title: Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation.
abstract: The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.
authors: From the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637.
authors: Gozde
authors: G
authors: Colak
authors: Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Olga
authors: O
authors: Pougovkina
authors: From the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637.
authors: Lunzhi
authors: L
authors: Dai
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Minjia
authors: M
authors: Tan
authors: Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Heleen
authors: H
authors: Te Brinke
authors: From the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637.
authors: He
authors: H
authors: Huang
authors: PTM Biolabs, Chicago, Illinois 60612.
authors: Zhongyi
authors: Z
authors: Cheng
authors: Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109.
authors: Jeongsoon
authors: J
authors: Park
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Xuelian
authors: X
authors: Wan
authors: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and.
authors: Xiaojing
authors: X
authors: Liu
authors: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors: Wyatt W
authors: WW
authors: Yue
authors: Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma's Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: Ronald J A
authors: RJ
authors: Wanders
authors: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and.
authors: Jason W
authors: JW
authors: Locasale
authors: Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109.
authors: David B
authors: DB
authors: Lombard
authors: Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma's Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands, v.c.deboer@amc.uva.nl.
authors: Vincent C J
authors: VC
authors: de Boer
authors: From the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, yingming.zhao@uchicago.edu.
authors: Yingming
authors: Y
authors: Zhao
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008764:Methylmalonic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics
chemical_list: D005227:Fatty Acids; D008314:Malonates; C542554:SIRT5 protein, mouse; D008316:Malonyl Coenzyme A; D008764:Methylmalonic Acid; C030290:malonic acid; D037761:Sirtuins; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D008239:Lysine