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J. Biol. Chem., Vol. 282, Issue 41, 30239-30245, October 12, 2007

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N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase^*

Jane Garrity¹, Jeffrey G. Gardner, William Hawse², Cynthia Wolberger³, and Jorge C. Escalante-Semerena⁴

From the Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin 53706 and Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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.

Received for publication, May 29, 2007 , and in revised form, July 27, 2007.

^* This work was supported in part by Public Health Service (PHS) Grant GM62203 (to J. C. E.-S.), by Subaward 8412-76121-8 (to J. C. E.-S.) and PHS Grant U54 RR020839. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S6-S12, supplemental Tables S1-S3, and supplemental references and "Experimental Procedures."

¹ Supported in part by PHS Biotechnology Training Grant T32 GM08349 and a Howard Hughes Medical Institute (HHMI) predoctoral fellowship.

² Supported by National Science Foundation (NSF) Grant MCB-0220191.

³ Supported by HHMI and NSF Grant MCB-0220191.

⁴ To whom correspondence should be addressed: Dept. of Bacteriology, University of Wisconsin, 1550 Linden Dr., Madison, WI 53706. Tel.: 608-262-7379; Fax: 608-265-7909; E-mail: escalante{at}bact.wisc.edu.

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