Experimental and Theoretical Characterization of Metabolic Coordination

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In this project, the PI will use a combination of experimental and theoretical approaches to revisit one of the intensively studied systems in molecular biology-catabolic repression. This is a widespread phenomenon whereby microorganisms grown in "good" (i.e., fast-growing) carbon sources such as glucose inhibit the synthesis of proteins needed for the consumption of "poor" (slow-growing) carbons. Despite a tremendous amount of knowledge characterized for this phenomenon at the molecular level for the bacterium E. coli, the "big picture" is still missing: In particular, what is this regulatory system for and how does the cell sense the quality of a carbon source? Based on a number of striking preliminary findings, the PI hypothesizes a radically different picture for the physiological function of catabolite repression, with its predominant role in coordinating the metabolism of carbon with other nutrient sources (e.g., nitrogen and sulfur), rather than in controlling the hierarchy of carbon metabolism. The PI will establish the new picture by quantitatively characterizing the expression of enzymes involved in carbon and nitrogen metabolism for a series of key mutants, under a variety of carbon-limiting and nitrogen-limiting conditions, paying special attention to changes in growth rates in the different growth conditions. The results will be analyzed by a phenomenological theory of exponential growth developed recently by the PI's lab. This research program will establish a new phenomenological approach to studying gene regulation and metabolism, an approach that involves very few parameters and is hence predictive. The simplicity of the approach will allow students with traditional biology training to grab the essence of quantitative physical reasoning, and allow students with physics training to learn a biological system in the context of physiology. The results of this research will exert a strong, transformative impact on the subject of metabolic regulation and more broadly on the field of quantitative biology. Due to the historical role catabolite repression played in the development of molecular biology, major revision in the understanding of this classic subject will also be noted broadly in other parts of the biology community. They will lend weight to the use of quantitative phenomenological approaches, which are very effective in elucidating complex physical systems but have so far seen very limited use in the study of biomolecular systems. Research output will be integrated into the PI's annual course on "quantitative biology", and the summer workshops the PI organizes for introducing physical scientists to quantitative biology.This project is being supported jointly by the Physics of Living Systems Program in the Physics Division and by Biomolecular Dynamics, Structure and Function in MCB.