Storage of Glucose as Glycogen

The liver secretes glucose into the bloodstream as an essential mechanism to keep blood glucose levels constant. Liver, muscle, and other tissues also store glucose as glycogen, a high‐molecular‐weight, branched polymer of glucose. Glycogen synthesis begins with glucose‐1‐phosphate, which can be synthesized from glucose‐6‐ phosphate by the action of phosphoglucomutase (an isomerase). Glucose‐1‐phosphate is also the product of glycogen breakdown by phosphorylase:







The K eq of the phosphorylase reaction lies in the direction of breakdown. In general, a biochemical pathway can't be used efficiently in both the synthetic and the catabolic direction. This limitation implies that there must be another step in glycogen synthesis that involves the input of extra energy to the reaction. The extra energy is supplied by the formation of the intermediate UDP‐glucose. This is the same compound found in galactose metabolism. It is formed along with inorganic pyrophosphate from glucose‐1‐phosphate and UTP. The inorganic pyrophosphate is then hydrolyzed to two phosphate ions; this step pulls the equilibrium of the reaction in the direction of UDP‐glucose synthesis (see Figure  1).



               
                             Figure 1


Glycogen synthase transfers the glucose of UDP‐glucose to the nonreducing end (the one with a free Carbon‐4 of glucose) of a preexisting glycogen molecule (another enzyme starts the glycogen molecule), making an A, 1‐4 linkage and releasing UDP (see Figure 2 ). This reaction is exergonic, though not as much as the synthesis of UDP‐ glucose is.


      


                  Figure 2


Summing up, the synthesis of glycogen from glucose‐1‐phosphate requires the consumption of a single high‐energy phosphate bond and releases pyrophosphate (converted to phosphates) and UDP. Overall, the reaction is: 



Glycogen phosphorylase breaks down glycogen by forming glucose‐1‐phosphate, in the following reaction:


 


This reaction does not require any energy donor. Notice that glycogen breakdown preserves the phosphate of the glucose‐1‐phosphate that was used for synthesis without the need for a separate phosphorylation step. The sum of the preceding two reactions is simply:


 


Since 38 ATPs are made from the oxidative metabolism of a single glucose molecule, this minimal energy investment is well worth the advantages of banking the glucose as glycogen.

Glycogen synthase and phosphorylase are reciprocally controlled by hormone‐induced protein phosphorylation. One of the most basic physiological reactions in animals is the reaction to danger. The symptoms are probably familiar to anyone who has had to give a public speech: rapid heartbeat, dry mouth, and quivering muscles. They are caused by the hormone epinephrine (adrenaline), which acts to promote the rapid release of glucose from glycogen, thereby providing a rapid supply of energy for “flight or fight.”

Epinephrine acts through cyclic AMP (cAMP), a “second messenger” molecule. 







Cyclic AMP


The epinephrine receptor causes the synthesis of cyclic AMP, which is an activator of an enzyme, a protein kinase C (see Figure  3). Protein kinases transfer phosphate from ATP to the hydroxyl group on the side chain of a serine, threonine, or tyrosine. Protein kinase C is a serine‐specific kinase. Protein kinase C is a tetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. When it has cAMP bound to it, the R subunit dissociates from the C subunits. The C subunits are now catalytically active.


                      Figure 3

               

Protein kinase C phosphorylates glycogen synthase directly, as well as another protein kinase, synthase/phosphorylase kinase. Phosphorylation has different effects on the two enzymes.

Phosphorylation of glycogen synthase, either by protein kinase C or by synthase/phosphorylase kinase, converts it from the more active I form (independent of glucose‐6‐phosphate) to the D form (dependent on glucose‐6‐phosphate). Glycogen synthesis is reduced; although, if glucose‐6‐phosphate is present in high amounts, the enzyme can still make glycogen.

Phosphorylation of glycogen phosphorylase by synthase/phosphorylase kinase has the opposite effect. The nonphosphorylated form of the enzyme, phosphorylase b, is less active than the phosphorylated form, phosphorylase a (see Figure  4). (Think of a for active to help remember the direction of regulation.) Phosphorylase a then converts glycogen to glucose‐1‐phosphate. The end result of this protein phosphorylation cascade is an increased energy supply for activity.




                Figure 4


Protein phosphorylation cascades, like the one discussed above, are a general mechanism of cellular regulation. Protein kinases are involved in the control of metabolism, gene expression, and cell growth, among other processes.