regulation of glycogen metabolism

Question 1

characteristic of glycogen

Answer 1

• Glucose storage:
  
  1. Glycogen for animals
  2. Starch for plants
     - Primarily found in liver (10% of weight) and muscle (1-2%)
     - Stored in granules:
  3. A-rosettes containing 20-40 B-particles
  4. B-particles contains 55K glu with 2k non-reducing ends
     - Depleted after 12-24h fasting in liver and 1h of strenuous exercise in muscle
     - Far less compared to stored fat
     Astrocytes, heart, adipose tissue store glycogen

Question 2

glycogenesis (glycogen is polymerized from glucose) starts with UDP-glucose

Answer 2

• • glycogenesis can be everywhere but mainly in liver
• • sugar nucleotide is the precursor

1. Sugar phospate + NTP (nucleoside triphosphate made of 3 P + ribose+base)
   
   2. The enzyme NDP-sugar pyrophosphorylase will create one pyrophosphate (2 P) + one sugar nucleotide (sugar + 2P+ribose+base)
      * * to transform pyruvate to 2 separate phosphate, we use the enzyme : inorganic pyrpophosphatase

So net reaction : sugar phosphate + NTP = NDP-sugar + 2P

Question 3

glycogenesis: initial short chains

Answer 3

** glycogenin catalyzes initial steps (Unique enzymes that is capable of taking a charge glucose and initiated the chain synthesis (or tjhe polymerization process)

1. Tyr is present on the enzyme (glycogenin): initial attack by the hydroxyl group of Tyr on C-1 of the glucosyl moiety of UDP-glucose.This is catalyze by the enzyme glycosyltransferase activity.
   UDP is released
2. The C-1 of another UDP-glucose molecule is now attacked by the C-4 hydroxyl group of the terminal glucose, and it continues for like 6-8 glucoses
   UDP is remove, glucose becomes part of glycogenin
   ** Link between C1 of the incoming glucose and the 4C of the already present glucose

** Can only do it for 6 to 8 timesso glycogen can only contain 6-8 glucose molecules which is not sufficient

Question 4

glycogenesis: elongation

Answer 4

** Glycogen synthase promotes the transfer of the glucose residue from UDP-glucose to a non-reducing end of a branched glycogen molecule

1. UDP + non-reducing end of a glycogen chain with more than 4 residues + glycogen synthase Will release a UDP and will create a link between C4 of the glucose from the chain with the C1 of the new one = elongated glycogen with n+1 residues

• glycogen synthase requires an existing short sequence of glucose to start its activity, it can not take an independent glucose molecule, it really requires a short chain
  Requires UDP glucose and create again the C1 (of the incoming glucose) and C4 link

** BUT glycogen synthase cannot make the (a1-6) bonds found at the branch points of glycogen

Question 5

glycogenesis: branching

Answer 5

The glycogen branching enzyme catalyzes transfer of a terminal fragment of 6-7 glucose residues from the nonreducing end of a glycogen branch having at least 11 residues to the C-6 hydroxyl group of a glucose residue at a more interior position of the same or another glycogen chain, thus creating a new branch. ** further glucose may be added by glycogen synthase to this new branch

*It is a unique one because it takes the bound between glucose 4 and 5
It will create a new type of bound (1 to 6 instead of 1 to 4), it can do that only from a core or from a branch

• branching increases:
  1. water solubility
  2. number of non-reducing ends (can release more glucose at ones when the enzymes attack it)

Question 6

4 steps of glycogenesis

Answer 6

1. Formation of UDP-glucose (NDP-sugar-pyrophosphorylase)
   
   2. Initial short chain synthesis (glycogenin)
   3. Elongation (glycogen synthase)
2. Branching (glycogen-branching enzyme)

**Glycogenin remains as the core whereas glycogen synthase leaves when its role is over

Question 7

glycogenolysis: formation of glu-1-phosphate

Answer 7

enzyme: glycogen phosphorylase
1. It attacks the extreme end of the glycogen polymer (non reducing end) and breaks the 1-4 glycosidic bond, and the phosphate that is release will be add to the glucose that is release at its 1C (glucose 1 phosphate)
It depends on pyridoxal phosphate cofactor because it requires a phosphate group all the time

result: glucose-1-phosphate + glycogen shortened by one residue

Question 8

glycogenolysis at the branch (what happens when we have branch)

