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Unformatted text preview: Regulation of Glycolysis and Gluconeogenesis Jonathan Galazka 3‐6‐2009 Because glycolysis and gluconeogenesis are essentially the reverse of one another, their regulation must be coordinated. We covered a few ways that this happened. They are outlined below. Hexokinase – Page 52 in your reader. As the first enzyme in glycolysis, hexokinase is an important point of regulation. Humans have four isozymes of hexokinase. Hexokinase I and II – These reside in muscle cells and have a high affinity for glucose (Km = 0.1 mM). Blood glucose is normally at about 4 mM. Therefore hexokinase I and II are saturated and work at maximal rate. These isozymes are allosterically inhibited by their product, glucose 6‐phosphate. Hexokinase IV – This is the major hexokinase in the liver. Recall that the liver often acts to supply glucose to other tissues, or as a place of glucose storage. Hexokinase IV has a lower affinity for glucose (Km = 10 mM). Because blood glucose levels do not saturate hexokinase IV, its activity is sensitive to changes in blood glucose concentration. Hexokinase IV is not inhibited by its product, glucose 6‐phosphate and can therefore continue to operate when the liver is converting blood glucose into glycogen. A final way that hexokinase IV is regulated is through the binding of a regulatory protein. When this protein binds it ‘hides’ hexokinase in the nucleus thus inactivating it. Glucose inhibits this binding, releasing hexokinase. Alternatively, fructose 6‐ phosphate enhances this binding. The presence of high levels of fructose 6‐phosphate signals that the glycolysis pathway is ‘filling up’ with metabolites, and that no more should be let in. Phosphofructokinase1 and Fructose 1,6bisphosphatase – Page 55 in your reader. Recall that phosphofructokinase‐1 and fructose 1,6‐bisphosphatase catalyze the interconversion of fructose 6‐phosphate and fructose 1,6‐bisphosphate. Phosphofructokinase‐1 is a part of glycolysis, while fructose 1,6‐bisphosphatase is a part of gluconeogenesis. Once fructose 6‐phosphate has been converted to fructose 1,6‐bisphosphate it is ‘committed’ to glycolysis. Before this point there are alternative routes that can be taken. The pentose phosphate pathway is an example. PFK1 (Phosphofructokinase1) – (Page 58 in reader, lower right) PFK‐1 is activated by metabolites that signal a low‐energy state in the cell (ADP, AMP) and inhibited by metabolites that signal a high‐energy state in the cell (ATP, citrate). Thus, when more energy is requires, glycolysis is switched on. When energy is abundant, glycolysis is switched off. There is one more activator of PFK‐1, fructose 2,6‐bisphosphate that will be discussed below. FBPase (Fructose 1,6bisphosphatase) – (Page 58 in your reader, lower right) FBPase is inhibited by metabolites that signal a low‐energy state in the cell (AMP). Thus, when more energy is needed from glycolysis, gluconeogenesis is turned off. There is one more inhibitor of FBPase, fructose 2,6‐bisphosphate that will be discussed below. Fructose 2,6bisphosphate (Page 58 in reader)– First of all, do not confuse fructose 2,6‐bisphosphate with fructose 1,6‐bisphosphate. Fructose 2,6 bisphosphate is not a metabolite of the glycolytic pathway. I’ll refer to it as F26BP. The liver plays a key role in maintaining blood glucose levels. Therefore the processes of glycolysis and gluconeogenesis must be able to respond to signals sent by the body to the liver. These signals are in the form of two hormones. Insulin signals that blood glucose levels are high. Glucagon signals that blood glucose levels are low. When cells receive signals in the form of insulin or glucagon they respond by changing their intracellular F26BP concentration. Two enzymes control F26BP levels, phosphofructokinase‐2 (PFK‐2) and fructose 2,6‐bisphosphatase (FBPase‐2) (Page 59 in your reader, top panel). Again, do not confuse these with PFK‐1 and FBPase‐1, which are involved in glycolysis. PFK‐2 and FBPase are actually part of the same protein. Think of a protein that contains two active sites. Glucagon activates a kinase that phosphorylates the FBPase‐2/PFK‐2 protein (Page 59 in your reader, lower panel). This phosphorylation activates the FBPase‐2 active site, which takes F26BP to fructose 6‐phosphate. This lowers F26BP levels. Insulin activates a phosphatase that removes the same phosphate from the FBPase‐ 2/PFK‐2 protein. This activates the PFK‐2 active site, which takes fructose 6‐ phosphate to F26BP. This raises F26BP levels. Now we’ll see how F26BP affects glycolysis and gluconeogenesis. F26BP activates PFK‐1, allowing glycolysis to proceed. Conversely, F26BP inhibits FBPase‐1, depressing gluconeogenesis (Page 58 in reader, lower left) Pyruvate Kinase – Page 60 in your reader. Pyruvate kinase is the exit point of glycolysis. Again, there are different isozymes in different tissues. Metabolites signaling a highenergy state inhibit pyruvate kinase (ATP, acetyl‐COA, long‐chain fatty acids). Alanine also inhibits pyruvate kinase. This is because alanine can be produced from pyruvate. So when there is abundant alanine, and no more needs to be made, it makes sense to turn off the source of alanine. Accumulation of fructose 1,6‐bisphosphate means that metabolites are building up within the glycolytic pathway and need to be released. Thus F16BP acts as an activator of pyruvate kinase. The liver isozyme of pyruvate kinase is subject to further regulation by phosphorylation. Low blood sugar releases a hormone called glucagon. Glucagon indirectly activates a kinase that phosphorylates pyruvate kinase. This inactivates pyruvate kinase, lowering the rates of glycolysis in the liver when blood glucose is low. ...
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This note was uploaded on 05/07/2009 for the course MCB 58168 taught by Professor Thorner during the Spring '09 term at Berkeley.
- Spring '09