Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice

• Main Authors: Adams, A.E (Author), Allie, C.M (Author), Anderson, K.A (Author), Backos, D.S (Author), Bhatt, D.P (Author), Francisco, S. (Author), Gomes, C.M (Author), Grimsrud, P.A (Author), Henriques, B.J (Author), Hirschey, M.D (Author), Ilkayeva, O.R (Author), Kulkarni, S.R (Author), Liu, J. (Author), Lucas, T.G (Author), Major, M.B (Author)
• Format: Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology Inc. 2022
• Subjects: Amino acids; Bioinformatics analysis; Catabolic pathway; Enzymatic activities; Enzymes; Lysine oxidations; Mammalian systems; Mammals; Metabolic process; Metabolism; Metabolites; Metabolomic analysis; Oxidation; Oxidation pathway; Oxidative pathways; Sirtuin
• Online Access: View Fulltext in Publisher

 A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme sirtuin 5 (SIRT5). Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal that glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We also demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic analyses indicate an expanded role for SIRT5 in regulating amino acid metabolism. Together, these data support a feedback loop model within the lysine/tryptophan oxidation pathway in which glutaryl-CoA is produced, in turn inhibiting GCDH function via glutaryl modification of GCDH lysine residues and can be relieved by SIRT5 deacylation activity. © 2022 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.