title: Small molecule inhibitors of arginyltransferase regulate arginylation-dependent protein degradation, cell motility, and angiogenesis.
abstract: Posttranslational arginylation mediated by arginyltransferase (ATE1) is an emerging major regulator of embryogenesis and cell physiology. Impairments of ATE1 are implicated in congenital heart defects, obesity, cancer, and neurodegeneration making this enzyme an important therapeutic target, whose potential has been virtually unexplored. Here we report the development of a biochemical assay for identification of small molecule inhibitors of ATE1 and application of this assay to screen a library of 3280 compounds. Our screen identified two compounds which specifically affect ATE1-regulated processes in vivo, including tannic acid, which has been previously shown to inhibit protein degradation and angiogenesis and to act as a therapeutic agent in heart disease and cancer. Our data suggest that these actions of tannic acid are mediated by its direct effect on ATE1, which regulates protein degradation and angiogenesis in vivo.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sougata
authors.initials: S
authors.lastname: Saha
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
authors.forename: Mikhail
authors.initials: M
authors.lastname: Chernov
authors.forename: Anna
authors.initials: A
authors.lastname: Kashina
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D057166:High-Throughput Screening Assays; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
chemical_list: D020533:Angiogenesis Inhibitors; D054852:Small Molecule Libraries; D019881:Aminoacyltransferases; C019727:arginyltransferase