Publications | Thompson Lab | UMass Medical School

Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode

Oct 5, 2021

Author(s): Gordon J. Lockbaum, Mina Henes, Jeong Min. Lee, Jennifer Timm, Ellen A. Nalivaika, Paul R. Thompson, Nese Kurt Yilmaz, Celia A. Schiffer

Source: Biochemistry

Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases...

A phase transition enhances the catalytic activity of SARM1, an NAD(+) glycohydrolase involved in neurodegeneration

Jun 29, 2021

Author(s): Heather S. Loring, Victoria L. Czech, Janneke D. Icso, Lauren C. O'Connor, Sangram Parelkar, Alexandra B. Byrne, Paul R. Thompson

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD(+) glycohydrolase whose activity is increas...

Structures of human peptidylarginine deiminase type III provide insights into substrate recognition and inhibitor design

May 7, 2021

Author(s): Kazumasa Funabashi, Mizuki Sawata, Anna Nagai, Megumi Akimoto, Ryutaro Mashimo, Hidenari Takahara, Kenji Kizawa, Paul R. Thompson, Kenji Ite, Kenichi Kitanishi,...

Source: Archives of biochemistry and biophysics

Peptidylarginine deiminase type III (PAD3) is an isozyme belonging to the PAD enzyme family that converts arginine to citrulline residue(s) within proteins. P...

Citrullinated vimentin mediates development and progression of lung fibrosis

Mar 17, 2021

Author(s): Fu Jun Li, Santanu Mondal, Paul R. Thompson, Veena B. Antony

Source: Science translational medicine

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) ...

Chemical biology of protein citrullination by the protein A arginine deiminases

Mar 3, 2021

Author(s): Santanu Mondal, Paul R. Thompson

Source: Current opinion in chemical biology

Citrullination is a post-translational modification (PTM) that converts peptidyl-arginine into peptidyl-citrulline; citrullination is catalyzed by the protein...

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

Jan 25, 2021

Author(s): Gordon J. Lockbaum, Archie C. Reyes, Jeong Min Lee, Ronak Tilvawala, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Paul R. Thompson, Celia A. Schiffer

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The cur...

Site-specific incorporation of citrulline into proteins in mammalian cells

Jan 4, 2021

Author(s): Santanu Mondal, Shu Wang, Yunan Zheng, Sudeshna Sen, Abhishek Chatterjee, Paul R. Thompson

Citrullination is a post-translational modification (PTM) of arginine that is crucial for several physiological processes, including gene regulation and neutr...

Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice

Nov 17, 2020

Author(s): Fernanda M. C. Sodré, Samal Bissenova, Ylke Bruggeman, Ronak Tilvawala, Dana P. Cook, Claire Berthault, Santanu Mondal, Aïsha Callebaut, Sylvaine You, Raphael S...

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through t...

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

Oct 15, 2020

Author(s): Yuzi Tian, Santanu Mondal, Paul R. Thompson, Yongqing Li

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmun...

Succination inactivates gasdermin D and blocks pyroptosis

Sep 25, 2020

Author(s): Fiachra Humphries, Liraz Shmuel-Galia, Natalia Ketelut-Carneiro, Ruth Wilson, Zhaozhao Jiang, Farnaz Khalighinejad, Khaja Muneeruddin, Scott A. Shaffer, Carolin...

Source: Science (New York, N.Y.)

Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response gene...

Identification of the first noncompetitive SARM1 inhibitors

Sep 15, 2020

Author(s): Heather S. Loring, Sangram Parelkar, Santanu Mondal, Paul R. Thompson

Source: Bioorganic and medicinal chemistry

Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) is a key therapeutic target for diseases that exhibit Wallerian-like degenerati...

Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock

Aug 1, 2020

Author(s): Zhenyu Wu, Qiufang Deng, Baihong Pan, Hasan B. Alam, Yuzi Tian, Umar F. Bhatti, Baoling Liu, Santanu Mondal, Paul R. Thompson, Yongqing Li

Source: Inflammation

Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracel...

Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome

Apr 10, 2020

Author(s): Guangyuan Li, Coleman H. Young, Bryce Snow, Amanda O. Christensen, M. Kristen Demoruelle, Venkatesh V. Nemmara, Paul R. Thompson, Heather M. Rothfuss, Brian D. ...

Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by pepti...

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

Feb 22, 2020

Author(s): Pinar Uysal-Onganer, Amy MacLatchy, Rayan Mahmoud, Igor Kraev, Paul R. Thompson, Jameel M. Inal, Sigrun Lange

Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been ...

Initial Kinetic Characterization of Sterile Alpha and Toll/Interleukin Receptor Motif-Containing Protein 1

Feb 12, 2020

Author(s): Heather S. Loring, Janneke D. Icso, Venkatesh V. Nemmara, Paul R. Thompson

Source: Biochemistry

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) plays a pivotal role in triggering the neurodegenerative processes that u...

Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases

Jan 16, 2020

Author(s): Heather S. Loring, Paul R. Thompson

Source: Cell chemical biology

Wallerian degeneration is a neuronal death pathway that is triggered in response to injury or disease. Death was thought to occur passively until the discover...

Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination

Nov 14, 2019

Author(s): Bo Sun, Hui-Hsin Chang, Ari J. Salinger, Beverly Tomita, Mandar Bawadekar, Caitlyn L. Holmes, Miriam A. Shelef, Eranthie Weerapana, Paul R. Thompson, I-Cheng Ho

Source: JCI insight

Dysregulated citrullination, a unique form of posttranslational modification catalyzed by the peptidylarginine deiminases (PADs), has been observed in several...

Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells

Oct 10, 2019

Author(s): Fujun Li, Lixia Miao, Teng Xue, Hao Qin, Santanu Mondal, Paul R. Thompson, Scott A. Coonrod, Xiaoqiu Liu, Xuesen Zhang

Source: Journal of experimental and clinical cancer research : CR; © The Author(s). 2019 Open Access. This article is distributed under the terms of the Creative Common...

BACKGROUND: Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can...

Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis

Sep 1, 2019

Author(s): Laura Cau, Hidenari Takahara, Paul R. Thompson, Guy Serre, Marie-Claire Mechin, Michel Simon

Source: The Journal of investigative dermatology

Deimination, a post-translational modification catalyzed by a family of enzymes called peptidylarginine deiminases (PADs), is the conversion of arginine into ...

Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis After Vessel Injury

Aug 16, 2019

Author(s): Nicoletta Sorvillo, Daniella M. Mizurini, Carmen Coxon, Kimberly Martinod, Ronak Tilvawala, Deya Cherpokova, Ari J. Salinger, Robert J. Seward, Caleb Staudinger...

Source: Circulation research

RATIONALE: PAD4 (peptidylarginine deiminase type IV), an enzyme essential for neutrophil extracellular trap formation (NETosis), is released together with neu...

Cutting Edge: Protein Arginine Deiminase 2 and 4 Regulate NLRP3 Inflammasome-Dependent IL-1β Maturation and ASC Speck Formation in Macrophages

Aug 15, 2019

Author(s): Neha Mishra, Lidja Schwerdtner, Kelly Sams, Santanu Mondal, Fareed Ahmad, Reinhold E. Schmidt, Scott A. Coonrod, Paul R. Thompson, Markus M. Lerch, Lukas Bossal...

