The Yeast Cyclin-Dependent Kinase Routes Carbon Fluxes to Fuel Cell Cycle Progression

Abstract

Cell division entails 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 division cycle. Here, we examine budding yeast to show that over half of all measured metabolites change significantly through the cell division cycle. Cell cycle-dependent changes in central carbon metabolism are controlled by the cyclin-dependent kinase Cdk1, a major cell cycle regulator, and the metabolic regulator protein kinase A. 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. Thus, the cell cycle entrains carbon metabolism to fuel biosynthesis. 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.

p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells

“…It is possible that p21-dependent inhibition of additional or alternative CDKs (e.g., CDK1/2) is required to conserve GSH and inhibits ferroptosis through induction of a more complete cell-cycle arrest. Alternatively, p21 could potentially enhance GSH retention through effects on CDK-regulated metabolic enzymes (Ewald et al, 2016). …”

Advances and challenges in logical modeling of cell cycle regulation: perspective for multi-scale, integrative yeast cell models

“…2012; Cai and Tu 2012; Ewald et al. 2016; Zhao et al. 2016) and in mammalian cells (Lim and Kaldis 2013; Kaplon, van Dam and Peeper 2015).…”

“…The integrative model has been validated by testing the regulation of trehalose degradation, which has been recently suggested to occur in both in vitro and in vivo experiments by Cdk1-mediated phosphorylation of the trehalase Nth1 (Ewald et al. 2016; Zhao et al. 2016).…”

Coupling of the cell cycle and metabolism in yeast cell-cycle-related oscillations via resource criticality and checkpoint gating

“…For instance, Zhao, Chen, Carey, and Futcher (2016) and Ewald, Kuehne, Zamboni, and Skotheim (2016) note that the CDC and metabolism have many regulatory genes in common. Additionally, understanding yeast oscillations and regulation of metabolism is important in the efficient management of bioprocesses (Beuse, Kopmann, Diekmann, & Thoma, 1999;Uchiyama, Morimoto, Yokoyama, & Shioya, 1996).…”

“…Detailed biochemical models of the growth and division processes within a single fission yeast's cell cycle, including checkpoint controls, were considered in Novak, Csikasz-Nagy, Gyorffy, Chen, and Tyson (1998). Recently, Zhao et al (2016) and Ewald et al (2016) observed that the use of internal carbohydrates is regulated by CDK activity. CDKs have long been known to be primary regulatory agents in the cell cycle.…”