Gluconeogenesis - Biochemistry
Gluconeogenesis is to make new glucose from non-carbon precursors which are lactate, glycerol, amino acids, and fatty acids.
Gluco Neo Genesis = Make new glucose
It occurs at kidneys and liver when there is enough energy in our body. It is like making glucose so ATP will not be wasted.
4 crucial enzymes: Pyruvate Carboxylase, Phosphoenolpyruvate (PEP) Carboxykinase, Fructose-1,6-Bisphosphatase, and Glucose-6-Phosphatase.
1] Pyruvate Carboxylase:
-Pyruvate → Oxaloacetate (OAA)
-Need ATP, Bicarbonate HCO3- as substrates
-Biotin as co-enzymes
-Acetyl-CoA is an allosteric activator
-Pyruvate carboxylase found only in mitochondrial matrix
-OAA cannot be transported across mithochondrial membrane
-OAA change into malate, transported across mitochondiral membrane
Pyruvate + HCO3- + ATP → Oxoloacetate + ADP + Pi
This is a compartmentalized reaction. Pyruvates from glycolysis that are entering into mitochondria for TCA Cycle will convert to OAA in the mitochondria because pyruvate carboxylase found in the mitochondria. OAA cannot transport across mitochondria so OAA → malate (reduced) by the enzyme malate dehydrogenase. NADH will then oxidize to NAD+. This conversion happens in mitochondria so that OAA can become malate and transport across mitochondria to cytosol. Then malate once enters the cytosol, it has to be converted back to OAA. So malate oxidizes to OAA with the aids of enzyme malate dehydrogenase, NAD+ will reduce to NADH.
Now this OAA successfully transported from mitochondria to cytosol and should convert to PEP ( So can go reverse reaction of glycolysis).
2] Phosphoenolpyruvate (PEP) Carboxykinase:
-Oxaloacetate → Phosphoenolpyruvate
-energy driven reaction
-energy source 2 ways
1.Decarboxylation a favourable reaction
2.GTP is hydrolyzed
-GTP used here is equivalent to ATP
Oxaloacetate + GTP → Phosphoenolpyruvate + GDP + CO2
Now, OAA successfully converted to PEP, PEP will convert to Fructose-1,6-Biphosphate (reverse of glycolysis reaction) and stop the conversion as it needs Fructose-1,6-Biphosphatase enzyme to convert Fructose-1,6-Biphosphate to Fructose-6-Biphosphate.
3] Fructose-1,6-Bisphosphatase:
-Fructose-1,6-Biphosphate cannot change back to Fructose-6-Bisphosphate
-Need Fructose-1,6-Bisphosphatase to remove Pi from Fructose-1,6-Bisphosphate so it will be converted to Fructose-6-Bisphosphate (the molecule we want).
Fructose-1,6-Bisphosphate ➝ Fructose-6-Bisphosphate + Pi
Now, Fructose-6-Bisphosphate convert back to Glucose-6-Phosphate which needs to transport back to the bloodstream via GLUT2 (the door to exit). Glucose-6-Phosphate could not transport to the bloodstream so need to convert into Glucose. This conversion happens in Smooth Endoplasmic Reticulum (S.E.R) as the enzyme that helps to convert available at S.E.R
4] Glucose-6-Phosphatase:
-Glucose-6-Phosphate cannot change back to glucose
-Glucose-6-Phosphatase in S.E.R convert G-6-P into Glucose
-Uses ATP
G-6-P + ATP ➝ Glucose + Pi + ADP
In the S.E.R, there are 3 specific channels (Doors to exit) which aid the G-6-P to enter and glucose to exit.
T1: G-6-P enter in S.E.R from the cytosol
T2: Glucose exits to the cytosol from S.E.R
T3: Transport Pi to the cytosol
Fasting: ATP; Acetyl CoA ↓
Pyruvate
￬
Acetyl CoA
￬
TCA cycle
￬
ATP
Enough Energy: ATP; Acetyl CoA ↑
Pyruvate
￬
OAA
￬
Gluconeogenesis
￬
Glucose
Gluconeogenesis inhibitors are utilizing in diabetes therapy. We can inhibit the transport activity by the G-6-Phosphatase so G-6-P cannot convert to Glucose, cannot transport out from S.E.R to the cytosol, glucose can not enter the blood, prevent diabetes.
