‘Domino’ systems biology and the ‘A’ of ATP

We develop a strategic ‘domino’ approach that starts with one key feature of cell function and the main process providing for it, and then adds additional processes and components only as necessary to explain provoked experimental observations. The approach is here applied to the energy metabolism of yeast in a glucose limited chemostat, subjected to a sudden increase in glucose. The puzzles addressed include (i) the lack of increase in Adenosine triphosphate (ATP) upon glucose addition, (ii) the lack of increase in Adenosine diphosphate (ADP) when ATP is hydrolyzed, and (iii) the rapid disappearance of the ‘A’ (adenine) moiety of ATP. Neither the incorporation of nucleotides into new biomass, nor steady de novo synthesis of Adenosine monophosphate (AMP) explains. Cycling of the ‘A’ moiety accelerates when the cell's energy state is endangered, another essential domino among the seven required for understanding of the experimental observations. This new domino analysis shows how strategic experimental design and observations in tandem with theory and modeling may identify and resolve important paradoxes. It also highlights the hitherto unexpected role of the ‘A’ component of ATP.

► A novel ‘domino’ systems biology approach is developed to explain ATP paradox.
► Domino systems biology starts with a key feature of cell function and main process.
► More processes are added only as needed to explain experimental observations.
► Domino approach explains rapid disappearance of ATP in glucose perturbed yeast.
► It explains new role of the adenine of ATP in energy endangered states of cell.