Glycogen Synthesis

Glycogen Degradation (Glycogen Phosphorylase)

yields glucose 1-phosphate

UDP-glucose

the monomer that is used to extend the glycogen chain in synthesis:

• synthesized from glucose 1-phosphate and the nucleotide uridine triphosphate (UTP) in a reaction catalyzed by UDP-glucose pyrophosphorylase

• This reaction liberates the outer two phosphoryl residues of UTP as pyrophosphate (PPi )

• This reaction is readily reversible

UDP-glucose Pyrophosphorylase Reaction

Glucose 1-phosphate + UTP <=> UDP-glucose + PPi

PPi + H2O → 2 Pi

Glucose 1-phosphate + UTP → UDP-glucose + 2Pi

New Glucosyl Units

added to the nonreducing terminal residues of glycogen

• The activated glucosyl unit of UDP-glucose is transferred to the hydroxyl group at C-4 of a terminal residue within a chain of glycogen to form an α-1,4-glycosidic linkage

• UDP is displaced by the terminal hydroxyl group of the growing

  glycogen molecule

Glycogen Synthase

Catalyzes the reaction of the activated glucosyl unit of UDP-glucose is transferred to the hydroxyl group at C-4 of a terminal residue within a chain of glycogen to form an α-1,4-glycosidic linkage, whereby the UDP is displaced by the terminal hydroxyl group of the growing glycogen molecule

• the key regulatory enzyme in glycogen synthesis

• can add glucosyl residues only to a polysaccharide chain already containing more than four residues

• requires a primer

Humans have two isozymic forms of glycogen synthase:

1. Expressed in the liver

2. Expressed in muscle and other tissues

Glycogenin

the primer for glycogen synthase:

• each subunit of glycogenin catalyzes the formation of α-1,4-glucose polymers on its partner subunit

• the polymers are 10 to 20 glucosyl units in length

Branching

• important because it increases the solubility of glycogen

• creates a large number of terminal residues which are the sites of action of glycogen phosphorylase and synthase

• increases the rate of glycogen synthesis and degradation

1,6 Branching (Branching Enzyme)

• takes place after a number of glucosyl residues are joined in α-1,4 linkages by glycogen synthase

• α-1,6 branch is created by the breaking of an α-1,4 link and the formation of an α-1,6 link

• a block of residues, typically seven in number, is transferred to a more interior site

• the block of 7 or so residues must include the nonreducing terminus and come from a chain at least 11 residues long

• the new branch point must be at least four residues away from a preexisting one

Glycogen synthase exists in two forms:

1. an active nonphosphorylated a form

2. a usually inactive phosphorylated b form

• The interconversion of the two forms is regulated by covalent modification

• Glucose 6-phosphate is a powerful activator of the enzyme

When muscle glycogen is depleted:

• the power output of the muscle falls to approximately 50% of maximum power output decreases despite the fact that ample supplies of fat are available

• if carbohydrate-rich meals are consumed after glycogen depletion, glycogen stores are rapidly restored; in fact, glycogen synthesis continues, increasing glycogen stores far above normal

• this phenomenon is called “super compensation” or, more commonly, carbo-loading

Glycogen Is an Efficient Storage Form of Glucose

• Only two molecules of ATP are required to incorporate dietary glucose into glycogen

• The complete oxidation of glucose derived from glycogen yields 31 molecules of ATP

Glycogen Synthesis

inhibited by the same glucagon and epinephrine signalling pathways that stimulate glycogen breakdown

Insulin

• stimulates glycogen synthesis by activating a signal transduction pathway

• also facilitates glycogen synthesis by increasing the number of glucose transporters (GLUT4)

High Blood Glucose

leads to inhibition of glycogen degradation (glycogen phosphorylase) in the liver, and increases glycogen synthesis (glycogen synthase)

Diabetes

• is characterized by the presence of excess glucose and underutilization of the fuel

• excess glucose is excreted in the urine

• in type 1, insulin is not produced

• in type 2, insulin is produced but the insulin-signaling pathway is not responsive, a condition referred to as insulin resistance

Diabetes Mellitus

• comes from Latin, meaning “sweetened with honey

• Aretaeus, a Cappadocian physician of the second century AD

• he perceptively characterized diabetes as “being a melting-down of the flesh and limbs into urine