Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy

被引:510
作者
Munger, Joshua [3 ,4 ]
Bennett, Bryson D. [1 ,2 ]
Parikh, Anuraag [1 ,2 ]
Feng, Xiao-Jiang [5 ]
McArdle, Jessica [4 ]
Rabitz, Herschel A. [5 ]
Shenk, Thomas [3 ]
Rabinowitz, Joshua D. [1 ,2 ]
机构
[1] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA
[2] Princeton Univ, Lewis Sigler Inst Integrat Genom, Carl Icahn Lab, Princeton, NJ 08544 USA
[3] Princeton Univ, Dept Mol Biol, Lewis Thomas Lab, Princeton, NJ 08544 USA
[4] Univ Rochester, Dept Biochem & Biophys, Sch Med & Dent, Rochester, NY 14642 USA
[5] Princeton Univ, Dept Chem, Frick Lab, Princeton, NJ 08544 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
D O I
10.1038/nbt.1500
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks for viral replication. We developed a flux measurement approach based on liquid chromatography -tandem mass spectrometry to quantify changes in metabolic activity induced by human cytomegalovirus (HCMV). This approach reliably elucidated fluxes in cultured mammalian cells by monitoring metabolome labeling kinetics after feeding cells C-13-labeled forms of glucose and glutamine. Infection with HCMV markedly upregulated flux through much of the central carbon metabolism, including glycolysis. Particularly notable increases occurred in flux through the tricarboxylic acid cycle and its efflux to the fatty acid biosynthesis pathway. Pharmacological inhibition of fatty acid biosynthesis suppressed the replication of both HCMV and influenza A, another enveloped virus. These results show that fatty acid synthesis is essential for the replication of two divergent enveloped viruses and that systems-level metabolic flux profiling can identify metabolic targets for antiviral therapy.
引用
收藏
页码:1179 / 1186
页数:8
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