Research Focus

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:

1. Quantitative modeling of the complete metabolic reaction network, using iterative series of computer simulations and experiments;
2. Exploration of the linkages between perturbation of the cellular environment (e.g., nutrient deprivation), metabolic response, and gene expression response; and
3. 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)

Selected Publications

• Olszewski, K., Barsotti, A., Feng, X. J., Momcilovic, M., Liu, K.G., Kim, J. I., Morris, K., Lamarque, C., Gaffney, J., Yu, X., Patel, J. P., Rabinowitz, J. D., Shackelford, D. B., Poyurovsky, M. V. Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors. (2022) Cell Chem Biol., 29: 423-435.e.10. Pubmed

• Nofal, M., Wang, T., Yang, L., Jankowski, C. S. R., Hsin-Jung, L. S., Han, S., Parsons, L., Frese, A. N., Gitai, Z., Anthony, T. G., Wühr, M., Sabatini, D. M., Rabinowitz, J. D. (2022) GCN2 adapts protein synthesis to scavenging-dependent growth. Cell Syst., 13: 158-172. Pubmed

• Yang, L., TeSlaa, T., Ng, S., Nofal, M., Wang, L., Lan, T., Zeng, X., Cowan, A., McBride, M., Lu, W., Davidson, S., Liang, G., Oh, T. G., Downes, M., Evans, R., Von Hoff, D., Guo, J. Y., Han, H., Rabinowitz, J.D. (2022) Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth. Med (N Y), 3:119-136.

View complete list of Publications.