Highlights Gluconeogenesis

1. Anabolic and catabolic pathways occurring at the same time and place create a futile cycle. Futile cycles generate heat, but that is the only product they make. Consequently, cells usually set up controls that turn one off when the other is turned on. If the same molecule has opposite effects on catabolic and anabolic pathways, the molecule is a reciprocal regulator of the pathways. Reciprocal regulation of catabolic and anabolic pathways is a very efficient means of control.

2. 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.

3. 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 PFK2/FBPase-2 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.

4. Phosphorylation of the enzyme by protein kinase A is favored by 7TM signaling whereas dephosphorylation by phosphoprotein phosphatase is activated by signaling by insulin.

5. 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.

6. Pyruvate kinase, pyruvate carboxylase, and PEPCK are all regulated, as well. 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.

Highlights Glycogen Metabolism I

1. The structure of glycogen consists of units of glucose linked in the alpha 1-4 configuration with branches linked in the 1-6 configuration.

2. Glycogen differs from amylopectin in the amount of branching (much more).

3. Glycogen is a storage form of energy that can yield ATP very quickly, because glucose-1-phosphate can be released very quickly.

4. You should know the function/activites of the enzymes in glycogen breakdown - glycogen phosphorylase, phosphoglucomutase, and debranching enzyme.

5. Glycogen phosphorylase action on glycogen yields glucose-1-phosphate. Glycogen phosphorylase exists in two forms - phosphorylase a and phosphorylase b. Phosphorylase a differs from phosphorylase b only in that phosphorylase a contains two phosphates and phosphorylase b contains none. Phosphate is added to glycogen phosphorylase by the enzyme phosphorylase kinase.

6. Glucose-6-phosphate (G6P) has many different fates and sources. First, breakdown of glycogen produces G1P, which is readily converted to G6P. G6P can then go three different directions. In muscle and brain (and most other tissues), G6P enters glycolysis. In liver only, G6P enters gluconeogenesis and is converted to glucose for export to the bloodstream. In other tissues, G6P enters the pentose phosphate pathway and is oxidized to produce NADPH.

7. Breakdown of glycogen by glycogen phosphorylase involves phosphorolysis (use of a phosphate to cleave molecules) instead of hydrolysis. The advantage of this is that the energy of the alpha1-4 bond is used to add phosphate to glucose (forming G1P) instead of using a triphosphate to do so. This saves energy for cells.

8. Glycogen phosphorylase catalyses phosphorolysis of glycogen to within 4 residues of a branch point and then stops. Further metabolism of glycogen requires action of Debranching Enzyme. Debranching enzyme removes three of the remaining four glucoses at a branch point and transfers them to another chain in a 1-4 configuration. The remaining glucose in the 1-6 configuration at the branch point is cleaved in a hydrolysis reaction to yield free glucose. It is the only free glucose released in glycogen metabolism.

9. Phosphoglucomutase interconverts G1P and G6P via a G1,6BP intermediate. The reaction is readily reversible (Delta G zero prime near zero) and the direction of the reaction depends on the concentration of substrates.

10. Synthesis of glycogen is not the simple reversal of the steps in glycogen breakdown. There is an energy barrier that must be overcome - synthesis of the alpha1,4 bond between adjacent glucoses in glycogen. This is accomplished by a 'side-step' reaction that creates uridine diphosphate glucose (UDP-Glucose or UDPG) from G1P

11. Synthesis of UDPG requires UTP and G1P and produces UDPG and pyrophosphate (PPi). UDPG is made by action of the enzyme UDPG pyrophosphorylase, also known in this class as "Lucy."