Source: Journal of immunology (Baltimore, Md. : 1950)

Protein arginine deiminase (PAD) enzymes catalyze the conversion of protein-bound arginine into citrulline, an irreversible posttranslational modification wit...

Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

Jul 9, 2019

Author(s): Li Zheng, Mitesh Nagar, Aaron J. Maurais, Daniel J. Slade, Sangram S. Parelkar, Scott A. Coonrod, Eranthie Weerapana, Paul R. Thompson

Protein arginine deiminases (PADs) are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated PAD ...

Halogen Bonding Increases the Potency and Isozyme-selectivity of Protein Arginine Deiminase 1 Inhibitors

Jul 5, 2019

Author(s): Santanu Mondal, Xuefeng Gong, Xiaoqian Zhang, Ari J. Salinger, Li Zheng, Sudeshna Sen, Eranthie Weerapana, Xuesen Zhang, Paul R. Thompson

Protein Arginine Deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, mul...

Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase

Apr 19, 2019

Author(s): Sudeshna Sen, Santanu Mondal, Li Zheng, Ari J. Salinger, Walter Fast, Eranthie Weerapana, Paul R. Thompson

Nicotinamide N-methyltransferase (NNMT) catalyzes the S-adenosyl-l-methionine-dependent methylation of nicotinamide to form N-methylnicotinamide. This enzyme ...

Protein Arginine Deiminases (PADs): Biochemistry and Chemical Biology of Protein Citrullination

Mar 19, 2019

Author(s): Santanu Mondal, Paul R. Thompson

Source: Accounts of chemical research

Proteins are well-known to undergo a variety of post-translational modifications (PTMs). One such PTM is citrullination, an arginine modification that is cata...

Peptidyl arginine deiminases: detection and functional analysis of protein citrullination

Mar 1, 2019

Author(s): Ronak Tilvawala, Paul R. Thompson

Source: Current opinion in structural biology

Citrullination is a post-translational modification of arginine that is catalyzed by the protein arginine deiminases (PADs). Abnormal citrullination is observ...

Thioredoxin Modulates Protein Arginine Deiminase 4 (PAD4)-Catalyzed Citrullination

Feb 19, 2019

Author(s): Mitesh Nagar, Ronak Tilvawala, Paul R. Thompson

Protein citrullination is a post-translational modification catalyzed by the protein arginine deiminases (PADs). This modification plays a crucial role in the...

Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus.

Dec 6, 2018

Author(s): Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus eryt...

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Nov 14, 2018

Author(s): A. E. Yuzhalin, A. N. Gordon-Weeks, M. L. Tognoli, K. Jones, B. Markelc, R. Konietzny, R. Fischer, Aaron Muth, E. O'Neill, Paul R. Thompson, P. J. Venables, B. ...

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumente...

Kinetic Mechanism of Nicotinamide N-Methyltransferase.

Sep 25, 2018

Author(s): Heather S. Loring, Paul R. Thompson

Source: Biochemistry

Nicotinamide N-methyltransferase (NNMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to nicotinamide, pyridine, and other structur...

Histone citrullination represses miRNA expression resulting in increased oncogene mRNAs in somatolactotrope cells.

Sep 14, 2018

Author(s): Stanley B DeVore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D....

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PA...

Development of Activity-Based Proteomic Probes for Protein Citrullination.

Sep 11, 2018

Author(s): Venkatesh V. Nemmara, Paul R. Thompson

Source: Current topics in microbiology and immunology

Protein arginine deiminases (PADs) catalyze the post-translational deimination of peptidyl arginine to form peptidyl citrulline. This modification is increase...

Citrullination Inactivates Nicotinamide-N-methyltransferase

Jul 25, 2018

Author(s): Venkatesh V. Nemmara, Ronak Tilvawala, Ari J. Salinger, Lacey Miller, Son Hong Nguyen, Eranthie Weerapana, Paul R. Thompson

Nicotinamide-N-methyl transferase (NNMT) catalyzes the irreversible methylation of nicotinamide (NAM) to form N-methyl nicotinamide (MeNAM) using SAM as a met...

The Rheumatoid Arthritis-Associated Citrullinome.

Jun 21, 2018

Author(s): Ronak Tilvawala, Son Hong Nguyen, Aaron J Maurais, Venkatesh V. Nemmara, Mitesh Nagar, Ari J. Salinger, Sunil Nagpal, Eranthie Weerapana, Paul R. Thompson

Source: Cell Chemical Biology

Increased protein citrullination is linked to various diseases including rheumatoid arthritis (RA), lupus, and cancer. Citrullinated autoantigens, a hallmark ...

Photochemical Control of Protein Arginine Deiminase (PAD) Activity

Apr 20, 2018

Author(s): Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson

Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ...

Donated chemical probes for open science

Apr 20, 2018

Author(s): Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical...

BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway

Apr 12, 2018

Author(s): Melissa M. Ledet, Robyn Anderson, Rebecca Harman, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Gerlinde R. Van de Walle

Source: BMC cancer; © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://...

BACKGROUND: Mammary cancer is highly prevalent in dogs and cats and results in a poor prognosis due to critically lacking viable treatment options. Recent hum...

A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA.

Apr 1, 2018

Author(s): Alicia Wong, Paul R. Thompson, Jan Potempa, Joanna Koziel

Source: Journal of immunology (Baltimore, Md. : 1950)

LL-37, the only human cathelicidin that is released during inflammation, is a potent regulator of immune responses by facilitating delivery of oligonucleotide...

The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs)

Mar 16, 2018

Author(s): Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thom...

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine de...

PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling.

Nov 28, 2017

Author(s): Hao Qin, Xiaoqiu Liu, Fujun Li, Lixia Miao, Tingting Li, Boqun Xu, Xiaofei An, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Source: Cancer letters

Peptidylargininedeiminase 1 (PAD1) catalyzes protein for citrullination, and this activity has been linked to the epidermal cornification. However, a role for...

Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription.

Jun 16, 2017

Author(s): Kathleen W. Clancy, Anna-Maria Russell, Venkataraman Subramanian, Hannah Nguyen, Yuewei Qian, Robert M. Campbell, Paul R. Thompson

Source: ACS Chemical Biology

Posttranslational modifications of histone tails are a key contributor to epigenetic regulation. Histone H3 Arg26 and Lys27 are both modified by multiple enzy...

Citrullination of NF-kappaB p65 promotes its nuclear localization and TLR-induced expression of IL-1beta and TNFalpha

Jun 9, 2017

Author(s): Bo Sun, Nishant Dwivedi, Tyler J. Bechtel, Janet L. Paulsen, Aaron Muth, Mandar Bawadekar, Gang Li, Paul R. Thompson, Miriam A. Shelef, Celia A. Schiffer, Erant...

Source: Science immunology

Many citrullinated proteins are known autoantigens in rheumatoid arthritis, a disease mediated by inflammatory cytokines, such as tumor necrosis factor-alpha ...

