N-lysine propionylation controls the activity of propionyl-CoA synthetase.
Reversible protein acetylation is a ubiquitous means for the rapid control of diverse cellular processes. Acetyltransferase enzymes transfer the acetyl group from acetyl-CoA to lysine residues, while deacetylase enzymes catalyze removal of the acetyl group by hydrolysis or by an NAD(+)-dependent reaction. Propionyl-coenzyme A (CoA), like acetyl-CoA, is a high energy product of fatty acid metabolism and is produced through a similar chemical reaction. Because acetyl-CoA is the donor molecule for protein acetylation, we investigated whether proteins can be propionylated in vivo, using propionyl-CoA as the donor molecule. We report that the Salmonella enterica propionyl-CoA synthetase enzyme PrpE is propionylated in vivo at lysine 592; propionylation inactivates PrpE. The propionyl-lysine modification is introduced by bacterial Gcn-5-related N-acetyltransferase enzymes and can be removed by bacterial and human Sir2 enzymes (sirtuins). Like the sirtuin deacetylation reaction, sirtuin-catalyzed depropionylation is NAD(+)-dependent and produces a byproduct, O-propionyl ADP-ribose, analogous to the O-acetyl ADP-ribose sirtuin product of deacetylation. Only a subset of the human sirtuins with deacetylase activity could also depropionylate substrate. The regulation of cellular propionyl-CoA by propionylation of PrpE parallels regulation of acetyl-CoA by acetylation of acetyl-CoA synthetase and raises the possibility that propionylation may serve as a regulatory modification in higher organisms.
Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Jane
J
Garrity
Jeffrey G
JG
Gardner
William
W
Hawse
Cynthia
C
Wolberger
Jorge C
JC
Escalante-Semerena
D001665:Binding Sites; D003066:Coenzyme A Ligases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D024101:Mitochondrial Proteins / Q000737:chemistry; D008968:Molecular Conformation; D009243:NAD / Q000737:chemistry; D009535:Nicotinamidase / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D019779:Salmonella enterica / Q000201:enzymology*; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3; D037761:Sirtuins / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors
D024101:Mitochondrial Proteins; D010455:Peptides; D009243:NAD; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; C466093:SIRT3 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3; D037761:Sirtuins; D009535:Nicotinamidase; D003066:Coenzyme A Ligases; C068072:propionate - CoA ligase; D008239:Lysine