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Mass-Action Ratios! Metabolomics: study of intermediates and their movement Mass-action ratios are the ratio of products over reactants for any given reaction knowing whether this ratio is > or < the Keq (the ratio at equilibrium) allows you to predict which way the reaction will adjust (classic Le Chatelier's approach) For instance Glucose-6-P Qphosphoglucomutase = Glucose-1-P Glycogen phosphorylase Glucose (shipped out) Glucose-1-P Glucose-6-P phosphoglucomutase UDP-Glucose pyrophosphatase Glycogen synthase Glycolysis However, in biochemical processes, where reactions are often linked to other reactions, Le Chatelier's Princple must take on a more global view. Looking at the ratio above, if Glu-6-P rises, bringing the ratio above its "resting" or Keq state, equilibrium can be regained by shifting the reactions to the right (glucose is shipped out, or glycolysis is continued). Similarly, if Glu-1-P builds up, it is too restrictive to simply say the phosphoglucomutase reaction will shift right, when equilibrium can be reasserted by shifting toward glycogen production (reaction on the left of Glu-1-P). To get a broader perspective about how a series of reactions adjust, it is important to take a broader view of the mass action ratio idea. Now consider any combination of related compounds (usually this is a chemical relationship, meaning they share the same basic structure or are interconverted enzymatically, though possibly indirectly) and think about what happens if that ratio is away from its natural "equilibrium" state. Both of these reactions say something about the overall energy level of the cell; when higher than a cell's average or "resting" state, it means that ATP or NADH is probably available for synthetic reactions (remember that ATP and NADH are high energy molecules, supplying energy for the cell's needs. When low, it tells the cell that NADH or ATP is/are needed, and breakdown reactions are probably coming in order to generate these high energy molecules (for instance, glycolysis). Common ratios to consider or AMP or Pi, etc NADH ATP or NAD+ ADP Notice that even with this broader ratio, high glucose can be adjusted by increasing glycolysis OR by shipping the glucose out....likewise, high pyruvate might encourage gluconeogenesis, or it might encourage pyruvate to take another path to keep glycolysis going.... glucose as a measure of Or how about pyruvate how the entire glycolytic path is working? Ratios can be considered like a switch or pressure valve for a system - everything naturally returns to equilibrium by releasing the "pressure" that concentration changes (causing ratios that are shifted from equilibrium) bring. For instance, muscles have two methods for releasing pressure, allowing glycolysis to continue at a high rate against the pressure of building up ATP, limiting NAD+ and possibly building up pyruvate ("anaerobic"): Releasing the pressure of increasing pyruvate concentration and decreasing NAD+: Lactic acid production O O NADH + H+ C C NAD+ O O CH3 O C H C OH lactate dehydrogenase pyruvate CH3 lactate (lactic acid) Because pyruvate is turned into lactate, it does not build up, which would slow down the pyruvate kinase reaction (PEP --> pyruvate). This would in turn slow down each of the enzymes in the pathway, blocking the path or leading to other pressure releases (branching pathways, like the pentose phosphate pathway). Similarly, regenerating NAD+ allows the glyceraldehyde-3-phosphate dehydrogenase reaction to continue (and NADH/NAD+ to remain steady, rather than rising and shutting off the sign that energy is still needed. "Hiding" ATP, thereby keeping the ATP/ADP ratio lower than it really is, by phosphorylating creatine C C CH2 ATP H3C N C NH2 NH2 creatine O O O O creatine kinase ADP CH2 H3C N O O P O C NH2 NH creatine phosphate or phosphocreatine Each cell has its own resting or average ATP/ADP ratio. Muscles need to keep a reservoir of ATP, but an extremely high ATP/ADP ratio would affect the equilibria of ALL reactions that involve these nucleotides. By keeping a large concentration of creatine, the high energy N-P bond can be made using creatine kinase. When soluble ATP levels fall, the reverse reaction spontaneously generates ATP by cleaving the N-P bond. In this way, the ATP is "there," but the ATP/ADP ratio is still low. Nolta 2009