Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cell Rep. 2021 Aug 3;36(5):109487. doi: 10.1016/j.celrep.2021.109487.
Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.
酮体是生物活性代谢物，可作为能量底物、信号分子和组蛋白修饰的调节剂。β-羟丁酸（β-OHB）用于组蛋白赖氨酸β-羟丁酰化（Kbhb），与饥饿反应基因相关，有效地将生酮代谢与基因表达偶联。赖氨酸酰化景观的新兴多样性促使我们研究 Kbhb 对蛋白质组的全面影响。各种干预措施可诱导β-OHB，以组织特异性方式诱导全局蛋白 Kbhb。通过质谱分析发现，在富含脂肪酸、氨基酸、解毒和一碳代谢途径的 267 种蛋白质中，有 891 个 Kbhb 位点。Kbhb 与代谢物水平的改变平行抑制 S-腺苷-L-同型半胱氨酸水解酶（AHCY），即蛋氨酸循环的限速酶。我们的结果阐明了生酮条件下 Kbhb 在肝代谢中的作用，并证明了这种修饰对中央代谢酶的功能后果。