Diverse stimuli engage different neutrophil extracellular trap pathways

Jun 2, 2017

Author(s): Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis p...

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

May 26, 2017

Author(s): Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. McElwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod

Source: BMC cancer; © The Author(s). 2017.

BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcin...

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy

May 9, 2017

Author(s): Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal, Sigrun Lange

Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increas...

Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown

May 1, 2017

Author(s): Laura Cau, Valerie Pendaries, Emeline Lhuillier, Paul R. Thompson, Guy Serre, Hidenari Takahara, Marie-Claire Mechin, Michel Simon

Source: Journal of dermatological science

BACKGROUND: Deimination (also known as citrullination), the conversion of arginine in a protein to citrulline, is catalyzed by a family of enzymes called pept...

Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis

Apr 14, 2017

Author(s): Carmelo Carmona-Rivera, Paul R. Thompson, Mariana J. Kaplan

Source: Science immunology

Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated ...

Development of a Selective Inhibitor of Protein Arginine Deiminase 2.

Apr 13, 2017

Author(s): Aaron Muth, Venkataraman Subramanian, Edward Beaumont, Mitesh Nagar, Philip Kerry, Paul McEwan, Hema Srinath, Kathleen W. Clancy, Sangram Parelkar, Paul R. Thom...

Source: Journal of medicinal chemistry

Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no ...

DTNB-Based Quantification of In Vitro Enzymatic N-Terminal Acetyltransferase Activity.

Mar 18, 2017

Author(s): Havard Foyn, Paul R. Thompson, Thomas Arnesen

Source: Methods in molecular biology (Clifton, N.J.)

We here describe a quick and easy method to quantitatively measure in vitro acetylation activity of not only N-terminal acetyltransferase (NAT) enzymes, but a...

Citrullination regulates the expression of insulin-like growth factor-binding protein 1 (IGFBP1) in ovine uterine luminal epithelial cells.

Jan 1, 2017

Author(s): Coleman H. Young, Heather M. Rothfuss, Philip F. Gard, Aaron Muth, Paul R. Thompson, Ryan L. Ashley, Brian D. Cherrington

Source: Reproduction (Cambridge, England)

There are five peptidylarginine deiminase (PAD) isozymes designated as PADs 1, 2, 3, 4 and 6, and many are expressed in female reproductive tissues. These enz...

Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development

Dec 8, 2016

Author(s): Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullin...

Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation

Nov 1, 2016

Author(s): Garyfalia Papadaki, Konstantinos Kambas, Christiana Choulaki, Katerina Vlachou, Elias Drakos, George Bertsias, Konstantinos Ritis, Dimitrios T. Boumpas, Paul R....

Source: European journal of immunology

Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in rheumatoid arthritis (RA) and plays a pivotal role in disease pathogenesis. Ho...

Nicotine induces neutrophil extracellular traps

Nov 1, 2016

Author(s): Ava Hosseinzadeh, Paul R. Thompson, Brahm H. Segal, Constantin F. Urban

Source: Journal of leukocyte biology

NETs serve to ensnare and kill microbial pathogens. However, NETs can at the same time contribute to tissue damage and excessive inflammation. Nicotine is a m...

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

Oct 20, 2016

Author(s): Hui-Hsin Chang, Paul R. Thompson, I-Cheng Ho

Source: JCI insight

A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increa...

GnRH Stimulates Peptidylarginine Deiminase Catalyzed Histone Citrullination in Gonadotrope Cells

Oct 1, 2016

Author(s): Shaihla A. Khan, Brian S. Edwards, Aaron Muth, Paul R. Thompson, Brian D. Cherrington, Amy M. Navratil

Source: Molecular endocrinology (Baltimore, Md.)

Peptidylarginine deiminase (PAD) enzymes convert histone tail arginine residues to citrulline resulting in chromatin decondensation. Our previous work found t...

Activity-Based Profiling Reveals a Regulatory Link between Oxidative Stress and Protein Arginine Phosphorylation

Aug 6, 2016

Author(s): Jakob Fuhrmann, Venkataraman Subramanian, Douglas J. Kojetin, Paul R. Thompson

Source: Cell Chemical Biology

Protein arginine phosphorylation is a recently discovered modification that affects multiple cellular pathways in Gram-positive bacteria. In particular, the p...

Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation

Jul 22, 2016

Author(s): Mandar Bawadekar, Annette Gendron-Fitzpatrick, Ryan Rebernick, Daeun Shim, Thomas F. Warner, Anthony P. Nicholas, Lennart K. Lundblad A, Paul R. Thompson, Miria...

BACKGROUND: The relationship between lung and joint inflammation in rheumatoid arthritis is poorly understood. Lung inflammation with resultant protein citrul...

Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses

May 23, 2016

Author(s): Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. L...

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins hav...

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

Mar 18, 2016

Author(s): Jakob Fuhrmann, Paul R. Thompson

Source: ACS chemical biology; This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any...

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone ...

Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response

Feb 5, 2016

Author(s): Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna McGouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Bene...

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disea...

Detection and identification of protein citrullination in complex biological systems

Feb 1, 2016

Author(s): Kathleen W. Clancy, Eranthie Weerapana, Paul R. Thompson

Source: Current opinion in chemical biology

Protein citrullination is a post-translational modification of arginine that is catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Aberrantl...

Peptidylarginine Deiminase 3 (PAD3) Is Upregulated by Prolactin Stimulation of CID-9 Cells and Expressed in the Lactating Mouse Mammary Gland

Jan 22, 2016

Author(s): Guangyuan Li, Isaac N. Hayward, Brittany R. Jenkins, Heather M. Rothfuss, Coleman H. Young, Marja T. Nevalainen, Aaron Muth, Paul R. Thompson, Amy M. Navratil, ...

Peptidylarginine deiminases (PADs) post-translationally convert arginine into neutral citrulline residues. Our past work shows that PADs are expressed in the ...

Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer

Nov 3, 2015

Author(s): Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth

Source: Oncotarget; This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution...

Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and r...

Synthesis and Use of a Phosphonate Amidine to Generate an Anti-Phosphoarginine-Specific Antibody

Oct 12, 2015

Author(s): Jakob Fuhrmann, Venkataraman Subramanian, Paul R. Thompson

Source: Angewandte Chemie (International ed. in English)

Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relev...

Chemical Proteomic Platform To Identify Citrullinated Proteins

Sep 23, 2015

Author(s): Daniel M. Lewallen, Kevin L. Bicker, Venkataraman Subramanian, Kathleen W. Clancy, Daniel J. Slade, Julianne Martell, Christina J. Dreyton, Jeremy Sokolove, Era...

Source: ACS chemical biology

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination...

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

Jun 10, 2015

Author(s): Jakob Fuhrmann, Kathleen W. Clancy, Paul R. Thompson

Source: Chemical reviews; This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution an...

Review article on histone citrullination (arginine deimination), histone arginine methylation, and noncanonical histone arginine modifications.

