, we identified NPD11033, selective small-molecule inhibitor, by high-throughput screen using RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins zinc-dependent deacetylases. Crystallographic analysis revealed...
Small ubiquitin like modifier (SUMO) specific proteases (SENPs) are cysteine that carry out the proteolytic processing of SUMO from its pro form as well deconjugation substrate proteins. SENPs attractive targets for drug discovery due to their crucial role in development various diseases. However, inhibitor efforts were limited, and only a few inhibitors or activity based probes have been identified until now. Here, we report new class SENP2 by combination structure virtual screening...
SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone (HMT), also methylates non-histone proteins including estrogen receptor (ER) α. ERα methylation by Set7/9 stabilizes and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, clinically approved antiallergy drug, as inhibitor high-throughput screen using fluorogenic substrate-based HMT assay. Kinetic X-ray crystallographic analyses revealed that...
Cortactin is an F-actin-binding protein that localizes to the cell cortex, where actin remodeling required for migration occurs. We found cortactin shuttled between cytoplasm and nucleus under basal conditions. identified Kelch-like ECH-associated 1 (Keap1), a cytosolic involved in oxidant stress responses, as binding partner of promoted cortical localization migration. The ability promote regulated by various posttranslational modifications, including acetylation. showed acetylated form was...
Identification of structurally novel inhibitors lysine methyltransferase G9a has been a subject intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit rac-10a obtained from chemical library University Tokyo Drug Discovery Initiative, structure–activity relationship unique substrate-competitive was established help X-ray crystallography and fragment molecular orbital (FMO) calculations for ligand–protein interaction. Further optimization vitro...