1. Glycogenolysis & Gluconeogenesis

2. Glycogenolysis
Glycogenolysis : Degradation of stored glycogen, termed glycogenolysis
Different pathways of glycogen breakdown
- In muscle: Glycogen → glucose-6-phosphate (G6P) → glycolysis
- In liver: Glycogen → G6P → glucose → bloodstream → various cells → glycolysis
Because the muscle cells mainly consume glucose molecules whereas the liver cells mainly store the glucose molecules.
Glycogen degradation consists of three steps:
The release of glucose 1- phosphate from glycogen.
The remodeling of the glycogen substrate to permit further degradation
The conversion of glucose 1- P to glucose 6-P.

3. Glycogen breakdown requires three enzymes
Glycogen phosphorylase (simply call it phosphorylase) the key enzyme glycogen breakdown which is aided by another molecule called pyridoxal phosphate , this enzyme cleaves the glucose residue sequentially and the addition of orthophosphate to yield glucose 1-P.
The cleavage of bond by the addition of orthophosphate is referred to as phosphorolysis.
(Glycogen)n + Pi ↔ (glycogen)n-1 + G1P
(n residues) (n-1 residues)
This enzyme releases a glucose unit one by one until it reaches ~ four units (limit branch) from a branch point.

4. 2. What does debranching enzyme do?
debranching enzyme is single molecule consisting of two enzymes activity
α(1-4)→ α(1-4)→ glycan transferase activity Removes branches so that glycogen phosphorylase can complete reaction.
The Transferase shift a block of three glucose units from the outer branch and reattached to the non-reducing end of the main chain.
The branch point, the glucose attached to the main chain by the α(1-6) glycosidic bond is hydrolyzed by the debranching enzyme(α(1-6) glycosidase) ,resulting the release of free glucose molecule.

5. Advantage of phosphoroylytic cleavage
3. Phosphoglucomutase
- G1P produced from the glycogen breakdown must be convert to G6P in order to enter glycolysis or to produce glucose in liver.
Phosphoglucomutase catalyzes the conversion of G1P to G6P.
Advantage of phosphoroylytic cleavage
The phosphoroylytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated .
In contrast a hydrolytic cleavage would yield glucose which would then have to be phosphorylated at the expense of the hydrolysis of a molecule of ATP to enter the glycolytic pathway .
A additional Advantage of phosphoroylytic cleavage for muscle cells is that glucose 1 –P, negatively charged under physiological conditions cannot diffuse out of the cell

6. Remember!
Liver contains glucose 6-phosphatase.
Muscle does not have this enzyme.
WHY?
The liver releases glucose to the blood to be taken up by brain and active muscle. The liver regulates blood glucose levels.
The muscle retains glucose 6-phosphate to be use for energy. Phosphorylated glucose is not transported out of muscle cells.
Gluconeogenesis Gluconeogenesis: is the process of synthesizing glucose from non carbohydrates precursors . it is of particular importance when carbohydrates is not available from the diet.

7. some tissues, such as the brain, red blood cells, kidney and exercising muscles require a continuous supply of glucose as a metabolic fuel.
Liver glycogen, an essential postprandial source of glucose, can meet these needs for only hours in the absence of dietary intake of carbohydrate.
The formation of glucose does not occur by a simple reversible reactions of glycolysis , because the overall pathway of glycolysis results in the formation of pyruvate in An irreversible reaction.

8. In simple fasting, approximately 90% of the Gluconeogenesis occurs in the liver with kidney providing 10% of the newly synthesized glucose molecule, but during prolonged fasting the kidney's become major glucose producing organ, contributing an estimated 40% of the total glucose production.

9. Substrates of gluconeogenesis:
The major substrates for gluconeogenesis include:
1. glycerol :
glycerol ( alcoholic in nature) is released during the hydrolysis of triglyceride (TG) in the adipose tissues and then delivered to the liver by the blood.
Glycerol is phosphorylated by glycerol kinase to glycerol phosphate which intern converted by dehdrogenase to di hydroxyl acetone phosphate to enter the pathway of gluconeogenesis .

10. 2. lactate: it is released into the blood by exercising skeletal muscles and by cells that lack mitochondria such as red blood cells. This lactate is taken up by the liver and reconverted to glucose which is released back to the circulation.

