Glycogen Structure and Synthesis

Sections

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ENDOGENOUS GLUCOSE POLYMERS

Glycogen

• Synthesized in liver & muscle (insulin: glucagon is high)
• Branched structure
• Linear segments: glucose monomers linked with alpha (1,4) glycosidic bonds
• Branch points: alpha (1,6) glycosidic bonds
• Branch point functions: i. solubilize glycogen ii. create terminal sugars for release
EXOGENOUS GLUCOSE POLYMERS
• Dietary

Amylopectin (starch)

• Fewer branches than glycogen
• Obtained from: potatoes, rice, etc.

Cellulose

• No branches
• Obtained from plants
• Glucose monomers linked with beta (1,4) glycosidic bonds
• Humans lack enzymes to break beta (1,4) glycosidic bonds

GLYCOGEN SYNTHESIS

1. Glucose + ATP --> Glucose 6P + ADP
   • Hexokinase (M) and Glucokinse (L)
2. Glucose 6P --> Glucose 1P (reversible)
   • Phosphoglucomutase
3. Glucose 1P + UTP --> UDP-glucose + PPi
   • PPi + H2O --> 2Pi (drives reaction forward)
   • UDP-glucose = substrate for glycogen synthesis
4. UDP-glucose + glycogen polymer --> glycogen polymer (+1 glucose residue) + UDP
   • Glycogen synthase: alpha (1,4) glycosidic bonds (adds 1 glucose-residue/rxn)
5. Branching enzyme adds branches
   • Breaks off (at least) 6 terminal residues from linear portion to make branch
   • Catalyzes alpha (1,6) linkage

Glycogenin: primer for glycogen chain

• Catalyzes first 4-8 glucose residues
• First glucose binds tyrosine residue in glycogenin
• Glycogen synthase adds glucose residues to preexisting glucose polymer

CLINICAL CORRELATION

Type IV Glycogen Storage Disease: Anderson's Disease

• Branching-enzyme deficiency
• Presents as long, linear polymers of glucose
• Visible at very young age, produces cell damage
• Aka amylopectosis (amylopectin ~ glycogen w/ less branching)

Full-Length Text

• Here we will learn about glycogen structure and synthesis.

• To begin, start a table to learn some key features of glycogen.

• Denote that it is synthesized for glucose storage and is a glucose polymer.

• Denote that it's synthesized in the liver and muscle; this occurs after a meal when the insulin to glucagon ratio is high.

Now, let's learn the structure of glycogen.

• In this first section of the tutorial, indicate that we'll divide key glucose polymers into:
  • Endogenous
  • Exogenous.

• Glycogen is the endogenous polymer.

We'll describe amylopectin (starch) and cellulose for the exogenous polymers.

Begin with glycogen.

• Draw a branching structure.

• Magnify both linear and branching segments.
  • For the linear segment, draw a hexagonal carbon-ring, but add one ether linkage, meaning replace one of the carbons with an oxygen.

• Now, number carbons 1 through 5.

• Attach a carbon 6.

• Then, an hydroxyl group to carbon 6.

• Attach hydroxyl groups to carbons 2, 3 and 4.

• Now, there is a hydroxyl group on carbon 1, but it forms the bond with the next glucose molecule in this polymer.
  • So, draw the oxygen of this hydroxyl group.

• Show that it forms an alpha (1,4) linkage with carbon 4 of the next glucose molecule; these linkages comprise the linear segments of glycogen.

• For the branched segment, draw another glucose molecule.
  • We leave out the C1, C4 and C6 hydroxyl groups for now.

• This time, show that the hydroxyl group attached to carbon 6 binds carbon 1 of another glucose molecule.

• Label this an alpha (1,6) linkage.

• Show that glucose molecules form alpha (1,4) glycosidic linkages adjacent to this branch point.

• Indicate that branch-points are important for two reasons in particular:
  • They make glycogen more soluble.
  • They produce many terminal sugars, the substrate for glycogenolysis (glycogen breakdown). Thus, glycogen can break down and release glucose quickly when blood concentrations are low.

Now for the two representative exogenous polymers (they are ingested).

• Draw a glucose polymer with fewer branches than glycogen.

• Draw another with no branches at all.

• Label the first amylopectin (starch) and the second cellulose.

• Indicate that amylopectin can be obtained from the diet (potatoes, rice, etc.)

• Write that cellulose is the plant-version of glycogen.

• Show that in cellulose, glucose residues are linked by beta (1,4) glycosidic bonds.

• Write that humans cannot digest cellulose because we lack enzymes that break beta (1,4) glycosidic bonds!

Finally, let's illustrate glycogen synthesis.

• To begin, represent glucose as a simple circle.

• Then, draw glucose 6-phosphate as glucose with a phosphate attached.
  • Indicate that this reaction is catalyzed by hexokinase in the muscle and glucokinase in the liver.
  • Show that this reaction consumes ATP.

• Next, show that glucose-6-phosphate rearranges to glucose 1-phosphate (glucose with a phosphate attached at a different carbon) via a reversible reaction.

• Show that phosphoglucomutase catalyzes this reaction.

• Finally, draw a glucose molecule attached to uridine diphosphate (UDP).

• Indicate that glucose 1-phosphate reversibly reacts with UTP to produce UDP-glucose.
  • Show that this reaction releases pyrophosphate.

• Finally, indicate that pyrophosphate combines with water immediately after it is synthesized to produce 2 phosphates.
  • Write that this drives the reaction forward.

• Now, label UDP-glucose the substrate for glycogen synthesis.

Now, let's add our substrate to a glycogen polymer.

• Draw a glycogen polymer with one branch.
  • Specifically, show that the branch contains six glucose molecules.

• Indicate that the linear portion links to a protein called glycogenin, which is a primer for the glycogen chain.

• Draw the first glucose residue in this chain and show that it specifically binds to a tyrosine residue in glycogenin.

• Show that the glucose-residue of our UDP-glucose binds to the terminal end of the glycogen branch; it can add to either the branching or linear segments, but we add it to the branched portion, here.

• Indicate that glycogen synthase catalyzes this reaction and releases UDP.
  • Note that glycogen synthase does not attach the first glucose residue to glycogenin.
  • Glycogen in itself catalyzes this to initiate glycogen synthesis.

• Next, show that this reaction occurs 5 times.

• Draw the corresponding five glucose molecules at the end of the branch.

• Indicate that each of these molecules forms an alpha (1,4) glycosidic linkage with their neighbors.

Now, what about adding branches?

• Draw another glycogen molecule, but show that the terminal 6 residues of our branch break off to form a new branch.

• Indicate that the appropriately named "branching enzyme" catalyzes this reaction.

• Indicate that it forms an alpha (1,6) linkage at the branch.

• Finally, write that branching enzyme transfers at least 6 glucose residues, which are linked by alpha (1,4) glycosidic bonds, at a time.

• As a clinical correlation, denote that Anderson's disease or Type IV glycogen storage disease can result from branching-enzyme deficiency.
  • Without branching enzyme, patients present with long linear polymers of glucose, which are visible in the liver at a very young age.
  • This produces cell damage, as these un-branched polymers cannot fit within cells.

• Denote that this disease is also called amylopectosis. Why?
  • Amylopectin is similar in structure to glycogen but contains less branching.
  • Thus, the glycogen in patients with this disease resembles amylopectin.