Скачать или смотреть Ahern's Biochemistry #24 - Sugar Metabolism Regulation

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Sugar Metabolism Regulation

1. Pyruvate kinase, pyruvate carboxylase, and PEPCK are all regulated. Pyruvate kinase is activated by feedforward activation by F1,6BP and is inibited by ATP and alanine (a product easily made from pyruvate). Pyruvate kinase is also controlled by covalent modification as described in the previous highlights. Phosphorylation of the enzyme makes it less active, whereas dephosphorylation make it more active.

2. Regulation of glycolysis and gluconeogenesis (besides the mechanisms noted above) occurs mostly allosterically using molecules that are indicative of the energy state of the cell. Molecules indicating high cellular energy (like ATP) favor gluconeogenesis and inhibit glycolysis, but molecules indicating low energy (like ADP or AMP) favor glycolysis and inhibit gluconeogenesis.

3. The enzymes of glycolysis that are regulated have corresponding gluconeogenesis enzymes that are also regulated. PFK and F1,6BPase exhibit the most complicated regulation. Both are controlled by several mechanisms. The most important one is the allosteric regulation by fructose-2,6-bisphosphate (F2,6BP). F2,6BP activates PFK and inhibits F1,6BPase.

4. F2,6BP is made and degraded by two different portions of the same protein (I'll use PFK2 to refer to the kinase portion and FBPase -2 to refer to the phosphatase portion). The portion of the PFK2 catalyzing the synthesis of F2,6BP from F6P is PFK2. The portion of the protein catalyzing the breakdown of F2,6BP to F6P is FBPase-2. The two activities are regulated by phosphorylation of the protein by protein kinase A. When phosphorylated, the PFK2 part of the enzyme is inactive and the FBPase-2 is active. When the phosphate is removed from the protein by phosphoprotein phosphatase, the PFK2 becomes active and the FBPase-2 becomes inactive.

5. Phosphorylation of the enzyme by protein kinase A is favored by 7TM signaling through the beta adrenergic receptor whereas dephosphorylation by phosphoprotein phosphatase is activated by signaling by insulin.

6. Thus phosphorylation of the PFK2 favors the breakdown of F2,6BP and the activation of gluconeogenesis and deactivation of glycolysis. Dephosphorylation of PFK2 favors the synthesis of F2,6BP and the activation of glycolysis and the deactivation of gluconeogenesis. This is the heart of reciprocal regulation of these pathways.

7. The Cori Cycle provides glucose for muscles that is made by the liver. This occurs when exercise is occurring faster than oxygen is being delivered to the muscles. Under these conditions, muscles are converting glucose to pyruvate and then to recreate NAD, they convert pyruvate to lactate. The lactate is exported from the cells and travels in the bloodstream to the liver. The liver re-oxidizes the lactate to pyruvate and then converts pyruvate to glucose by gluconeogenesis. The glucose is then dumped into the bloodstream where it is picked up by the muscles.