Bioorthogonal pro-metabolites for profiling short chain fatty acylation† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00247e
Bioorthogonal pro-metabolites for profiling short chain fatty acylation† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00247e
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用于分析短链脂肪酰化的生物正交前代谢物† †提供电子补充信息 (ESI)，请参阅 DOI：10.1039/c7sc00247e。
DOI：
10.1101/097360
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发表时间：
2016
期刊：
影响因子：
8.4
通讯作者：
J. Meier
中科院分区：
文献类型：
--
作者：
Wilson R. Sinclair;Jonathan H. Shrimp;Thomas T. Zengeya;Rhushikesh A. Kulkarni;Julie M. Garlick;Hans F. Luecke;A. Worth;I. Blair;N. Snyder;J. Meier
短链脂肪酸（SCFA）在健康和疾病中起着重要作用。这些信号分子的一个功能是作为短链脂肪酰化的前体，这是一类由赖氨酸乙酰转移酶（KAT）和赖氨酸脱乙酰酶（KDAC）建立的代谢衍生的翻译后修饰（PTM）。通过这种机制，短链脂肪酰化作为代谢以及KAT和KDAC活性的综合报告者，并有可能阐明这些过程在疾病中的作用。然而，研究短链脂肪酰化的方法很少。在这里，我们报告了一个生物正交的前代谢物的策略，在活细胞中的短链脂肪酰化。受膳食成分三丁酸甘油酯的启发，我们合成了一组酯笼生物正交短链脂肪酸。这些试剂的细胞评价导致发现了代谢为其同源酰基辅酶A（CoA）并提供稳健的蛋白质标记谱的叠氮基酯。我们全面表征了这些生物正交前代谢物的代谢依赖性、毒性和组蛋白脱乙酰酶（HDAC）抑制活性，并应用优化的探针来识别细胞中短链脂肪酸的新候选蛋白质靶点。我们的研究展示了生物正交前代谢物用于细胞蛋白酰化的无偏分析的效用，并提出了研究SCFAs在分化和疾病中的信号功能的新方法。
Short chain fatty acids (SCFAs) play a central role in health and disease. One function of these signaling molecules is to serve as precursors for short chain fatty acylation, a class of metabolically-derived posttranslational modifications (PTMs) that are established by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Via this mechanism, short chain fatty acylation serves as an integrated reporter of metabolism as well as KAT and KDAC activity, and has the potential to illuminate the role of these processes in disease. However, few methods to study short chain fatty acylation exist. Here we report a bioorthogonal pro-metabolite strategy for profiling short chain fatty acylation in living cells. Inspired by the dietary component tributyrin, we synthesized a panel of ester-caged bioorthogonal short chain fatty acids. Cellular evaluation of these agents led to the discovery of an azido-ester that is metabolized to its cognate acyl-coenzyme A (CoA) and affords robust protein labeling profiles. We comprehensively characterize the metabolic dependence, toxicity, and histone deacetylase (HDAC) inhibitory activity of these bioorthogonal pro-metabolites, and apply an optimized probe to identify novel candidate protein targets of short chain fatty acids in cells. Our studies showcase the utility of bioorthogonal pro-metabolites for unbiased profiling of cellular protein acylation, and suggest new approaches for studying the signaling functions of SCFAs in differentiation and disease.
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影响因子：
29
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
通讯作者：
Wellen KE
gnotobiotic小鼠模型表明，饮食纤维以微生物群和丁酸酯依赖性方式预防结肠直肠肿瘤发生。
影响因子：
28.2
作者：
Donohoe DR;Holley D;Collins LB;Montgomery SA;Whitmore AC;Hillhouse A;Curry KP;Renner SW;Greenwalt A;Ryan EP;Godfrey V;Heise MT;Threadgill DS;Han A;Swenberg JA;Threadgill DW;Bultman SJ
通讯作者：
Bultman SJ
影响因子：
3.9
作者：
Thinon E;Hang HC
通讯作者：
Hang HC
影响因子：
11.2
作者：
B. Heerdt;M. Houston;L. Augenlicht
通讯作者：
B. Heerdt;M. Houston;L. Augenlicht
赖氨酸乙酰转移酶的微流体迁移率变化分析可实现细胞乙酰化抑制剂的筛选和机理分析。
影响因子：
4
作者：
Sorum,AlexanderW;Shrimp,JonathanH;Roberts,AllisonM;Montgomery,DavidC;Tiwari,NeilK;Lal-Nag,Madhu;Simeonov,Anton;Jadhav,Ajit;Meier,JordanL
通讯作者：
Meier,JordanL