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https://www.readbyqxmd.com/read/28087667/prmt5-selective-inhibitors-suppress-inflammatory-t-cell-responses-and-experimental-autoimmune-encephalomyelitis
#1
Lindsay M Webb, Stephanie A Amici, Kyle A Jablonski, Himanshu Savardekar, Amanda R Panfil, Linsen Li, Wei Zhou, Kevin Peine, Vrajesh Karkhanis, Eric M Bachelder, Kristy M Ainslie, Patrick L Green, Chenglong Li, Robert A Baiocchi, Mireia Guerau-de-Arellano
In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking...
January 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28061334/arginine-methylation-the-coming-of-age
#2
REVIEW
Roméo S Blanc, Stéphane Richard
Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription and playing key roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. Recently, a wealth of studies using transgenic mouse models and selective PRMT inhibitors helped define physiological roles for protein arginine methyltransferases (PRMTs) linking them to diseases such as cancer and metabolic, neurodegenerative, and muscular disorders...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28042453/design-and-synthesis-of-selective-small-molecule-inhibitors-of-coactivator-associated-arginine-methyltransferase-1-carm1
#3
H Ü Kaniskan, M S Eram, J Liu, D Smil, M L Martini, Y Shen, V Santhakumar, P J Brown, C Arrowsmith, M Vedadi, J Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/27998975/the-major-protein-arginine-methyltransferase-in-trypanosoma-brucei-functions-as-an-enzyme-prozyme-complex
#4
Lucie Kafkova, Erik W Debler, John C Fisk, Kanishk Jain, Steven G Clarke, Laurie K Read
Prozymes are catalytically inactive enzyme paralogs that dramatically stimulate the function of weakly active enzymes through complex formation. The two prozymes described to date reside in the polyamine biosynthesis pathway of the human parasite, Trypanosoma brucei, an early branching eukaryote that lacks transcriptional regulation and regulates proteome through posttranscriptional and posttranslational means. Arginine methylation is a common posttranslational modification in eukaryotes catalyzed by protein arginine methyltransferases (PRMTs) that are typically thought to function as homodimers...
December 20, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27994012/asymmetric-arginine-dimethylation-modulates-mitochondrial-energy-metabolism-and-homeostasis-in-caenorhabditis-elegans
#5
Liang Sha, Hiroaki Daitoku, Sho Araoi, Yuta Kaneko, Yuta Takahashi, Koichiro Kako, Akiyoshi Fukamizu
Protein Arginine Methyltransferase 1 (PRMT1) catalyzes asymmetric arginine dimethylation on cellular proteins and modulates various aspects of biological processes, such as signal transduction, DNA repair, and transcriptional regulation. We have previously reported that the null mutant of prmt-1 in C. elegans exhibits a slightly short lifespan, but the physiological significances of PRMT-1 remains largely unclear. Here we explored the role of PRMT-1 on mitochondrial function as hinted by a two-dimensional Western blot-based proteomic study...
December 19, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27935040/network-based-characterization-of-the-synaptic-proteome-reveals-that-removal-of-epigenetic-regulator-prmt8-restricts-proteins-associated-with-synaptic-maturation
#6
Patrick Kia Ming Lee, Wilson Wen Bin Goh, Judy Chia Ghee Sng
The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome-wide approach to characterize the synaptic proteome of Prmt8 knockout versus wildtype mice...
December 9, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27897114/ureas-applications-in-drug-design-and-development
#7
Ajit Dhananjay Jagtap, Nagendra Bharatrao Kondekar, Amit A Sadani, Ji-Wang Chern
The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small molecules displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead molecules have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivatives as modulators biological targets (viz...