11. 3. amino acids: The metabolism of amino acids occur by different metabolic pathways and can result in the production of different metabolites.
However according to the product of their metabolism amino acids can be classified into:
glucogenic amino acids:Glucogenic amino acids produce intermediates that enter directly to the gluconeogenesis pathway (including pyruvate and oxaloacetate )

12. or producing metabolites that enter krebs cycle and then converted to oxaloacetate which enter the gluconeogenesis pathway (including α-ketoglutarate, succinyl Co-A and fumarate).
ketogenic amino acids: include those amino acids that when metabolized can produce intermediates like acetyl- Co A and acetoacetate which cannot be converted directly to glucose and instead they are utilized for the production of fatty acids and ketone bodies.
For example: lysine and luceine. this is due to irreversible nature of pyruvate dehydrogenase which involved in the metabolism of these amino acids and responsible about converting pyruvate to acetyl co A.

13. gluconeogenesis
In gluconeogenesis: Seven glycolytic reactions are reversible and are used in the synthesis of glucose from lactate or pyruvate but running in reverse except those reactions catalyzed by
hexokinase or glucokinase.
phosphofructokinase.
pyruvate kinase.
Because these enzymes catalyze irreversible reactions.

14. The gluconeogenesis include the following reactions:
1. the first step in this pathway is the conversion of pyruvate to oxaloacetate by pyruvate carboxylase , this carboxylation reaction is a mitochondrial reaction ,

16. it is an ATP-requiring reaction in which biotin (B7) act as a co enzyme , biotin binds a CO2 group and giving it pyrovate forming oxaloacetate.

17. Step2: oxaloacetate then decarboxylated and phosphorylated in one step catalyzed by phospho enol pyruvate kinase yielding phospho enol pyruvate with CO2 and GDP.
Step 3: phospho enol pyruvate is converted to 2- phosphoglycerate by enolase , this reaction is a reversible reaction of glycolytic pathway.
Step 4: 2-phosphoglycerate is converted to 3 phosphoglycerate by enzyme phosphoglycerate mutase ( this reaction is a reversible reaction of glycolytic pathway).

18. Step 5: 3-phosphoglycerate is converted to 1,3 bisphosphoglycerate by the activity of phosphoglycerate kinase .
This reaction require 1 ATP to give it's phosphate group to 3 phosphoglycerate to produce 1,3 bis phosphoglycerate .
Step 6: 1,3 bis phosphoglycerate is then converted to glycerol aldehyde 3 phosphate catalyzed by glycerol aldehyde 3 phosphate dehydrogenase , this reaction utilize NADH which oxidized to NAD+.
Step 7: glyceol aldehyde 3 phosphate and di hydroxyl acetone phosphate are interchangeable with each other and can interact with each other in an reversible reaction, these two molecules are bound to each other forming fructose 1,6 bisphosphate .

19. Step 8: in this step fructose 1,6 bisphosphate is hydrolyzed by irreversible reaction catalyzed by fructose 1,6 bisphosphatase forming fructose 6 phosphate with releasing free phosphate.
Step 9: fructose 6-phosphate is converted to glucose 6 phosphate by isomerase.
Step10: glucose 6 phosphate is converted to glucose by glucose 6 phosphatase. Irreversible reaction

20. There are two major types of metabolic hormones that cooperate together to regulate blood glucose level in two opposite manner . These hormones include:
glucagon: act to increase blood glucose level.
insulin: which allow the entry of glucose to the inside of the cells, allowing a reduction in blood glucose level.

21. when there is a low blood level → release of glucagon from α- cells of pancreas → Glucagon binding to its' receptors on (liver cells) → an increase in cAMP production → increased rate glycogenolysis.
The produced glucose will diffused to the blood → increase in blood glucose → stimulate the release of insulin from β- islets of langerhans.
Insulin will stimulate the entry of glucose to various extra hepatic cells, inside these cells glucose will be phosphorylated by hexokinase and the glycolytic pathway is established.

22. Insulin, initially synthesized as single polypeptide chain (pro insulin),it is later activated by enzymatic cleavage into two chains linked together by disulphide bridges.
Summary of insulin functions:
Increase the entry of glucose into the body cells.
Inhibits glycogen breakdown in liver and muscles.
Inhibit lipid breakdown in liver and adipose tissues.
Increases the uptake of amino acids by cells and increases the rate of protein synthesis.

23. Other hormones that affect blood glucose levels:
Summary of glucagon action:
1.it stimulate the breakdown of glycogen into glucose.
2. increases lipid breakdown.
3. stimulates the formation of glucose from amino acids in the liver.
Other hormones that affect blood glucose levels:
Epinephrine and Norepinephrine further increase glycogenolysis
Cortisol levels also increase during exercise for protein catabolism for later gluconeogenesis.
Thyroxine promotes glucose catabolism.
Growth hormone: it decreases glucose uptake in muscle