Answer 8

1. glycogen phosphorylase Can keep removing glucose until there is 4 subunits left in the branch, at this point it can not do its function anymore
   result: any glucose-1-phosphate molecules and a branch molecules (long chain with a branch of 4 glucose)
2. enzyme: TRANSFERASE activity of the debranching enzyme
   Glucosyl transferase function: all the 4 glucose molecules that are left takes the short chain of 3 glucose units and attached it to the other branch : it will create a longer chain of glycogen with only one glucose that is attached out
   ** so it breaks the 1-4 link between 3 glucose and the last one and it attached it in the glycogen chain with a a1-4 linkage
3. GLUCOSIDASE activity of debranching enzyme: bond is 1-6 and not 1-4, so the enzyme will remove it
   The glucose is not phosphorylated, not require phosphate (free glucose qithout phosphate group)
   result: unbranched polymer + one glucose is released

** so the enzyme glycogen phosphorylase can now continue its job!!

Question 9

glycogenolysis: formation of glucose-1-phosphate

Answer 9

n glycogen degradation, glucose-1-phosphate is converted to glucose-6-phosphate by the enzyme phosphoglucomutase (which will be useful for glycolysis)
1. Phosphate group is add on C1 from serine of the phosphglucomutase
2. Formation of glucose 1,6-biphosphate
Phosphate on C6 is removed and go to phosphoglucomutase (Ser)

In glycogen synthesis, glucose-6-phosphate is converted to glucose-1-phosphate (reversible!!!)

Question 10

what happened to glucose-6-phosphate in the liver

Answer 10

** will be dephosphorylated!

- Glucose 6 phosphatase removes the phosphate group =- gluconeogenesis
- Glucose-6-phosphate is converted into a regular glucose so this free glucose is able to pass through the glucose transporter (GLUT2 is present in the liver and its a facilitate transporter, allows the glucose to move in any direction depending on the chemical gradient), in that time, the glucose will go out because the concentration is higher in the liver cells

** because glucose-6-phosphatase is inside the ER, the cell separates this reaction with the glycolysis which is in the cytosol

Muscles do not contribute to blood glucose concentration because they not expressed this glucose-6-phosphatase so glucose can only be used for glycolysis

- Glucose 6 phosphatase expression is low
- Hexokinase I and II have high affinity for glucose (as soon as glucose is release from glycogen in the muscle, glycolysis starts) GLUT4 in the muscle is sensitive to insulin (the only time the GLUT4 come to the plasma membrane so the only time it is available) (GLUT4 is insulin dependent) * * so it is always from blood to muscle, never the opposite

Question 11

hormonal regulation of glycogenolysis

Answer 11

Steps:

1. Epinephrine (in myocyte) or glucagon (in hepatocyte) activates Gsa (GOCR)
2. Gsa activates adenyl cyclase which activates cyclic AMP
3. Cyclic AMP activates PKA
4. PKA active phosphorylase b kinase
5. Phosphorylase b kinase active glycogen phosphorylase a
6. Glycogen phosphorylase a activate formation of glucose-1-phosphate from glycogen (glycogenolysisi)
7. Glucose 1-phosphate does glycolysis in muscle contraction or go to blood glucose in case of hepatocyte

Question 12

difference between muscles and liver

Answer 12

Glucose create by gluconeogenesis will stay in the muscle and create energy whereas in the liver, it can go in the glucose (explain why glycolysis diminue)
2 differences between muscles and liver:
1) Myocytes lack receptors for glucagon
2) The muscle isozyme of pyruvate kinase is not phosphorylated by PKA, so glycolysis is not turn off when concentration of cAMP is high. In fact, cAMP increases the rate fo glycolysis in muscle, probably by activating glycogen phosphorylase
** glucose 6-phosphate in muscle does not go out in the blood (this is why glycolysis increases)
** in the liver: glycolysis decreases because low concentration of glucose so hexokinase does not react, glucose-6-phosphate goes in the blood