Gluco Neo Genesis = Make new glucose
It occurs at kidneys and liver when there is enough energy in our body. It is like making glucose so ATP will not be wasted.
4 crucial enzymes: Pyruvate Carboxylase, Phosphoenolpyruvate (PEP) Carboxykinase, Fructose-1,6-Bisphosphatase, and Glucose-6-Phosphatase.
1] Pyruvate Carboxylase:
-Pyruvate → Oxaloacetate (OAA)
-Need ATP, Bicarbonate HCO3- as substrates
-Biotin as co-enzymes
-Acetyl-CoA is an allosteric activator
-Pyruvate carboxylase found only in mitochondrial matrix
-OAA cannot be transported across mithochondrial membrane
-OAA change into malate, transported across mitochondiral membrane
Pyruvate + HCO3- + ATP → Oxoloacetate + ADP + Pi
This is a compartmentalized reaction. Pyruvates from glycolysis that are entering into mitochondria for TCA Cycle will convert to OAA in the mitochondria because pyruvate carboxylase found in the mitochondria. OAA cannot transport across mitochondria so OAA → malate (reduced) by the enzyme malate dehydrogenase. NADH will then oxidize to NAD+. This conversion happens in mitochondria so that OAA can become malate and transport across mitochondria to cytosol. Then malate once enters the cytosol, it has to be converted back to OAA. So malate oxidizes to OAA with the aids of enzyme malate dehydrogenase, NAD+ will reduce to NADH.
Now this OAA successfully transported from mitochondria to cytosol and should convert to PEP ( So can go reverse reaction of glycolysis).
2] Phosphoenolpyruvate (PEP) Carboxykinase:
-Oxaloacetate → Phosphoenolpyruvate
-energy driven reaction
-energy source 2 ways
1.Decarboxylation a favourable reaction
2.GTP is hydrolyzed
-GTP used here is equivalent to ATP
Oxaloacetate + GTP → Phosphoenolpyruvate + GDP + CO2
Now, OAA successfully converted to PEP, PEP will convert to Fructose-1,6-Biphosphate (reverse of glycolysis reaction) and stop the conversion as it needs Fructose-1,6-Biphosphatase enzyme to convert Fructose-1,6-Biphosphate to Fructose-6-Biphosphate.
3] Fructose-1,6-Bisphosphatase:
-Fructose-1,6-Biphosphate cannot change back to Fructose-6-Bisphosphate
-Need Fructose-1,6-Bisphosphatase to remove Pi from Fructose-1,6-Bisphosphate so it will be converted to Fructose-6-Bisphosphate (the molecule we want).
Fructose-1,6-Bisphosphate ➝ Fructose-6-Bisphosphate + Pi
Now, Fructose-6-Bisphosphate convert back to Glucose-6-Phosphate which needs to transport back to the bloodstream via GLUT2 (the door to exit). Glucose-6-Phosphate could not transport to the bloodstream so need to convert into Glucose. This conversion happens in Smooth Endoplasmic Reticulum (S.E.R) as the enzyme that helps to convert available at S.E.R
4] Glucose-6-Phosphatase:
-Glucose-6-Phosphate cannot change back to glucose
-Glucose-6-Phosphatase in S.E.R convert G-6-P into Glucose
-Uses ATP
G-6-P + ATP ➝ Glucose + Pi + ADP
In the S.E.R, there are 3 specific channels (Doors to exit) which aid the G-6-P to enter and glucose to exit.
T1: G-6-P enter in S.E.R from the cytosol
T2: Glucose exits to the cytosol from S.E.R
T3: Transport Pi to the cytosol
Fasting: ATP; Acetyl CoA ↓
Pyruvate
￬
Acetyl CoA
￬
TCA cycle
￬
ATP
Enough Energy: ATP; Acetyl CoA ↑
Pyruvate
￬
OAA
￬
Gluconeogenesis
￬
Glucose
Gluconeogenesis inhibitors are utilizing in diabetes therapy. We can inhibit the transport activity by the G-6-Phosphatase so G-6-P cannot convert to Glucose, cannot transport out from S.E.R to the cytosol, glucose can not enter the blood, prevent diabetes.
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