November 29, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27872854/identification-of-novel-inhibitors-against-coactivator-associated-arginine-methyltransferase-1-based-on-virtual-screening-and-biological-assays
#8
Fei Ye, Weiyao Zhang, Wenchao Lu, Yiqian Xie, Hao Jiang, Jia Jin, Cheng Luo
Overexpression of coactivator associated arginine methyltransferase 1 (CARM1), a protein arginine N-methyltransferase (PRMT) family enzyme, is associated with various diseases including cancers. Consequently, the development of small-molecule inhibitors targeting PRMTs has significant value for both research and therapeutic purposes. In this study, together with structure-based virtual screening with biochemical assays, two compounds DC_C11 and DC_C66 were identified as novel inhibitors of CARM1. Cellular studies revealed that the two inhibitors are cell membrane permeable and effectively blocked proliferation of cancer cells including HELA, K562, and MCF7...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27834681/transient-kinetics-define-a-complete-kinetic-model-for-protein-arginine-methyltransferase-1
#9
Hao Hu, Cheng Luo, Y George Zheng
Protein arginine methyltransferases (PRMTs) are the enzymes responsible for posttranslational methylation of protein arginine residues in eukaryotic cells, particularly within the histone tails. A detailed mechanistic model of PRMT-catalyzed methylation is currently lacking, but it is essential for understanding the functions of PRMTs in various cellular pathways and for efficient design of PRMT inhibitors as potential treatments for a range of human diseases. In this work, we used stopped-flow fluorescence in combination with global kinetic simulation to dissect the transient kinetics of PRMT1, the predominant type I arginine methyltransferase...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27780782/atprmt5-regulates-shoot-regeneration-through-mediating-histone-h4r3-dimethylation-on-krps-and-pre-mrna-splicing-of-rkp-in-arabidopsis
#10
Hui Liu, Xu Ma, Hua Nan Han, Yu Jin Hao, Xian Sheng Zhang
Protein arginine methylation plays important roles in diverse biological processes, but its role in regulating shoot regeneration remains elusive. In this study, we characterized the function of the protein arginine methyltransferase AtPRMT5 during de novo shoot regeneration in Arabidopsis. AtPRMT5 encodes a type II protein arginine methyltransferase that methylates proteins, including histones and RNA splicing factors. The frequency of shoot regeneration and the number of shoots per callus were decreased in the atprmt5 mutant compared with those in the wild type...
December 5, 2016: Molecular Plant
https://www.readbyqxmd.com/read/27604291/intracerebral-administration-of-s-adenosylhomocysteine-or-s-adenosylmethionine-attenuates-the-increases-in-the-cortical-extracellular-levels-of-dimethylarginines-without-affecting-cgmp-level-in-rats-with-acute-liver-failure
#11
Anna Czarnecka, Krzysztof Milewski, Radosław Jaźwiec, Magdalena Zielińska
Alterations in brain nitric oxide (NO)/cGMP synthesis contribute to the pathogenesis of hepatic encephalopathy (HE). An increased asymmetrically dimethylated derivative of L-arginine (ADMA), an endogenous inhibitor of NO synthases, was observed in plasma of HE patients and animal models. It is not clear whether changes in brain ADMA reflect its increased local synthesis therefore affecting NO/cGMP pathway, or are a consequence of its increased peripheral blood content. We measured extracellular concentration of ADMA and symmetrically dimethylated isoform (SDMA) in the prefrontal cortex of control and thioacetamide (TAA)-induced HE rats...
January 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/27601476/arginine-demethylation-of-g3bp1-promotes-stress-granule-assembly
#12
Wei-Chih Tsai, Sitaram Gayatri, Lucas C Reineke, Gianluca Sbardella, Mark T Bedford, Richard E Lloyd
Stress granules (SGs) are cytoplasmic condensates of stalled messenger ribonucleoprotein complexes (mRNPs) that form when eukaryotic cells encounter environmental stress. RNA-binding proteins are enriched for arginine methylation and facilitate SG assembly through interactions involving regions of low amino acid complexity. How methylation of specific RNA-binding proteins regulates RNA granule assembly has not been characterized. Here, we examined the potent SG-nucleating protein Ras-GAP SH3-binding protein 1 (G3BP1), and found that G3BP1 is differentially methylated on specific arginine residues by protein arginine methyltransferase (PRMT) 1 and PRMT5 in its RGG domain...
October 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27577262/proteome-wide-analysis-of-arginine-monomethylation-reveals-widespread-occurrence-in-human-cells
#13
Sara C Larsen, Kathrine B Sylvestersen, Andreas Mund, David Lyon, Meeli Mullari, Maria V Madsen, Jeremy A Daniel, Lars J Jensen, Michael L Nielsen
The posttranslational modification of proteins by arginine methylation is functionally important, yet the breadth of this modification is not well characterized. Using high-resolution mass spectrometry, we identified 8030 arginine methylation sites within 3300 human proteins in human embryonic kidney 293 cells, indicating that the occurrence of this modification is comparable to phosphorylation and ubiquitylation. A site-level conservation analysis revealed that arginine methylation sites are less evolutionarily conserved compared to arginines that were not identified as modified by methylation...
2016: Science Signaling
https://www.readbyqxmd.com/read/27556302/protein-arginine-methylation-demethylation-and-cancer
#14
REVIEW
Coralie Poulard, Laura Corbo, Muriel Le Romancer
Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Currently, there are nine known members of the protein arginine methyltransferase (PRMT) family, but only one arginine demethylase has been identified, namely the Jumonji domain-containing 6 (JMJD6). Although its demethylase activity was initially challenged, its dual activity as an arginine demethylase and a lysine hydroxylase is now recognized...
