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 and Anna Kashina ()
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Fangliang Zhang: University of Pennsylvania School of Veterinary Medicine
Devang M. Patel: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center
Kristen Colavita: University of Pennsylvania School of Veterinary Medicine
Irina Rodionova: Sanford Burnham Medical Research Institute
Brian Buckley: Roswell Park Cancer Institute
David A. Scott: Sanford Burnham Medical Research Institute
Akhilesh Kumar: University of Miami School of Medicine, and Sylvester Comprehensive Cancer Center
Svetlana A. Shabalina: National Center for Biotechnology Information, NLM, NIH
Sougata Saha: University of Pennsylvania School of Veterinary Medicine
Andrei L. Osterman: Sanford Burnham Medical Research Institute
Anna Kashina: University of Pennsylvania School of Veterinary Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8517

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