Arginylation regulates purine nucleotide biosynthesis by enhancing the activity of phosphoribosyl pyrophosphate synthase.
Fangliang Zhang, Devang M Patel, Kristen Colavita, Irina Rodionova, Brian Buckley, David A Scott, Akhilesh Kumar, Svetlana A Shabalina, Sougata Saha, Mikhail Chernov, Andrei L Osterman, Anna Kashina
Author Information
Fangliang Zhang: 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.
Devang M Patel: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Kristen Colavita: University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA.
Irina Rodionova: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
Brian Buckley: Roswell Park Cancer Institute, Buffalo, New York, 14263, USA.
David A Scott: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
Akhilesh Kumar: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Svetlana A Shabalina: National Center for Biotechnology Information, NLM, NIH, Bethesda, Maryland 20894, USA.
Sougata Saha: 1] University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA. [2] Department of Molecular Biology and Biotechnology, Tezpur University, Napaam 784028, India.
Mikhail Chernov: Roswell Park Cancer Institute, Buffalo, New York, 14263, USA.
Andrei L Osterman: Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA.
Anna Kashina: University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA.
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.