Utilization of the Soft Agar Colony Formation Assay to Identify Inhibitors of Tumorigenicity in Breast Cancer Cells

May 20, 2015

Author(s): Sachi Horibata, Tommy V. Vo, Venkataraman Subramanian, Paul R. Thompson, Scott A. Coonrod

Source: Journal of Visualized Experiments : JoVE

Here, we document the use of the soft agar colony formation assay to test the effects of a peptidylarginine deiminase (PADI) enzyme inhibitor, BB-Cl-amidine, ...

Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design

Apr 17, 2015

Author(s): Daniel J. Slade, Pengfei Fang, Christina J. Dreyton, Ying Zhang, Jakob Fuhrmann, Don Rempel, Benjamin D. Bax, Scott A. Coonrod, Huw D. Lewis, Min Guo, Michael L...

Source: ACS chemical biology

Protein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 fu...

Inhibiting protein arginine deiminases has antioxidant consequences.

Apr 1, 2015

Author(s): Erin E. Witalison, Xiangli Cui, Anne B. Hofseth, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth

Source: The Journal of pharmacology and experimental therapeutics

Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a sma...

Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.

Mar 1, 2015

Author(s): Huw D. Lewis, Paul R. Thompson

Source: Nature chemical biology

PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in ...

Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors.

Feb 12, 2015

Author(s): Venkataraman Subramanian, Jason S. Knight, Sangram Parelkar, Lynne Anguish, Scott A. Coonrod, Mariana J. Kaplan, Paul R. Thompson

Source: Journal of medicinal chemistry

Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now k...

Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation.

Feb 2, 2015

Author(s): Erin E. Witalison, Paul R. Thompson, Lorne J. Hofseth

Source: Current drug targets

Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosyla...

Protein arginine methyltransferase 5 catalyzes substrate dimethylation in a distributive fashion.

Dec 23, 2014

Author(s): Min Wang, Jakob Fuhrmann, Paul R. Thompson

Source: Biochemistry

Protein arginine methyltransferase 5 (PRMT5) is a histone-modifying enzyme whose activity is aberrantly upregulated in various cancers and thereby contributes...

Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus.

Sep 1, 2014

Author(s): Carolyne K. Smith, Anuradha Vivekanandan-Giri, Chongren Tang, Jason S. Knight, Anna Mathew, Robin L. Padilla, Brenda W. Gillespie, Carmelo Carmona-Rivera, Xiaod...

Source: Arthritis and rheumatology (Hoboken, N.J.)

OBJECTIVE: Oxidative stress and oxidized high-density lipoprotein (HDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus eryt...

Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates.

Aug 26, 2014

Author(s): Sigrun Lange, Eridan Rocha-Ferreira, Laura Thei, Priyanka Mawjee, Kate Bennett, Paul R. Thompson, Venkataraman Subramanian, Anthony P. Nicholas, Donald Peebles,...

Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still...

Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.

Aug 7, 2014

Author(s): Jason S. Knight, Venkataraman Subramanian, Alexander A. O'Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Carolyne K. Smith, Jeffrey B. Hodgin, Paul R. Thompson, Maria...

Source: Annals of the rheumatic diseases

OBJECTIVES: An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), poten...

A novel role for protein arginine deiminase 4 in pluripotency: the emerging role of citrullinated histone H1 in cellular programming.

Aug 1, 2014

Author(s): Daniel J. Slade, Sachi Horibata, Scott A. Coonrod, Paul R. Thompson

Source: BioEssays : news and reviews in molecular, cellular and developmental biology

Histone post-translational modifications (PTMs) alter the chromatin architecture, generating "open" and "closed" states, and these structural changes can modu...

Mechanistic studies of protein arginine deiminase 2: evidence for a substrate-assisted mechanism

Jul 15, 2014

Author(s): Christina J. Dreyton, Bryan Knuckley, Justin E. Jones, Daniel M. Lewallen, Paul R. Thompson

Source: Biochemistry

Citrullination, which is catalyzed by protein arginine deiminases (PADs 1-4 and 6), is a post-translational modification (PTM) that effectively neutralizes th...

Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity

Jul 1, 2014

Author(s): Nishant Dwivedi, Indira Neeli, Nicolas Schall, Haibao Wan, Dominic M. Desiderio, Elena Csernok, Paul R. Thompson, Hayet Dali, Jean-Paul Briand, Sylviane Muller,...

Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Autoantibodies to nuclear antigens arise in human autoimmune diseases, but a unifying pathogenetic mechanism remains elusive. Recently we reported that exposu...

Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.

Jun 1, 2014

Author(s): Kin Pong U, Venkataraman Subramanian, Antony P. Nicholas, Paul R. Thompson, Patrizia Ferretti

PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting prote...

Pluripotency: citrullination unravels stem cells

May 1, 2014

Author(s): Daniel J. Slade, Venkataraman Subramanian, Paul R. Thompson

Source: Nature chemical biology

A FluoPol-ABPP PAD2 high-throughput screen identifies the first calcium site inhibitor targeting the PADs.

Apr 18, 2014

Author(s): Daniel M. Lewallen, Kevin L. Bicker, Franck Madoux, Peter Chase, Lynne Anguish, Scott Coonrod, Peter Hodder, Paul R. Thompson

Source: ACS chemical biology

The protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of peptidyl-arginine to form peptidyl-citrulline in a process termed deimina...

Using unnatural amino acid mutagenesis to probe the regulation of PRMT1.

Mar 21, 2014

Author(s): Heather L. Rust, Venkataraman Subramanian, Graham M. West, Douglas D. Young, Peter G. Schultz, Paul R. Thompson

Source: ACS chemical biology

Protein arginine methyltransferase 1 (PRMT1)-dependent methylation contributes to the onset and progression of numerous diseases (e.g., cancer, heart disease,...

Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

Mar 14, 2014

Author(s): Jason S. Knight, Wei Luo, Alexander A. O'Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Venkataraman Subramanian, Chiao Guo, Robert C. Grenn, Paul R. Thompson, Daniel...

Source: Circulation research

RATIONALE: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-alpha-producing plasmacytoid dendr...

Inhibiting AMPylation: a novel screen to identify the first small molecule inhibitors of protein AMPylation

Feb 21, 2014

Author(s): Daniel M. Lewallen, Anju Sreelatha, Venkatasubramanian Dharmarajan, Franck Madoux, Peter Chase, Patrick R. Griffin, Kim Orth, Peter Hodder, Paul R. Thompson

Source: ACS chemical biology

Enzymatic transfer of the AMP portion of ATP to substrate proteins has recently been described as an essential mechanism of bacterial infection for several pa...

Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.

Feb 15, 2014

Author(s): Christina J. Dreyton, Erin D. Anderson, Venkataraman Subramanian, Dale L. Boger, Paul R. Thompson

Source: Bioorganic and medicinal chemistry

Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the protein arginine deiminases (PADs 1-4 and PAD6 in humans),...

Chemical and biological methods to detect post-translational modifications of arginine.

Feb 1, 2014

Author(s): Daniel J. Slade, Venkataraman Subramanian, Jakob Fuhrmann, Paul R. Thompson

Source: Biopolymers

Post-translational modifications (PTMs) of protein embedded arginines are increasingly being recognized as playing an important role in both prokaryotic and e...

