Synthesis and degradation occur by different paths:

One might be tempted to propose that glycogen synthesis occurs by the simple reversal of glycogen breakdown (glycogen phosphorolysis). This position is even more attractive due to the fact that glucose-1-phosphate is formed upon breakdown, providing an activated sugar for possible synthesis reactions.

The following observations provide evidence that glycogen phosphorylase is not involved in synthesis of glycogen (glycogen + Pi ---> G 1-P --x--> glycogen + Pi)

a. ratio of [ Pi ]/[ glucose-1-phosphate ] is approximately 100 in the cell; this ratio does not favor synthesis of glycogen. The Keq is 3.6, therefore G-1-P levels are very low relative to Pi.

b. hormones that activate phosphorylase activity do not stimulate glycogen synthesis but they do stimulate breakdown.

c. patients with no muscle phosphorylase can make glycogen (this condition is called McArdle's disease).

UDP-glucose as reactive substrate:

The actual biosynthetic reaction occurs as follows:

(glucose)n + UDP- glucose ----> (glucose)n+1 + UDP (synthesis)

structure of UDP-glucose:

UDP-glucose is formed from glucose-1-phosphate:

glucose 6-P <==> glucose 1-P + UTP ----> UDP-glucose + PPi ----> 2 Pi

(lower energy) (higher energy)

As is frequently the case, the hydrolysis of pyrophosphate (DGo' = - 30 kJ/mol) drives the reaction to completion.

UDP-glucose adds sequentially to the C-4 hydroxyl group (not the reducing end of the sugar) to produce a linear polymer of glucose.

The branching pattern seen in glycogen is produced by the branching enzyme [amylo-(1,4 --> 1,6)-transglycosylase], which:

a. moves 6 - 7 glucose residues from the growing end of the glycogen molecule to a position nearer the reducing end.

b. joins this oligosaccharide to the C-6 hydroxyl that is located at least 4 residues from the last branch point.

Inactivation of Glycogen Synthase:

Steps in the inactivation sequence:

a. hormone binds to membrane receptor

b. adenylate synthetase is activated (via G-proteins)

c. the cAMP that is formed binds to a protein kinase, causing it to dissociate (to an active form)

d. the synthase/phosphorylase kinase (SPK) is activated

e. it phosphorylates glycogen synthase I (active) to form glycogen synthase D (which is inactive unless glucose-6-phosphate levels are high)

The activity of glycogen synthase D (for Dependent) depends on the levels of G-6-P, which is logical when you consider that lots of G 6-P is necessary to drive the formation of G 1-P by mass action.

When glycogen synthase is completely shut down and glycogen phosphorylase is fully activated, the rate of glycogen breakdown is 300 x the rate of glycogen synthesis.

Release from hormonal regulation:

2 C (proteins kinase - active)

phosphoprotein phosphatase inhibitor 1 ----> PPI-1--P

(inactive) (active)

phosphoprotein phosphatase -1 ----> PP-1-PPI-1--P

(active) (inactive)

glycogen synthase D (phosphorylated and inactive) ----> glycogen synthase I (free OH and active)

a. when cAMP levels drop, one gets a reversal of the dissociation of R2C2 (above)

b. insulin also plays a role, it activates phosphoprotein phosphatase-1 (PP-1)

Glycogen a major energy source for active muscle (liver uses fats). Hitting the wall in marathon results, in part, from the exhaustion of muscle glycogen.

Athletes who engage in carbohydrate loading first starve themselves for carbohydrates and then eat large amounts. They are attempting to deceive this regulatory system.