Linking Metabolic and Cell Cycle Regulation

One of the most fundamental challenges in modern biology is to understand how cells process and integrate information into coordinated physiological responses. Importantly, cells must coordinate the regulation of growth and division, i.e. the cell cycle, with the catabolic and anabolic pathways that provide the energy and raw materials necessary for all cellular activities. Determining the mechanisms responsible for this coordination of metabolism with the cell division cycle is fundamental for understanding human physiology and disease states such as cancer, the ecology and evolution of single cell organisms in their environments, as well as the constraints governing metabolic engineering of these organisms.

The cell division cycle consists of a sequence of processes whose specific demands for biosynthetic precursors and energy place dynamic requirements on metabolism. However, little is known about how metabolic fluxes are coordinated with the cell cycle. We examined budding yeast to show that over half of all (>500) measured metabolites change significantly in the course of the cell division cycle (Ewald et al 2016: The yeast cyclin-dependent kinase routes carbon fluxes to fuel cell cycle progression). We found that the cyclin-dependent kinase Cdk1, a major cell cycle regulator, also controls carbon metabolism. At the G1/S transition, Cdk1 phosphorylates and activates the enzyme Nth1, which funnels the storage carbohydrate trehalose into central carbon metabolism. Trehalose utilization fuels anabolic processes required to reliably complete cell division. This demonstrates how cell cycle regulation can entrain carbon metabolism to dynamically fuel biosynthesis during proliferation. Since the oscillation of Cdk-activity is a conserved feature of the eukaryotic cell cycle, we anticipate its frequent use in dynamically regulating metabolism for efficient proliferation.

Despite our and other’s recent advances, our understanding of the mechanisms that govern the cell cycle ‑ metabolism interface remains largely rudimentary and phenomenological. The Ewald lab combines metabolomics, biochemistry and live cell imaging to address the multiple layers of the fundamental question: How is metabolism coordinated with cell division?