A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.
A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.
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DOI：
10.1016/j.cmet.2017.03.006
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发表时间：
2017-04-04
期刊：
影响因子：
29
通讯作者：
Hirschey MD
中科院分区：
文献类型：
--
作者：
Wagner GR;Bhatt DP;O'Connell TM;Thompson JW;Dubois LG;Backos DS;Yang H;Mitchell GA;Ilkayeva OR;Stevens RD;Grimsrud PA;Hirschey MD
形成酰基蛋白修饰的机制仍然知之甚少。通过考察内源性酰基-辅酶A代谢产物的反应性，我们发现了一类在分子内催化形成活性中间体的酰基-辅酶A，这些中间体可以非酶修饰蛋白质。基于这一机制，我们预测、验证和表征了一种蛋白质修饰：3-羟基-3-甲基戊二醛(HMG)-赖氨酸。在HMG-CoA代谢改变的模型中，我们发现了两个额外的蛋白质修饰的证据：3-甲基谷氨酰基(MGC)-赖氨酸和3-甲基戊二酰基(MG)-赖氨酸。利用定量蛋白质组学，我们比较了两种反应性酰基辅酶A，即HMG-辅酶A和戊二酰辅酶A，它们以不同的途径生成的‘酰基体’。我们发现了每种反应性代谢物唯一修饰的蛋白质，以及常见的蛋白质和途径。我们确定三羧酸循环是一条通常由酰化调节的途径，并验证了苹果酸脱氢酶是一个关键靶点。这些数据揭示了反应性酰辅酶A物种和蛋白质之间的基本关系，并定义了新陈代谢的新调节范式。
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 undergoes intramolecular catalysis to form reactive intermediates which 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.