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Lysine specific demethylase

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https://www.readbyqxmd.com/read/28345007/partial-occupancy-binders-identified-by-the-pan-dataset-density-analysis-method-offer-new-chemical-opportunities-and-reveal-cryptic-binding-sites
#1
Nicholas M Pearce, Anthony R Bradley, Tobias Krojer, Brian D Marsden, Charlotte M Deane, Frank von Delft
Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously unidentified fragments reveal multiple binding sites and demonstrate: the versatility of crystallographic fragment screening; that surprisingly large conformational changes are possible in crystals; and that low crystallographic occupancy does not by itself reflect a protein-ligand complex's significance...
May 2017: Structural Dynamics (Melville, N.Y.)
https://www.readbyqxmd.com/read/28344766/phosphorylation-of-lsd1-by-plk1-promotes-its-chromatin-release-during-mitosis
#2
Bin Peng, Ruifeng Shi, Weiwei Jiang, Yue-He Ding, Meng-Qiu Dong, Wei-Guo Zhu, Xingzhi Xu
BACKGROUND: Lysine-specific histone demethylase 1 (LSD1) modulates chromatin status through demethylation of H3K4 and H3K9. It has been demonstrated that LSD1 is hyperphosphorylated and dissociates from chromatin during mitosis. However, the molecular mechanism of LSD1 detachment is unknown. RESULTS: In this report, we found that polo-like kinase 1 (PLK1) directly interacted with LSD1 and phosphorylated LSD1 at Ser-126 . Nocodazole-induced metaphase arrest promoted release of LSD1 from chromatin, and the phosphorylation-defective mutant LSD1 (S126A) failed to dissociate from chromatin upon nocodazole treatment...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28336409/development-and-crystallographic-evaluation-of-histone-h3-peptide-with-n-terminal-serine-substitution-as-a-potent-inhibitor-of-lysine-specific-demethylase-1
#3
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
March 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#4
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28319137/the-h3k27-demethylase-utx-regulates-adipogenesis-in-a-differentiation-stage-dependent-manner
#5
Kazushige Ota, Kit I Tong, Kouichiro Goto, Shuta Tomida, Akiyoshi Komuro, Zhong Wang, Kazuto Nishio, Hitoshi Okada
Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes...
2017: PloS One
https://www.readbyqxmd.com/read/28316154/-the-influence-and-mechanisms-of-lysine-specific-demethylase-1-lsd1-on-invasion-and-metastasis-of-colon-cancer-cells
#6
J Ding, Z M Zhang, Q Dong, R Mi, K S Xu, X F Yang, G Q Liao
Objective: To investigate the effect and molecular mechanisms of LSD1 on proliferation and metastasis of colon cancer. Methods: The influence of down-regulated LSD1 expression on proliferation, invasion and apoptosis of colon cancer cells were detected by transwell invasion assay, cell proliferation assay and apoptosis assay, respectively. Results: Three independent siRNAs targeting LSD1 (siRNA-1554, siRNA-705, and siRNA-1973) were transfected to SW620 cells to detect gene-silencing efficiency, and the result showed that the knockdown effect of siRNA-705 were better than the other two siRNAs at both mRNA and protein levels...
March 14, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28304334/kdm2-family-members-are-regulated-by-hif-1-in-hypoxia
#7
Michael Batie, Jimena Druker, Laura D'Ignazio, Sonia Rocha
Hypoxia is not only a developmental cue but also a stress and pathological stimulus in many human diseases. The response to hypoxia at the cellular level relies on the activity of the transcription factor family, hypoxia inducible factor (HIF). HIF-1 is responsible for the acute response and transactivates a variety of genes involved in cellular metabolism, cell death, and cell growth. Here, we show that hypoxia results in increased mRNA levels for human lysine (K)-specific demethylase 2 (KDM2) family members, KDM2A and KDM2B, and also for Drosophila melanogaster KDM2, a histone and protein demethylase...
March 17, 2017: Cells
https://www.readbyqxmd.com/read/28284523/demethylase-kdm6a-epigenetically-promotes-il-6-and-ifn-%C3%AE-production-in-macrophages
#8
Xia Li, Qian Zhang, Qingzhu Shi, Yin Liu, Kai Zhao, Qicong Shen, Yang Shi, Xingguang Liu, Chunmei Wang, Nan Li, Yuanfang Ma, Xuetao Cao
Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown...
March 8, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28279976/regulation-of-hypoxia-responses-by-flavin-adenine-dinucleotide-dependent-modulation-of-hif-1%C3%AE-protein-stability
#9
Suk-Jin Yang, Young Soo Park, Jung Hee Cho, Byul Moon, Hyun-Jung Ahn, Ju Yeon Lee, Zhi Xie, Yuli Wang, David Pocalyko, Dong Chul Lee, Hyun Ahm Sohn, Minho Kang, Jin Young Kim, Eunhee Kim, Kyung Chan Park, Jung-Ae Kim, Young Il Yeom
Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1α. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1α downregulation in later stages of hypoxia...
