title: Arginylation regulates purine nucleotide biosynthesis by enhancing the activity of phosphoribosyl pyrophosphate synthase.
abstract: Protein arginylation is an emerging post-translational modification that targets a number of metabolic enzymes; however, the mechanisms and downstream effects of this modification are unknown. Here we show that lack of arginylation renders cells vulnerable to purine nucleotide synthesis inhibitors and affects the related glycine and serine biosynthesis pathways. We show that the purine nucleotide biosynthesis enzyme PRPS2 is selectively arginylated, unlike its close homologue PRPS1, and that arginylation of PRPS2 directly facilitates its biological activity. Moreover, selective arginylation of PRPS2 but not PRPS1 is regulated through a coding sequence-dependent mechanism that combines elements of mRNA secondary structure with lysine residues encoded near the N-terminus of PRPS1. This mechanism promotes arginylation-specific degradation of PRPS1 and selective retention of arginylated PRPS2 in vivo. We therefore demonstrate that arginylation affects both the activity and stability of a major metabolic enzyme.
authors.affiliation: 1] University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA. [2] University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
authors.forename: Fangliang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
authors.forename: Devang M
authors.initials: DM
authors.lastname: Patel
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Colavita
authors.affiliation: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Rodionova
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York, 14263, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.affiliation: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: National Center for Biotechnology Information, NLM, NIH, Bethesda, Maryland 20894, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Shabalina
authors.affiliation: 1] University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA. [2] Department of Molecular Biology and Biotechnology, Tezpur University, Napaam 784028, India.
authors.forename: Sougata
authors.initials: S
authors.lastname: Saha
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York, 14263, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Chernov
authors.affiliation: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kashina
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005998:Glycine / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D011499:Protein Processing, Post-Translational; D011685:Purine Nucleotides / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism*; D012694:Serine / Q000096:biosynthesis; D054875:Ubiquitination
chemical_list: D011685:Purine Nucleotides; D012333:RNA, Messenger; D012694:Serine; D001120:Arginine; D019881:Aminoacyltransferases; C019727:arginyltransferase; C000606570:PRPS1 protein, mouse; C000606571:PRPS2 protein, mouse; D012268:Ribose-Phosphate Pyrophosphokinase; D008239:Lysine; D005998:Glycine