Areas of Research: Quantitative and comprehensive understanding of metabolism.
- Chemistry and the Lewis-Sigler Institute for Integrative Genomics
241 Carl Icahn Laboratory
Towards a Holistic Understanding of Cellular Metabolism
The 20th century saw remarkable progress in understanding key biochemical structures and processes, such as the enzymatic pathway by which glucose is used to generate ATP and the mechanism of replication of genetic material. Until very recently, however, chemical biology focused almost exclusively on understanding biological processes in relative isolation, with minimal attention to the mechanisms by which the complete chemical constituents of cells, or even more dauntingly multi-cellular organisms, function together. With newfound knowledge of the full genetic sequences of multiple organisms, chemical biology is for the first time beginning to investigate the means by which the integrated functioning of the full complement of biological chemicals yields life.
To succeed in developing a complete chemical model of even a simple organism, it is necessary to gain a comprehensive understanding of the molecular constituents involved, including their function, production, consumption, and geometrical organization. These constituents can be broadly divided into large molecule biopolymers such as DNA, RNA, and proteins, and small molecules such metabolic intermediates and membrane lipids. Currently, progress towards a complete understanding of biopolymers is progressing with remarkable speed, largely due to the advent of powerful new analytical tools such as DNA microarrays.
A critical complement to the current holistic studies of cellular large molecules is comparably comprehensive study of the dynamics of the intracellular metabolites. Currently, methods for comprehensive characterization of small molecule concentrations and fluxes in living cells lag behind those for biopolymer expression. The overall goal of our lab is to develop robust means of measuring the concentrations and fluxes of numerous intracellular metabolites in parallel.
Scientific and Biomedical Applications
In our research, beyond developing analytical tools, we apply our metabolite concentration and flux measurement capabilities in three areas:
- Quantitative modeling of the complete metabolic reaction network, using iterative series of computer simulations and experiments;
- Exploration of the linkages between perturbation of the cellular environment (e.g., nutrient deprivation), metabolic response, and gene expression response; and
- Discovery of improved metabolic inhibitors (a large number of important drugs, including some antibiotics, anticancer agents, and cholesterol lowering drugs, function by blocking specific metabolic reactions)
- Davila, A., Liu. L., Chellappa, K., Redpath, P., Nakamaru-Ogiso, E., Paolella, L. M., Zhang, Z., Migaud, M. E., Rabinowitz, J. D., Baur, J. A. (2018) Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. Elife, 7. pii: e33246. Pubmed
- Nofal, M. and Rabinowitz, J. D. (2018) Ribosomes on the night shift. Science, 360(6390):710-711. Pubmed
- Jang, C., Chen, L., Rabinowitz, J. D. (2018) Metabolomics and isotope tracing. Cell, 173: 822-837. Pubmed
- Liu, L., Su, X., Quinn, W. J. 3rd, Hui, S., Krukenberg, K., Frederick, D. W., Redpath, P., Zhan, L., Chellappa, K., White, E., Migaud, M., Mitchison, T. J., Baur, J. A., Rabinowitz, J. D. (2018) Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab., 27: 1067-1080 e5. Pubmed
- Miller, R. A., Shi, Y., Lu, W., Pirman, D. A., Jatkar, A., Blatnik, M., Wu, H., Cárdenas, C., Wan, M., Foskett, J. K., Park, J. O., Zhang, Y., Holland, W. L., Rabinowitz, J. D., Birnbaum, M. J. (2018) Targeting hepatic glutaminase activity to ameliorate hyperglycemia. Nat Med., 24: 518-524. Pubmed
- Lanaspa, M. A., Andres-Hernando, A., Orlicky, D. J., Cicerchi, C., Jang, C., Li, N., Milagres, T., Kuwabara, M., Wempe, M. F., Rabinowitz, J. D., Johnson, R. J., Tolan, D. R. (2018) Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest., 128: 2226-2238. Pubmed
- Gibney, P. A., Schieler, A., Chen, J. C., Bacha-Hummel, J. M., Botstein, M., Volpe, M., Silverman, S. J., Xu, Y., Bennett, B. D., Rabinowitz, J. D., Botstein, D. (2018) Common and Divergent Features of Galactose-1-phosphate and Fructose-1-phosphate Toxicity in Yeast. Mol Biol Cell, 29: 897-910. Pubmed
- McKee, S. E., Zhang, S., Chen, L., Rabinowitz, J. D., Reyes, T. M. (2018) Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain. J Neurochem. 145: 362-373. Pubmed
- Jang, C. J., Hui, S., Lu, W., Cowan, A. J., Morscher, R. J., Lee, G., Liu, W., Tesz, G. J., Birnbaum, M. J., Rabinowitz, J. D. (2018) The small intestine converts dietary fructose into glucose and organic acids. Cell Metab., 27: 351-361. Pubmed
- Morscher, R. J., Ducker, G. S., Li, H. S., Mayer, J. A., Gitai, Z., Sper, W., Rabinowitz, J. D. Mitochondrial translation requires folate-dependent tRNA methylation. Nature, 554: 128-132. Pubmed
- Pavlova, N. N., Hui, S., Ghergurovich, J. M., Fan, J., Intlekofer, A. M., White, R. M., Rabinowitz, J. D., Thompson, C. B., Zhang, J. (2018) As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab., 27: 428-438.e5. Pubmed
- Lin, K. C., Torga, G., Wu, A., Rabinowitz, J. D., Murray, W. J., Sturm, J. C., Pienta, K. J., Austin, R. (2017) Epithelial and mesenchymal prostate cancer cell population dynamics on a complex drug landscape. Converg Sci Phys Oncol., 3: pii: 045001. Pubmed
- Lee, G., Zheng, Y., Cho, S., Jang, C., England, C., Dempsey, J. M., Yu, Y., Liu, X., He, L., Cavaliere, P. M., Chavez, A., Zhang, E., Isik, M., Couvillon, A., Dephoure, N. E., Blackwell, T. K., Yu, J. J., Rabinowitz, J. D., Cantley, L. C., Blenis, J. (2017) Post-transcriptional regulation of de novo lipogenesis by mTORC1-S6K1-SRPK2 signaling. Cell, 171: 1545-1558. Pubmed
- Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung, Li S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., Rabinowitz, J.D. (2017) Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. USA, 114: 11404-11409. Pubmed
- Liu, L. X., Rowe, G. C., Yang, S., Li, J., Damilano, F., Chan, M. C., Lu, W., Jang, C., Wada, S., Morley, M., Hesse, M., Fleischmann, B. K., Rabinowitz, J., Das, S., Rosenzweig, A., Arany, Z. (2017) PDK4 inhibits cardiac pyruvate oxidation in late pregnancy. Circ Res., 121: 1370-1378. Pubmed
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