Automethylation of protein arginine methyltransferase 8 (PRMT8) regulates activity by impeding S-adenosylmethionine sensitivity.

Sep 27, 2013

Author(s): Myles B.C. Dillon, Heather L. Rust, Paul R. Thompson, Kerri A. Mowen

Source: The Journal of biological chemistry

Protein arginine methyltransferase (PRMT) 8 is unique among the PRMTs, as it has a highly restricted tissue expression pattern and an N terminus that contains...

Targeting the arginine phosphatase YwlE with a catalytic redox-based inhibitor.

Sep 20, 2013

Author(s): Jakob Fuhrmann, Venkataraman Subramanian, Paul R. Thompson

Source: ACS chemical biology

Protein phosphatases are critical regulators of cellular signaling in both eukaryotes and prokaryotes. The majority of protein phosphatases dephosphorylate ph...

Substrate specificity, processivity, and kinetic mechanism of protein arginine methyltransferase 5.

Aug 13, 2013

Author(s): Min Wang, Rui-Ming Xu, Paul R. Thompson

Source: Biochemistry

Protein arginine methyltransferases (PRMTs) have emerged as attractive therapeutic targets for heart disease and cancers. PRMT5 is a particularly interesting ...

Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus.

Jul 1, 2013

Author(s): Jason S. Knight, Wenpu Zhao, Wei Luo, Venkataraman Subramanian, Alexander A. O'Dell, Srilakshmi Yalavarthi, Jeffrey B. Hodgin, Daniel T. Eitzman, Paul R. Thomps...

Source: The Journal of clinical investigation

Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoanti...

Design, synthesis, and kinetic characterization of protein N-terminal acetyltransferase inhibitors.

Apr 4, 2013

Author(s): Havard Foyn, Justin E. Jones, Dan Lewallen, Rashmi Narawane, Jan Erik Varhaug, Paul R. Thompson, Thomas Arnesen

Source: ACS chemical biology

The N-termini of 80-90% of human proteins are acetylated by the N-terminal acetyltransferases (NATs), NatA-NatF. The major NAT complex, NatA, and particularly...

NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.

Mar 27, 2013

Author(s): Ritika Khandpur, Carmelo Carmona-Rivera, Anuradha Vivekanandan-Giri, Alison Gizinski, Srilakshmi Yalavarthi, Jason S. Knight, Sean Friday, Sam Li, Rajiv M. Pate...

Source: Science translational medicine

The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (AC...

The protein arginine deiminases: Structure, function, inhibition, and disease.

Feb 1, 2013

Author(s): Kevin L. Bicker, Paul R. Thompson

Source: Biopolymers

The post-translational modification of histones has significant effects on overall chromatin function. One such modification is citrullination, which is catal...

The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest.

Jan 7, 2013

Author(s): Xiangli Cui, Erin E. Witalison, Alena P. Chumanevich, Alexander A. Chumanevich, Deepak Poudyal, Venkataraman Subramanian, Aaron J. Schetter, Curtis C. Harris, P...

Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible...

Activation of PAD4 in NET formation

Nov 29, 2012

Author(s): Amanda S. Rohrbach, Daniel J. Slade, Paul R. Thompson, Kerri A. Mowen

Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 ...

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target.

Oct 30, 2012

Author(s): John L. McElwee, Sunish Mohanan, Obi L. Griffith, Heike C. Breuer, Lynne J. Anguish, Brian D. Cherrington, Ashley M. Palmer, Louise R. Howe, Venkataraman Subram...

BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to p...

D-amino acid based protein arginine deiminase inhibitors: Synthesis, pharmacokinetics, and in cellulo efficacy.

Oct 26, 2012

Author(s): Kevin L. Bicker, Lynne Anguish, Alexander A. Chumanevich, Michael D. Cameron, Xiangli Cui, Erin E. Witalison, Venkataraman Subramanian, Xuesen Zhang, Alena P. C...

Source: ACS medicinal chemistry letters

The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid a...

Seeing citrulline: development of a phenylglyoxal-based probe to visualize protein citrullination.

Oct 17, 2012

Author(s): Kevin L. Bicker, Venkataraman Subramanian, Alexander A. Chumanevich, Lorne J. Hofseth, Paul R. Thompson

Source: Journal of the American Chemical Society

Protein arginine deiminases (PADs) catalyze the hydrolysis of peptidyl arginine to form peptidyl citrulline. Abnormally high PAD activity is observed in a hos...

Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis.

Sep 29, 2012

Author(s): Sunish Mohanan, Brian D. Cherrington, Sachi Horibata, John L. McElwee, Paul R. Thompson, Scott A. Coonrod

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound...

Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation.

Aug 14, 2012

Author(s): Xuesen Zhang, Michael Bolt, Michael J. Guertin, Wei Chen, Sheng Zhang, Brian D. Cherrington, Daniel J. Slade, Christina J. Dreyton, Venkataraman Subramanian, Ke...

Source: Proceedings of the National Academy of Sciences of the United States of America

Cofactors for estrogen receptor alpha (ERalpha) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found ...

Citrullination of proteins: a common post-translational modification pathway induced by different nanoparticles in vitro and in vivo.

Aug 1, 2012

Author(s): Bashir M. Mohamed, Navin K. Verma, Anthony M. Davies, Aoife McGowan, Kieran Crosbie-Staunton, Adriele Prina-Mello, Dermot Kelleher, Catherine H. Botting, Corey ...

Source: Nanomedicine (London, England)

AIM: Rapidly expanding manufacture and use of nanomaterials emphasize the requirements for thorough assessment of health outcomes associated with novel applic...

Potential role for PADI-mediated histone citrullination in preimplantation development.

Jun 19, 2012

Author(s): Rui Kan, Mei Jin, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Scott A. Coonrod

BACKGROUND: The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a pr...

Probing adenylation: using a fluorescently labelled ATP probe to directly label and immunoprecipitate VopS substrates.

Jun 1, 2012

Author(s): Daniel M. Lewallen, Caitlin J. Steckler, Bryan Knuckley, Michael J. Chalmers, Paul R. Thompson

Source: Molecular bioSystems

The bacterial effector VopS from Vibrio parahaemolyticus modifies host Rho GTPases to prevent downstream signalling, which leads to cell rounding and eventual...

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.

Apr 1, 2012

Author(s): Nishant Dwivedi, Jagriti Upadhyay, Indira Neeli, Salar Khan, Debendra Pattanaik, Linda Myers, Kyriakos A. Kirou, Bernhard Hellmich, Bryan Knuckley, Paul R. Thom...

Source: Arthritis and rheumatism

OBJECTIVE: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS: We assembled...

Human protein N-terminal acetyltransferase hNaa50p (hNAT5/hSAN) follows ordered sequential catalytic mechanism: combined kinetic and NMR study.

Mar 23, 2012

Author(s): Rune H. Evjenth, Annette K. Brenner, Paul R. Thompson, Thomas Arnesen, Nils Age Froystein, Johan R. Lillehaug

Source: The Journal of biological chemistry

N(alpha)-acetylation is a common protein modification catalyzed by different N-terminal acetyltransferases (NATs). Their essential role in the biogenesis and ...

