Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.
We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.
Schwer
Bjoern
B
*Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158; and.
Bunkenborg
Jakob
J
Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark-Odense University, DK-5230 Odense M, Denmark.
Verdin
Regis O
RO
*Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158; and.
Andersen
Jens S
JS
Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark-Odense University, DK-5230 Odense M, Denmark.
Verdin
Eric
E
*Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158; and everdin@gladstone.ucsf.edu.
D000106:Acetate-CoA Ligase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
D024101:Mitochondrial Proteins; C466093:SIRT3 protein, human; C508544:SIRT5 protein, human; D056566:Sirtuin 3; D037761:Sirtuins; D000106:Acetate-CoA Ligase; D008239:Lysine