title: Activity-Based Profiling Reveals a Regulatory Link between Oxidative Stress and Protein Arginine Phosphorylation.
abstract: Protein arginine phosphorylation is a recently discovered modification that affects multiple cellular pathways in Gram-positive bacteria. In particular, the phosphorylation of arginine residues by McsB is critical for regulating the cellular stress response. Given that the highly efficient protein arginine phosphatase YwlE prevents arginine phosphorylation under non-stress conditions, we hypothesized that this enzyme negatively regulates arginine phosphorylation and acts as a sensor of cell stress. To evaluate this hypothesis, we developed the first suite of highly potent and specific SO3-amidine-based YwlE inhibitors. With these protein arginine phosphatase-specific probes, we demonstrated that YwlE activity is suppressed by oxidative stress, which consequently increases arginine phosphorylation, thereby inducing the expression of stress-response genes, which is critical for bacterial virulence. Overall, we predict that these novel chemical tools will be widely used to study the regulation of protein arginine phosphorylation in multiple organisms.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Fuhrmann
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, UMass Medical School, 364 Plantation Street, Worcester, MA 01605, USA; Program in Chemical Biology, UMass Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, UMass Medical School, 364 Plantation Street, Worcester, MA 01605, USA; Program in Chemical Biology, UMass Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address: paul.thompson@umassmed.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D001412:Bacillus subtilis / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001411:Geobacillus stearothermophilus / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D018384:Oxidative Stress / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013461:Sulfur Oxides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000578:Amidines; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013461:Sulfur Oxides; D001120:Arginine; D010749:Phosphoprotein Phosphatases; C011118:sulfur trioxide