Download Gluconeogenesis

Glycogenolysis & Gluconeogenesis
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.
Glycogen breakdown requires three enzymes
1. 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.
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.
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
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.
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 10-18 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.
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.
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 .
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.
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 )
or producing metabolites that enter krebs cycle and then converted to
oxaloacetate which enter the gluconeogenesis pathway (including αketoglutarate, 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.
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
1.
hexokinase or glucokinase.
2.
phosphofructokinase.
3.
pyruvate kinase.
Because these enzymes catalyze irreversible reactions.
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 ,
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.
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).
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 .
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
There are two major types of metabolic
hormones that cooperate together to
regulate blood glucose level in two
opposite manner . These hormones
include:
1.
2.
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.
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.
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:
1.
Increase the entry of glucose into the body cells.
2.
Inhibits glycogen breakdown in liver and muscles.
3.
Inhibit lipid breakdown in liver and adipose tissues.
4.
Increases the uptake of amino acids by cells and increases the
rate of protein synthesis.
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