Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform.
| Autor: | Shumar SA; From the Departments of Biochemistry and., Kerr EW; From the Departments of Biochemistry and., Geldenhuys WJ; Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26501 and., Montgomery GE; From the Departments of Biochemistry and., Fagone P; From the Departments of Biochemistry and., Thirawatananond P; the Departments of Biophysics and Biophysical Chemistry.; Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205., Saavedra H; the Departments of Biophysics and Biophysical Chemistry., Gabelli SB; the Departments of Biophysics and Biophysical Chemistry.; Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.; Medicine, and., Leonardi R; From the Departments of Biochemistry and roleonardi@hsc.wvu.edu. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2018 Mar 16; Vol. 293 (11), pp. 4134-4148. Date of Electronic Publication: 2018 Jan 29. |
| DOI: | 10.1074/jbc.RA117.001358 |
| Abstrakt: | CoA is 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 kidney CoA levels 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 k (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.) |
| Databáze: | MEDLINE |
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