Kinetic mechanism of protein arginine methyltransferase 6 (PRMT6).

Feb 17, 2012

Author(s): Obiamaka Obianyo, Paul R. Thompson

Source: The Journal of biological chemistry

The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the mono- and dimethylation of arginine residues in a variety of protein...

Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors.

Jan 20, 2012

Author(s): Justin E. Jones, Jessica L. Slack, Pengfei Fang, Xuesen Zhang, Venkataraman Subramanian, Corey P. Causey, Scott A. Coonrod, Min Guo, Paul R. Thompson

Source: ACS chemical biology

Protein arginine deiminase activity (PAD) is increased in cancer, rheumatoid arthritis, and ulcerative colitis. Although the link between abnormal PAD activit...

Activity-based protein profiling of protein arginine methyltransferase 1

Oct 21, 2011

Author(s): Obiamaka Obianyo, Corey P. Causey, Justin E. Jones, Paul R. Thompson

Source: ACS chemical biology

The protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. PRMT1 is th...

The development of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors

Oct 13, 2011

Author(s): Corey P. Causey, Justin E. Jones, Jessica L. Slack, Daisuke Kamei, Larry E. Jones, Venkataraman Subramanian, Bryan Knuckley, Pedram Ebrahimi, Alexander A. Chuma...

Source: Journal of medicinal chemistry

Protein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These ...

Kinase consensus sequences: a breeding ground for crosstalk

Sep 16, 2011

Author(s): Heather L. Rust, Paul R. Thompson

Source: ACS chemical biology

The best characterized examples of crosstalk between two or more different post-translational modifications (PTMs) occur with respect to histones. These examp...

Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability.

Jul 15, 2011

Author(s): Sigrun Lange, Stefanie Gogel, Kit-Yi Leung, Bertrand Vernay, Anthony P. Nicholas, Corey P. Causey, Paul R. Thompson, Nicholas D.E. Greene, Patrizia Ferretti

Source: Developmental biology

Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective re...

Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.

Jun 1, 2011

Author(s): Alexander A. Chumanevich, Corey P. Causey, Bryan Knuckley, Justin E. Jones, Deepak Poudyal, Tia Davis, Alena P. Chumanevich, Lydia E. Matesic, Paul R. Thompson,...

Source: American journal of physiology. Gastrointestinal and liver physiology

Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an in...

Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells.

Jun 1, 2011

Author(s): Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W Lee Kraus, Scott A. Coonrod

Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and...

Development and use of clickable activity based protein profiling agents for protein arginine deiminase 4.

May 20, 2011

Author(s): Jessica L. Slack, Corey P. Causey, Yuan Luo, Paul R. Thompson

Source: ACS chemical biology

The protein arginine deiminases (PADs), which catalyze the hydrolysis of peptidyl-arginine to form peptidyl-citrulline, are potential targets for the developm...

Autodeimination of protein arginine deiminase 4 alters protein-protein interactions but not activity.

May 17, 2011

Author(s): Jessica L. Slack, Larry E. Jones Jr., Monica M. Bhatia, Paul R. Thompson

Source: Biochemistry

The protein arginine deiminases (PAD), which catalyze the hydrolysis of peptidyl-arginine to form peptidyl-citrulline, play important roles in a variety of ce...

Boronic acid functionalized peptidyl synthetic lectins: combinatorial library design, peptide sequencing, and selective glycoprotein recognition

May 9, 2011

Author(s): Kevin L. Bicker, Jing Sun, John J. Lavigne, Paul R. Thompson

Source: ACS combinatorial science

Aberrant glycosylation of cell membrane and secreted glycoproteins is a hallmark of various disease states, including cancer. The natural lectins currently us...

Mechanistic studies on transcriptional coactivator protein arginine methyltransferase 1

Apr 26, 2011

Author(s): Heather L. Rust, Cecilia I. Zurita-Lopez, Steven Clarke, Paul R. Thompson

Source: Biochemistry

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to the guanidinium group of arginine residu...

N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis

Apr 1, 2011

Author(s): Van C. Willis, Paul R. Thompson, V. Michael Holers

Source: Journal of immunology (Baltimore, Md. : 1950)

Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated...

Protein arginine deiminase 4: a target for an epigenetic cancer therapy

Feb 1, 2011

Author(s): Jessica L. Slack, Corey P. Causey, Paul R. Thompson

Source: Cellular and molecular life sciences : CMLS

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that e...

A combinatorial approach to characterize the substrate specificity of protein arginine methyltransferase 1

Jan 1, 2011

Author(s): Kevin L. Bicker, Obiamaka Obianyo, Heather L. Rust, Paul R. Thompson

Source: Molecular bioSystems

The dysregulation of protein arginine methyltransferases (PRMTs) is implicated in a wide variety of disease states. Here we report the design, synthesis, and ...

Mechanistic studies of agmatine deiminase from multiple bacterial species

Nov 2, 2010

Author(s): Justin E. Jones, Christina J. Dreyton, Heather Flick, Corey P. Causey, Paul R. Thompson

Source: Biochemistry

One subfamily of guanidino group-modifying enzymes (GMEs) consists of the agmatine deiminases (AgDs). These enzymes catalyze the conversion of agmatine (decar...

A fluopol-ABPP HTS assay to identify PAD inhibitors

Oct 14, 2010

Author(s): Bryan Knuckley, Justin E. Jones, Daniel A. Bachovchin, Jessica Slack, Corey P. Causey, Steven J. Brown, Hugh Rosen, Benjamin F. Cravatt, Paul R. Thompson

Source: Chemical communications (Cambridge, England)

Protein Arginine Deiminase (PAD) activity is dysregulated in numerous diseases, e.g., Rheumatoid Arthritis. Herein we describe the development of a fluorescen...

Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3

Jun 15, 2010

Author(s): Bryan Knuckley, Corey P. Causey, Justin E. Jones, Monica Bhatia, Christina J. Dreyton, Tanesha C. Osborne, Hidenari Takahara, Paul R. Thompson

Source: Biochemistry

Protein citrullination has been shown to regulate numerous physiological pathways (e.g., the innate immune response and gene transcription) and is, when dysre...

A chloroacetamidine-based inactivator of protein arginine methyltransferase 1: design, synthesis, and in vitro and in vivo evaluation

Jun 14, 2010

Author(s): Obiamaka Obianyo, Corey P. Causey, Tanesha C. Osborne, Justin E. Jones, Young-Ho Lee, Michael R. Stallcup, Paul R. Thompson

Source: Chembiochem : a European journal of chemical biology

Characterization and inactivation of an agmatine deiminase from Helicobacter pylori

Apr 1, 2010

Author(s): Justin E. Jones, Corey P. Causey, Leslie Lovelace, Bryan Knuckley, Heather Flick, Lukasz Lebioda, Paul R. Thompson

Source: Bioorganic chemistry

Helicobacter pylori encodes a potential virulence factor, agmatine deiminase (HpAgD), which catalyzes the conversion of agmatine to N-carbamoyl putrescine (NC...

Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that general acid catalysis promotes efficient inactivation

Jan 25, 2010

Author(s): Bryan Knuckley, Corey P. Causey, Perry J. Pellechia, Paul F. Cook, Paul R. Thompson

Source: Chembiochem : a European journal of chemical biology

Dysregulated protein arginine deiminase (PAD) activity, particularly PAD4, has been suggested to play a role in the onset and progression of numerous human di...

Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential

Sep 1, 2009

Author(s): Justin E. Jones, Corey P. Causey, Bryan Knuckley, Jessica L. Slack-Noyes, Paul R. Thompson

Source: Current opinion in drug discovery and development

The protein arginine deiminases (PADs), and in particular PAD4, have emerged as potential therapeutic targets for the treatment of rheumatoid arthritis (RA). ...

The tomato brassinosteroid receptor BRI1 increases binding of systemin to tobacco plasma membranes, but is not involved in systemin signaling

Jul 1, 2009

Author(s): Robert Malinowski, Rebecca Higgins, Yuan Luo, Laverne Piper, Azka Nazir, Vikramjit S. Bajwa, Steven D. Clouse, Paul R. Thompson, Johannes W. Stratmann

Source: Plant molecular biology

The tomato wound signal systemin is perceived by a specific high-affinity, saturable, and reversible cell surface receptor. This receptor was identified as th...

The protein acetyltransferase ARD1: a novel cancer drug target

Nov 1, 2008

Author(s): Thomas Arnesen, Paul R. Thompson, Jan Erik. Varhaug, Johan R. Lillehaug

Source: Current cancer drug targets

Evasion of apoptosis and active cell proliferation are among the characteristics of cancer cells. Triggering the induction of apoptosis or reducing the prolif...

Kinetic mechanism of protein arginine methyltransferase 1

Sep 30, 2008

Author(s): Obiamaka Obianyo, Tanesha C. Osborne, Paul R. Thompson

Source: Biochemistry

Protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. Although all PR...

Regulation of p53 target gene expression by peptidylarginine deiminase 4

Aug 1, 2008

Author(s): Pingxin Li, Hongjie Yao, Zhiqiang Zhang, Ming Li, Yuan Luo, Paul R. Thompson, David S. Gilmour, Yanming Wang

Source: Molecular and cellular biology

Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the...

Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis

Jul 18, 2008

Author(s): Hongjie Yao, Pingxin Li, Bryan J. Venters, Suting Zheng, Paul R. Thompson, B. Franklin Pugh, Yanming Wang

Source: The Journal of biological chemistry

Protein Arg methyltransferases function as coactivators of the tumor suppressor p53 to regulate gene expression. Peptidylarginine deiminase 4 (PAD4/PADI4) cou...

An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 4 (PAD4)

Jul 7, 2008

Author(s): Corey P. Causey, Paul R. Thompson

Source: Tetrahedron letters

Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in...

In situ generation of a bisubstrate analogue for protein arginine methyltransferase 1

Apr 9, 2008

Author(s): Tanesha C. Osborne, Rachel L. Roska Weller, Scott R. Rajski, Paul R. Thompson

Source: Journal of the American Chemical Society

Protein arginine methyltransferases (PRMTs) are (S)-adenosylmethionine (SAM)-dependent methyltransferases that catalyze the post-translational methylation of ...

The structural basis of protein acetylation by the p300/CBP transcriptional coactivator

Feb 14, 2008

Author(s): Xin Liu, Ling Wang, Kehao Zhao, Paul R. Thompson, Yousang Hwang, Ronen Marmorstein, Philip A. Cole

Source: Nature

The transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transc...

Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors

Jan 15, 2008

Author(s): Bryan Knuckley, Yuan Luo, Paul R. Thompson

Source: Bioorganic and medicinal chemistry

Protein Arginine Deiminase 4 (PAD4) has emerged as a leading target for the development of a Rheumatoid Arthritis (RA) pharmaceutical. Herein, we describe the...

Peptide borono lectins (PBLs): a new tool for glycomics and cancer diagnostics

Nov 23, 2007

Author(s): Yuejiao Zou, Dana L. Broughton, Kevin L. Bicker, Paul R. Thompson, John J. Lavigne

Source: Chembiochem : a European journal of chemical biology

Protein arginine methyltransferase 1: positively charged residues in substrate peptides distal to the site of methylation are important for substrate binding and catalysis

Nov 20, 2007

Author(s): Tanesha C. Osborne, Obiamaka Obianyo, Xing Zhang, Xiaodong Cheng, Paul R. Thompson

Source: Biochemistry

Protein arginine methyltransferases (PRMTs) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., hi...

A selective chemical probe for coenzyme A-requiring enzymes

Oct 8, 2007

Author(s): Yousang Hwang, Paul R. Thompson, Ling Wang, Lihua Jiang, Neil L. Kelleher, Philip A. Cole

Source: Angewandte Chemie (International ed. in English)

Protein arginine deiminase 4: evidence for a reverse protonation mechanism

Jun 5, 2007

Author(s): Bryan Knuckley, Monica Bhatia, Paul R. Thompson

Source: Biochemistry

The presumed role of an overactive protein arginine deiminase 4 (PAD4) in the pathophysiology of rheumatoid arthritis (RA) suggests that PAD4 inhibitors could...

Methyllysine analogs: rewriting the code

May 1, 2007

Author(s): Monica Bhatia, Paul R. Thompson

Source: Nature chemical biology

Activity-based protein profiling reagents for protein arginine deiminase 4 (PAD4): synthesis and in vitro evaluation of a fluorescently labeled probe

Nov 15, 2006

Author(s): Yuan Luo, Bryan Knuckley, Monica Bhatia, Perry J. Pellechia, Paul R. Thompson

Source: Journal of the American Chemical Society

Protein arginine deiminase 4 (PAD4), which catalyzes the post-translational conversion of peptidyl arginine to peptidyl citrulline, is widely regarded as one ...

Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization

Oct 3, 2006

Author(s): Yuan Luo, Kyouhei Arita, Monica Bhatia, Bryan Knuckley, Young-Ho Lee, Michael R. Stallcup, Mamoru Sato, Paul R. Thompson

Source: Biochemistry

Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins...

Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock

Aug 22, 2006

Author(s): Paul R. Thompson, Walter Fast

Source: ACS chemical biology

Protein citrullination, a once-obscure post-translational modification (PTM) of peptidylarginine, has recently become an area of significant interest because ...

A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation

Feb 1, 2006

Author(s): Yuan Luo, Bryan Knuckley, Young-Ho Lee, Michael R. Stallcup, Paul R. Thompson

Source: Journal of the American Chemical Society

Protein arginine deiminase 4 (PAD4) is a calcium-dependent transcriptional corepressor that has been implicated in the onset and progression of rheumatoid art...

Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis

Aug 9, 2005

Author(s): Patricia L. Kearney, Monica Bhatia, Nelroy G. Jones, Luo Yuan, Mary C. Glascock, Kristen L. Catchings, Michiyuki Yamada, Paul R. Thompson

Source: Biochemistry

Protein arginine deiminase 4 (PAD4) is a Ca(2+)-dependent enzyme that catalyzes the posttranslational conversion of arginine to citrulline (Arg to Cit) in a n...