March 9, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28277979/structural-insight-into-inhibitors-of-flavin-adenine-dinucleotide-dependent-lysine-demethylases
#10
Hideaki Niwa, Takashi Umehara
Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors...
February 10, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28265301/assessing-histone-demethylase-inhibitors-in-cells-lessons-learned
#11
Stephanie B Hatch, Clarence Yapp, Raquel C Montenegro, Pavel Savitsky, Vicki Gamble, Anthony Tumber, Gian Filippo Ruda, Vassilios Bavetsias, Oleg Fedorov, Butrus Atrash, Florence Raynaud, Rachel Lanigan, LeAnne Carmichael, Kathy Tomlin, Rosemary Burke, Susan M Westaway, Jack A Brown, Rab K Prinjha, Elisabeth D Martinez, Udo Oppermann, Christopher J Schofield, Chas Bountra, Akane Kawamura, Julian Blagg, Paul E Brennan, Olivia Rossanese, Susanne Müller
BACKGROUND: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28250322/-drug-discovery-with-the-help-of-organic-chemistry
#12
Yukihiro Itoh, Takayoshi Suzuki
 The first step in "drug" discovery is to find compounds binding to a potential drug target. In modern medicinal chemistry, the screening of a chemical library, structure-based drug design, and ligand-based drug design, or a combination of these methods, are generally used for identifying the desired compounds. However, they do not necessarily lead to success and there is no infallible method for drug discovery. Therefore, it is important to explore medicinal chemistry based on not only the conventional methods but also new ideas...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28230862/inactivation-of-lsd1-triggers-senescence-in-trophoblast-stem-cells-by-induction-of-sirt4
#13
Josefina Castex, Dominica Willmann, Toufike Kanouni, Laura Arrigoni, Yan Li, Marcel Friedrich, Michael Schleicher, Simon Wöhrle, Mark Pearson, Norbert Kraut, Michaël Méret, Thomas Manke, Eric Metzger, Roland Schüle, Thomas Günther
Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28223039/oncogene-lsd1-is-epigenetically-suppressed-by-mir-137-overexpression-in-human-non-small-cell-lung-cancer
#14
Xin Zhang, Xiujuan Zhang, Bo Yu, Rongpeng Hu, Lanxiang Hao
PURPOSE: We examined the epigenetic regulation of microRNA-137 (miR-137) on lysine-specific demethylase 1 (KDM1A, or LSD1) induced oncogenic effects in NSCLC. METHODS: NSCLC cell lines, A549 and H460 cells were transfected with a mammalian LSD1 overexpression plasmid. It's effects on endogenous KDM1A gene and LSD1 protein expressions were examined by qRT-PCR and western blot assays. NSCLC proliferation and migration were also examined by MTT proliferation and wound-scratch assays, respectively...
February 18, 2017: Biochimie
https://www.readbyqxmd.com/read/28219005/a-rhodium-iii-based-inhibitor-of-lysine-specific-histone-demethylase-1-as-an-epigenetic-modulator-in-prostate-cancer-cells
#15
Chao Yang, Wanhe Wang, Jia-Xin Liang, Guodong Li, Kasipandi Vellaisamy, Chun-Yuen Wong, Dik-Lung Ma, Chung-Hang Leung
We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells and enhanced the amplification of p21, FOXA2, and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7, and MAO activities, and also showed antiproliferative activity toward human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.
March 1, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28212444/sumo-modification-of-a-heterochromatin-histone-demethylase-jmjd2a-enables-viral-gene-transactivation-and-viral-replication
#16
Wan-Shan Yang, Mel Campbell, Pei-Ching Chang
Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi's sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#17
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28188179/new-insights-into-the-role-of-jmjd3-and-utx-in-axial-skeletal-formation-in-mice
#18
Chie Naruse, Shinwa Shibata, Masaru Tamura, Takayuki Kawaguchi, Kanae Abe, Kazushi Sugihara, Tomoaki Kato, Takumi Nishiuchi, Shigeharu Wakana, Masahito Ikawa, Masahide Asano
Jmjd3 and Utx are demethylases specific for lysine 27 of histone H3. Previous reports indicate that Jmjd3 is essential for differentiation of various cell types, such as macrophages and epidermal cells in mice, whereas Utx is involved in cancer and developmental diseases in humans and mice as well as Hox regulation in zebrafish and nematodes. Here, we report that Jmjd3, but not Utx, is involved in axial skeletal formation in mice. A Jmjd3 mutant embryo (Jmjd3(Δ18/Δ18)), but not a catalytically inactive Utx truncation mutant (Utx(-/y)), showed anterior homeotic transformation...
February 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28186755/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-1-high-throughput-screening-and-preliminary-exploration
#19
Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello
Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2...
February 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28158205/structure-activity-relationship-and-modeling-studies-of-inhibitors-of-lysine-specific-demethylase-1
#20
Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B...
2017: PloS One
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