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. 2010 Feb 19;327(5968):1000-4.
doi: 10.1126/science.1179689.

"VSports在线直播" Regulation of cellular metabolism by protein lysine acetylation

Shimin Zhao  1 , Wei Xu, Wenqing Jiang, Wei Yu, Yan Lin, Tengfei Zhang, Jun Yao, Li Zhou, Yaxue Zeng, Hong Li, Yixue Li, Jiong Shi, Wenlin An, Susan M Hancock, Fuchu He, Lunxiu Qin, Jason Chin, Pengyuan Yang, Xian Chen, Qunying Lei, Yue Xiong, Kun-Liang Guan
Affiliations

Regulation of cellular metabolism by protein lysine acetylation

Shimin Zhao et al. Science. .

Abstract

Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation, in particular through the modification of histones and nuclear transcription regulators. We show that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoyl-coenzyme A hydratase/3-hydroxyacyl-coenzyme A dehydrogenase in fatty acid oxidation and malate dehydrogenase in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase in gluconeogenesis. Our study reveals that acetylation plays a major role in metabolic regulation VSports手机版. .

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VSports最新版本 - Figures

Fig. 1
Fig. 1
Acetylation of liver metabolic enzymes. (A) Comparison of three acetylation proteomic studies: this study and (2, 3). (B) Preferential acetylation of enzymes in intermediary metabolism. Fisher’s exact test of comparing acetylated proteins to total liver proteins shows that acetylation is much more prevalent in intermediary metabolic enzymes. (C to G) Acetylated metabolic enzymes identified by proteomic survey are marked in red. See supporting online material for key to abbreviations.
Fig. 2
Fig. 2
Activation of EHHADH and MDH by acetylation. (A) Acetylation of EHHADH was increased by deacetylase inhibitors. Ectopically expressed and immunoprecipitated (IP) EHHADH was examined by immunoblotting (IB) with antibody to acetyllysine (α-AcK). (B) Quantification of EHHADH acetylation by iTRAQ MS. Quantification of peptides was calculated on the basis of relative intensity of the iTRAQ tags. (C) Activation of EHHADH in cells expose to deacetylase inhibitors. Data in this panel and subsequent figures are from triplicate experiments. (D) Fatty acid induced EHHADH acetylation and activity. Acetylation and activity of EHHDH ectopically expressed in HEK293T cells were monitored. (E) MDH acetylation. MDH-Myc was expressed in HEK293T cells and acetylation was determined by immunoblotting. (F) Quantitative MS analysis of MDH. FLAG tagged MDH was overexpressed in HEK293T cells and purified by immunoprecipitation. Eluted intact MDH proteins were analyzed by FTICR MS. (G) Glucose enhances MDH acetylation. (H) Activation of MDH by acetylation. The activity of endogenous and ectopically expressed MDH from Chang and HEK293T cells, respectively, were assayed and normalized against actin. (I) Inactivation of MDH by in vitro deacetylation. Immunoprecipitated MDH was incubated with or without CobB deacetylase and activity was assayed. NAD, an essential cofactor for CobB, was omitted as a negative control. (J) Activation of MDH by glucose. Experiments were similar to (H) except cells were treated with glucose.
Fig. 3
Fig. 3
Inactivation of ASL by acetylation. (A and B) ASL acetylation. FLAG-tagged ASL or ASLK288R was overex-pressed in HEK293T cells, immunoprecipitated, and probed with antibody to acetyllysine (A) or to acetyl-Lys288 (B). (C) Inhibition of ASL acetylation by extra amino acids. ASL was immunoprecipitated from transfected HEK293T cells, which were treated with various amino acid concentrations. (D) Inhibition of ASL in response to NAM and TSA. Wild-type and mutant ASL-K288R (132% of wild-type activity) proteins were expressed in HEK293T cells that were treated with NAM and TSA as indicated. Activity of immuno-precipitated ASL was normalized to total protein. (E) Requirement of Lys288 acetylation for ASL activation by amino acids. Wild-type and mutant ASL proteins were overexpressed in HEK293T cells incubated in medium containing various amino acid concentrations. (F and G) Effects of glucose on acetylation and activity of ASL. ASL was overexpressed in HEK293T cells that were treated with various concentrations of glucose. Acetylation and activity of immunoprecipitated ASL were determined. (H) Activation of ASL by in vitro deacetylation. In vitro deacetylation was similar to Fig. 2I.
Fig. 4
Fig. 4
Destabilization of PEPCK1 by acetylation. (A) Glucose induces PEPCK1 acetylation. (B) Amino acids decrease PEPCK1 acetylation. (C) Glucose induces depletion in of PEPCK1 protein. Endogenous PEPCK levels were detected with a PEPCK1 antibody. (D) TSA and NAM reduce PEPCK1 protein abundance. (E) Glucose destabilizes PEPCK1. Cycloheximide was added at time zero to block translation in HEK293 cells. PEPCK1 protein abundance was determined by Western blotting. (F) Inhibition of deacetylases destabilizes the wild type but not the acetylation-defective mutant PEPCK1.
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Comment in

  • Cell biology. Rise of the rival.
    Norvell A, McMahon SB. Norvell A, et al. Science. 2010 Feb 19;327(5968):964-5. doi: 10.1126/science.1187159. Science. 2010. PMID: 20167774 No abstract available.

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