Structural analysis of a highly acetylated protein using a curved-field reflectron mass spectrometer

Jun 1, 2005

Author(s): Dongxia Wang, Paul R. Thompson, Philip A. Cole, Robert J. Cotter

Source: Proteomics

Matrix-assisted laser desorption/ionization mass spectrometry and tandem mass spectrometry (MS/MS) were used to determine the multiple acetylation sites in th...

Bisubstrate analogue structure-activity relationships for p300 histone acetyltransferase inhibitors

Jun 15, 2004

Author(s): Vatsala Sagar, Weiping Zheng, Paul R. Thompson, Philip A. Cole

Source: Bioorganic and medicinal chemistry

p300 and CBP are important histone acetyltransferases (HATs) that regulate gene expression and may be anti-cancer drug targets. Based on a previous lead compo...

Regulation of the p300 HAT domain via a novel activation loop

Apr 1, 2004

Author(s): Paul R. Thompson, Dongxia Wang, Ling Wang, Marcella Fulco, Natalia Pediconi, Dianzheng Zhang, Woojin An, Qingyuan Ge, Robert G. Roeder, Jiemin Wong, Massimo Lev...

Source: Nature structural and molecular biology

The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is critical for regulating gene expression in mammalian cells. Howeve...

Selective HAT inhibitors as mechanistic tools for protein acetylation

Feb 21, 2004

Author(s): Yujun Zheng, Paul R. Thompson, Marek Cebrat, Ling Wang, Meghann K. Devlin, Rhoda M. Alani, Philip A. Cole

Source: Methods in enzymology

Synthesis and analysis of potential prodrugs of coenzyme A analogues for the inhibition of the histone acetyltransferase p300

Jul 31, 2003

Author(s): Marek Cebrat, Cheol M. Kim, Paul R. Thompson, Matthew Daugherty, Philip A. Cole

Source: Bioorganic and medicinal chemistry

Lys-CoA (1) is a selective inhibitor of p300 histone acetyltransferase (HAT) but shows poor pharmacokinetic properties because of its multiply charged phospha...

Mechanism of aminoglycoside antibiotic kinase APH(3')-IIIa: role of the nucleotide positioning loop

Jun 4, 2002

Author(s): Paul R. Thompson, David D. Boehr, Albert M. Berghuis, Gerard D. Wright

Source: Biochemistry

The aminoglycoside antibiotic resistance kinases (APHs) and the Ser/Thr/Tyr protein kinases share structural and functional homology but very little primary s...

Transcriptional coactivator protein p300. Kinetic characterization of its histone acetyltransferase activity

Sep 7, 2001

Author(s): Paul R. Thompson, H. Kurooka, Y. Nakatani, P. A. Cole

Source: The Journal of biological chemistry

The p300/cAMP response element-binding protein-binding protein (CBP) family members include human p300 and cAMP response element-binding protein-binding prote...

Probing the mechanism of enzymatic phosphoryl transfer with a chemical trick

Jul 17, 2001

Author(s): Paul R. Thompson, P. A. Cole

Source: Proceedings of the National Academy of Sciences of the United States of America

Molecular mechanism of aminoglycoside antibiotic kinase APH(3')-IIIa: roles of conserved active site residues

Jun 29, 2001

Author(s): D. D. Boehr, Paul R. Thompson, G. D. Wright

Source: The Journal of biological chemistry

The aminoglycoside antibiotic kinases (APHs) constitute a clinically important group of antibiotic resistance enzymes. APHs share structural and functional ho...

Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases

Mar 1, 2000

Author(s): B. DeLaBarre, Paul R. Thompson, G. D. Wright, A. M. Berghuis

Source: Nature structural biology

The structure of the antifungal drug target homoserine dehydrogenase (HSD) was determined from Saccharomyces cerevisiae in apo and holo forms, and as a ternar...

The COOH terminus of aminoglycoside phosphotransferase (3')-IIIa is critical for antibiotic recognition and resistance

Oct 22, 1999

Author(s): Paul R. Thompson, J. Schwartzenhauer, D. W. Hughes, A. M. Berghuis, G. D. Wright

Source: The Journal of biological chemistry

The aminoglycoside phosphotransferases (APHs) are widely distributed among pathogenic bacteria and are employed to covalently modify, and thereby detoxify, th...

Aminoglycoside antibiotic phosphotransferases are also serine protein kinases

Jan 1, 1999

Author(s): D. M. Daigle, G. A. McKay, Paul R. Thompson, G. D. Wright

Source: Chemistry and biology

BACKGROUND: Bacterial resistance to aminoglycoside antibiotics occurs primarily through the expression of modifying enzymes that covalently alter the drugs by...

Aminoglycoside phosphotransferases: proteins, structure, and mechanism

Jan 1, 1999

Author(s): G. D. Wright, Paul R. Thompson

Source: Frontiers in bioscience : a journal and virtual library

Aminoglycoside antibiotics constitute an important class of clinically useful drugs which are imperiled by the emergence of resistant organisms. Aminoglycosid...

Spectinomycin kinase from Legionella pneumophila. Characterization of substrate specificity and identification of catalytically important residues

Jun 12, 1998

Author(s): Paul R. Thompson, D. W. Hughes, N. P. Cianciotto, G. D. Wright

Source: The Journal of biological chemistry

The bacterium Legionella pneumophila is the responsible agent for Legionnaires' disease and has recently been shown to harbor a gene encoding a kinase that co...

Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases

Jun 13, 1997

Author(s): W. C. Hon, G. A. McKay, Paul R. Thompson, R. M. Sweet, D. S. Yang, G. D. Wright, A. M. Berghuis

Source: Cell

Bacterial resistance to aminoglycoside antibiotics is almost exclusively accomplished through either phosphorylation, adenylylation, or acetylation of the ant...

Mechanism of aminoglycoside 3'-phosphotransferase type IIIa: His188 is not a phosphate-accepting residue

Sep 1, 1996

Author(s): Paul R. Thompson, D. W. Hughes, G. D. Wright

Source: Chemistry and biology

BACKGROUND: The enzyme aminoglycoside 3'-phosphotransferase Type IIIa (APH(3')-IIIa), confers resistance to many aminoglycoside antibiotics by regiospecific p...

Regiospecificity of aminoglycoside phosphotransferase from Enterococci and Staphylococci (APH(3')-IIIa)

Jul 2, 1996

Author(s): Paul R. Thompson, D. W. Hughes, G. D. Wright

Source: Biochemistry

The broad-spectrum aminoglycoside phosphotransferase, APH(3')-IIIa, confers resistance to several aminoglycoside antibiotics in opportunistic pathogens of the...

Broad spectrum aminoglycoside phosphotransferase type III from Enterococcus: overexpression, purification, and substrate specificity

Jun 7, 1994

Author(s): G. A. McKay, Paul R. Thompson, G. D. Wright

Source: Biochemistry

The aminoglycoside phosphotransferases (APHs) are responsible for the bacterial inactivation of many clinically useful aminoglycoside antibiotics. We report t...