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27545444/understanding-protein-arginine-methyltransferase-1-prmt1-product-specificity-from-molecular-dynamics
#15
Symon Gathiaka, Brittany Boykin, Tamar Cáceres, Joan M Hevel, Orlando Acevedo
Protein arginine methyltransferases (PRMTs) catalyze the post-translational methylation of specific arginyl groups within targeted proteins to regulate fundamental biological responses in eukaryotic cells. The major Type I PRMT enzyme, PRMT1, strictly generates monomethyl arginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). Multiple diseases can arise from the dysregulation of PRMT1, including heart disease and cancer, which underscores the need to elucidate the origin of product specificity...
October 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27515561/conformationally-constrained-peptidomimetics-as-inhibitors-of-the-protein-arginine-methyl-transferases
#16
Astrid Knuhtsen, Baptiste Legrand, Olivier Van der Poorten, Muriel Amblard, Jean Martinez, Steven Ballet, Jesper L Kristensen, Daniel Sejer Pedersen
Protein arginine N-methyl transferases (PRMTs) belong to a family of enzymes that modulate the epigenetic code through modifications of histones. In the present study, peptides emerging from a phage display screening were modified in the search for PRMT inhibitors through substitution with non-proteinogenic amino acids, N-alkylation of the peptide backbone, and incorporation of constrained dipeptide mimics. One of the modified peptides (23) showed an increased inhibitory activity towards several PRMTs in the low μm range and the conformational preference of this peptide was investigated and compared with the original hit using circular dichroism and NMR spectroscopy...
September 19, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27513432/the-effects-of-novokinin-an-at2-agonist-on-blood-pressure-vascular-responses-and-levels-of-adma-nadph-oxidase-and-rho-kinase-in-hypertension-induced-by-nos-inhibition-and-salt
#17
Emre Mutlu, Selçuk İlhan, Elif Onat, Murat Kara, Engin Şahna
BACKGROUND/AIM: The effects of AT2 receptor agonist novokinin on blood pressure, eNOS, NADPH oxidase, protein arginine methyltransferases (PRMTs), and Rho kinase in hypertension were investigated. Furthermore, in isolated thoracic aorta rings, contractile and dilator responses were studied. MATERIALS AND METHODS: To develop hypertension, L-NAME was administered intraperitoneally and salt was given with tap water (1%) for 4 weeks. Novokinin was administered intraperitoneally for the last 2 weeks...
2016: Turkish Journal of Medical Sciences
https://www.readbyqxmd.com/read/27394758/rediscovery-and-redescription-of-coenagrion-persicum-lohmann-1993-with-description-of-the-female-and-some-notes-on-habitat-selection-odonata-coenagrionidae
#18
Thomas Schneider, Dietmar Ikemeyer, Sónia Ferreira, Ole Müller
Coenagrion persicum was described by Heinrich Lohmann in 1993 on the basis of a single male and two larvae captured in 1937 by E.W. Kaiser in Lorestãn Province (W-Iran). In June 2015 two of the authors (TS and DI) rediscovered individual-rich populations of this species in two Iranian provinces (Lorestãn and Esfahãn). We could confirm the structural differences of the male appendages between C. persicum and C. pulchellum based on a larger number of specimens than in the original description. The structural differences from C...
April 18, 2016: Zootaxa
https://www.readbyqxmd.com/read/27390919/discovery-of-a-potent-and-selective-coactivator-associated-arginine-methyltransferase-1-carm1-inhibitor-by-virtual-screening
#19
Renato Ferreira de Freitas, Mohammad S Eram, David Smil, Magdalena M Szewczyk, Steven Kennedy, Peter J Brown, Vijayaratnam Santhakumar, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Masoud Vedadi, Matthieu Schapira
Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods...
July 28, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27387499/protein-arginine-methyltransferase-product-specificity-is-mediated-by-distinct-active-site-architectures
#20
Kanishk Jain, Rebeccah A Warmack, Erik W Debler, Andrea Hadjikyriacou, Peter Stavropoulos, Steven G Clarke
In the family of protein arginine methyltransferases (PRMTs) that predominantly generate either asymmetric or symmetric dimethylarginine (SDMA), PRMT7 is unique in producing solely monomethylarginine (MMA) products. The type of methylation on histones and other proteins dictates changes in gene expression, and numerous studies have linked altered profiles of methyl marks with disease phenotypes. Given the importance of specific inhibitor development, it is crucial to understand the mechanisms by which PRMT product specificity is conferred...
August 26, 2016: Journal of Biological Chemistry
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