GLUCONEOGENESIS -sources, reactions, significance & regulation - EASY NOTES
Definition:
The synthesis of glucose from non-carbohydrate precursors is called gluconeogenesis (i.e., synthesis of new glucose).
Sources for gluconeogenesis
--The major non-carbohydrate substrates for gluconeogenesis are:
1. 1.Lactate
--In anaerobic glycolysis, in the muscle, lactate is formed from glucose
-----From muscle, it is transported to the liver by Cori's cycle and is converted to glucose by gluconeogenesis
2.2.Glucogenic amino acids and intermediates of the TCA cycle
----When glucose is not readily available as in starvation or diabetes mellitus, the glucogenic amino acids (Alanine, glutamic acid, aspartic acid, etc.) are transaminated to corresponding carbon skeletons.
----These then enter the TCA cycle and form oxaloacetate or pyruvate
3. 3.Propionate:
----Fatty acids with an odd number of carbons and carbon skeleton of some amino acids produce propionate.
----Propionate enters the gluconeogenic pathway via citric acid cycle after conversion of succinyl-CoA
4. 4.Glycerol ;
----In the adipose tissue, triacylglycerol on hydrolysis forms glycerol.
----But in the adipose tissue, the glycerol cannot be utilized because of the enzyme glycerol kinase's deficiency.
----And so it is transferred to the liver where it is phosphorylated to Glyceraldehyde 3 Phosphate.
Location of Gluconeogenesis
-Partly in the cytoplasm & partly in the mitochondria
-The liver is the major tissue for gluconeogenesis and the kidney to a minor extent.
Characteristics of Gluconeogenesis
--The pathway for glycolysis and gluconeogenesis is the same but in the opposite direction.
--Out
of 10 reactions, seven reactions of glycolysis are reversible and are used in
the synthesis of glucose by gluconeogenesis
Key Gluconeogenic Enzymes
1.Pyruvate carboxylase
2.Phosphoenolpyruvate
carboxykinase
3.Fructose-1-6-bisphosphatase
4.Glucose-6-phosphatase
Reactions of Gluconeogenesis
Step -1 Carboxylation of pyruvate to oxaloacetate
-Pyruvate is first carboxylated to oxaloacetate in mitochondria.
-The reaction is catalyzed in the presence of the enzyme pyruvate carboxylase
-The reaction occurs in the presence of ATP, vitamin biotin
Step-2 - Malate Aspartate Shuttle-
-Oxaloacetate, formed in mitochondria, has to be transported to the cytoplasm as other enzymes for gluconeogenesis are located in the cytoplasm.
-But as the oxaloacetate cannot cross the mitochondrial membrane, it is reduced to malate and then transported from mitochondria to cytosol.
-In the cytosol, malate is reoxidized to oxaloacetate
-These reactions are catalyzed by malate dehydrogenase that is present in both cytoplasm and mitochondria.
-Oxaloacetate can also be transported as aspartate formed by a transamination reaction.
-When alanine is the substrate for gluconeogenesis, the malate shuttle predominantly operates as NADH is required
-When lactate is the substrate for gluconeogenesis, the aspartate shuttle operates, as NADH is sufficient
Step- 3. Decarboxylation of cytosolic oxaloacetate to phosphoenolpyruvate (PEP):
-Oxaloacetate is decarboxylated and phosphorylated in the cytosol.
-The reaction is catalyzed by phosphoenolpyruvate carboxykinase.
-High energy phosphate in the form of GTP is required in this reaction.
· -PEP then enters the reversed reaction of glycolysis until it reaches fructose-1, 6-bisphosphate
Step-4,5,6,7,8 - Partial Reversal of Glycolysis
-The phosphoenolpyruvate undergoes further reactions.
-The reactions are catalyzed by the glycolytic enzymes to form fructose-1,6- bisphosphate
-All these reactions are freely reversible.
Step-9-Fructose-1,6-bisphosphatase
-Fructose 1,6-bisphosphate is then acted upon by fructose 1,6-bisphosphatase to form fructose-6-phosphate
-This will bypass the step of the PFK reaction (see step 3 of glycolysis)
-Then fructose-6-phosphate is isomerized to glucose-6-phosphate by the freely reversible reaction catalyzed by hexose phosphate isomerase (second step in glycolysis).
Step-10 - Glucose-6-phosphatase Reaction
--The glucose 6-phosphate is hydrolyzed to free glucose by glucose-6-phosphatase.Glucose-6-phosphatase is active in the liver.It is present in kidney and intestinal mucosa to a lesser extent but is absent in muscle.
Significance of Gluconeogenesis
--Gluconeogenesis maintains blood glucose level when carbohydrate is not available in sufficient amounts from the diet.
--Only the liver can replenish blood sugar through gluconeogenesis because glucose-6-phosphatase is present mainly in the liver. So the liver plays a significant role in maintaining the blood glucose level
--During starvation, when hepatic glycogen reserve is depleted, glucose is provided by gluconeogenesis to the brain and other tissues like erythrocytes, lens, the cornea of the eye, and the kidney medulla. They require a continuous supply of glucose as a source of energy.
--Gluconeogenesis is used to clear the products of the metabolism of other tissues from the blood, for example
---Lactate, produced by muscle and erythrocytes
---Glycerol produced by adipose tissue
---Propionyl-CoA is produced by oxidation of odd carbon number fatty acids and carbon skeleton of some amino acids.
Regulation of Gluconeogenesis
Gluconeogenesis is regulated by
1. Allosteric Activation of Pyruvate carboxylase -
--Pyruvate carboxylase is an allosteric enzyme activated by acetyl-CoA,
--Increased levels of acetyl CoA increase the conversion of pyruvate to oxaloacetate by activating pyruvate carboxylase enzyme
2.Hormonal regulation
--The hormones glucagon and epinephrine stimulate gluconeogenesis by inducing the key enzymes' synthesis (fructose 1,6 bisphosphatase)
--insulin inhibits the gluconeogenesis by repressing their synthesis.
--During starvation and diabetes mellitus, a high level of glucagon stimulates gluconeogenesis. However, in a well-fed state, insulin suppresses gluconeogenesis
3.Glucogenic amino acids availability -
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