Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

Stephanie A. Shumar, Evan W. Kerr, Werner J. Geldenhuys, Grace E. Montgomery, Paolo Fagone, Puchong Thirawatananond, Harry Saavedra, Sandra B. Gabelli, Roberta Leonardi

Research output: Contribution to journalArticle

Abstract

CoAis the major acyl carrier in mammals and a key cofactor in energy metabolism. Dynamic regulation of CoA in different tissues and organs supports metabolic flexibility. Two mammalian Nudix hydrolases, Nudt19 and Nudt7, degrade CoA in vitro. Nudt19 and Nudt7 possess conserved Nudix and CoA signature sequences and specifically hydrolyze the diphosphate bond of free CoA and acyl-CoAs to form 3',5'-ADP and 4'-(acyl)phosphopantetheine. Limited information is available on these enzymes, but the relatively high abundance of Nudt19 and Nudt7 mRNA in the kidney and liver, respectively, suggests that they play specific roles in the regulation of CoA levels in these organs. Here, we analyzed Nudt19-/- mice and found that deletion of Nudt19 elevates kidneyCoAlevels in mice fed ad libitum, indicating that Nudt19 contributes to the regulation of CoA in vivo. Unlike what was observed for the regulation of Nudt7 in the liver, Nudt19 transcript and protein levels in the kidney did not differ between fed and fasted states. Instead, we identified chenodeoxycholic acid as a specific Nudt19 inhibitor that competed with CoA for Nudt19 binding but did not bind to Nudt7. Exchange of the Nudix and CoA signature motifs between the two isoforms dramatically decreased their kcat. Furthermore, substitutions of conserved residues within these motifs identified amino acids playing different roles in CoA binding and hydrolysis in Nudt19 and Nudt7. Our results reveal that the kidney and liver each possesses a distinct peroxisomal CoA diphosphohydrolase.

Original languageEnglish (US)
Pages (from-to)4134-4148
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number11
DOIs
StatePublished - Mar 16 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shumar, S. A., Kerr, E. W., Geldenhuys, W. J., Montgomery, G. E., Fagone, P., Thirawatananond, P., Saavedra, H., Gabelli, S. B., & Leonardi, R. (2018). Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform. Journal of Biological Chemistry, 293(11), 4134-4148. https://doi.org/10.1074/jbc.RA117.001358