期刊
CELL METABOLISM
卷 25, 期 4, 页码 823-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2017.03.006
关键词
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资金
- American Heart Association [12IRG9010008]
- Edward Mallinckrodt, Jr. Foundation
- Ellison Medical Foundation
- National Institutes of Health
- NIAAA [R01AA022146]
- NIA [R01AG045351]
- Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research - National Institute of Aging [P30AG028716-01]
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [2T32DK007012]
- NIH/NCATS Colorado CTSI [UL1TR001082]
- Canadian Institutes for Health Research [178978]
- NIH [B6.129S4-Gcdhtm1Dmk/Mmnc, 034368-UNC, 8U42OD010924-13]
The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive intermediates that non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized a protein modification: 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications: 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)lysine. Using quantitative proteomics, we compared the acylomes'' of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation and validated malate dehydrogenase as a key target. These data uncover a fundamental relationship between reactive acyl-CoA species and proteins and define a new regulatory paradigm in metabolism.
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