(133e) Bistability In Glycolysis Pathway As a Physiological Switch In Energy Metabolism

Mammalian cells in culture consume large amounts of glucose and divert most of it towards lactate production.  Such high glucose consumption rates are in general typical of rapidly proliferating cells including embryonic stem cells and tumor cells.  In contrast, non-proliferating tissues consume glucose at much slower rates and oxidize most of it to carbon dioxide in the mitochondria.  Such differences in glucose metabolism can be attributed to the coordinated expression of different glycolytic isozymes, which can form mutually regulated networks.  The regulations governing such networks are mediated through the allosteric control of the expressed isozymes by reaction intermediates upstream and downstream of the glycolysis pathway.  These regulatory networks can result in different glycolytic behavior ranging from sustained oscillations to bistability. 

Here, using kinetic modeling we focus on the importance of these regulations in the occurrence of bistability in glycolytic activity.  Results demonstrate that bistability is mainly limited to conditions when cells express isozymes specific to rapidly proliferating cells including muscle isozyme of phosphofructokinase (PFKM), hexokinase 1 (HK1) or hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) isozyme.  We identified fructose-1,6-bisphosphate (F16BP) as a critical regulator of the bistable behavior through its modulation of the above mentioned isozymes, directly or indirectly. Further, the physiological significance of this bistable switch and its modulation by various signaling pathways and other metabolic intermediates will be discussed.  These novel findings will enhance our understanding of metabolic control in mammalian cells and help in designing strategies for process enhancement through manipulation of cellular energy metabolism.