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

Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
Nature Biotechnology (Impact Factor: 41.51). 10/2008; 26(10):1179-86. DOI: 10.1038/nbt.1500
Source: PubMed


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 (13)C-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.

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Available from: Thomas Shenk, Oct 24, 2014
    • "Acid hydrolysis is commonly used in metabolic flux analysis (MFA) applications, but the extent of labeling in glycans is not commonly measured [34] . This is particularly true in MFA applied to mammalian cells353637. To validate our approach we analyzed standards for specific glycan residues and compared the mass isotopomer distributions (MIDs) of specific fragments to those measured in cells cultured in the presence of [U-13 C 6 ] glucose. "
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    • "The fatty acids and other lipid materials that are generated by these processes are essential substrates for energy metabolism (Menendez and Lupu, 2007; Mashima et al., 2009) as well as the major components of all biological lipid membranes (Menendez and Lupu, 2007; Vander Heiden et al., 2009; Mashima et al., 2009). The Warburg Effect is also seen in vertebrate cells infected by oncogenic viruses such as KSHV (Kaposi's sarcoma-associated herpesvirus) (Delgado et al., 2010) and HCMV (Human cytomegalovirus ) (Munger et al., 2008), and a recent paper (Chen et al., 2011) further showed that it occurs in shrimp hemocytes that are infected by the White Spot Syndrome Virus (WSSV). WSSV, which is a large enveloped (approximately 300 kbp) dsDNA invertebrate virus with an in vivo replication cycle of 22e24 h, was found to trigger the Warburg effect at the WSSV genome replication stage (12 hpi [hours post infection]) via the activation of the PI3K-Akt-mTOR pathway (Su et al., 2014). "
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