Gluconeogenesis Flashcards
1
Q
Gluconeogenesis
A
- production of new glucose from non-carbohydrate sources
2
Q
The need for gluconeogenesis
A
- Some tissues require a constant supply of glucose as a metabolic fuel
- Humans must be able to synthesise glucose from other precursors and maintain blood glucose with narrow limits
- Liver and kidney cortex are the primary gluconeogenic tissues
3
Q
Tissues that require constant glucose supply as fuel
A
- Brain & CNS
- Erythrocytes
- Kidney medulla
- Lens and cornea
- Testes
- Exercising muscle
4
Q
Synthesis and use of glucose
A
- Liver glycogen an essential post-prandial source of glucose can meet the needs for ~24 hrs in the absence of dietary intake
- however in a prolonged fast when glycogen reserves are depleted, glucose must be made from non-carbohydrates sources
5
Q
Precursors required for gluconeogenesis
A
- Pyruvate 3C (from glycolysis)
- Glycerol 3C (from hydrolysis of TAGs)
- Lactate 3C (from anaerobic glycolysis)
- α-keto acids 3, 4, 5C (obtained from the metabolism of AAs)
6
Q
Glycolytic pathway
A
- Reactions 1, 3 & 10 of Glycolysis are so strongly exergonic (high ΔG0’) as to be essentially irreversible
- In gluconeogenesis different enzymes are used at each of these steps
7
Q
Bypass 1 of gluconeogenesis
A
- CO2 from bicarbonate is activated and transferred by pyruvate carboxylase to its biotin prosthetic group
- enzyme transfers CO2 to pyruvate, form oxaloacetate
- oxaloacetate can’t cross mitochondrial membrane and reduced to malate
- malate reoxidised to oxaloacetate, which is oxidatively decarboxylated to phosphophenolpyruvate by PEP carboxykinase
8
Q
Bypass 2 of gluconeogenesis
A
- Conversion of Fructose 1,6-bisphosphate to fructose 6-Phosphate
- catalysed by Fructose 1,6-bisphosphatase
- hydrolysis reaction
- phosphate removed
9
Q
Bypass 3 of gluconeogenesis
A
- Conversion of Glucose 6-phosphate to Glucose
- catalysed by Glucose 6-phosphatase
- hydrolysis reaction
- phosphate removed
- Glucose 6-phosphatase is expressed predominantly in the liver and kidney and is embedded in the ER membrane
10
Q
Amount and location of gluconeogenesis
A
- During an overnight fast ~90% of Gluconeogenesis occurs in the liver and ~10% in the kidney.
- During a prolonged fast ~40 % of Gluconeogenesis will take place in the kidneys.
- A small amount can take place in the small intestine too
11
Q
Cori cycle - glucose from lactate
A
- pyruvate to lactate
- catalysed by lactate dehydrogenase
- Lactate from anaerobic glycolysis is released into the blood – from cells that lack mitochondria or excising Muscle.
- Lactate taken up by liver and oxidised to pyruvate which can then be converted to glucose
- cycle is especially in muscular exercise
12
Q
Glucose-alanine cycle in muscle
A
- Pyruvate is converted to alanine (transamination)
- Prevents toxic levels of ammonia in muscle & in blood
13
Q
Glucose-alanine cycle in liver
A
- Alanine donates NH3 to a ketoglutarate to form glutamate (transamination) and Pyruvate is reformed which can be used for gluconeogenesis.
- Glutamate is deaminated releasing NH3
- cycle is especially active in starvation
14
Q
Regulation of hepatic gluconeogenesis
A
- Regulation of CHO metabolism
- High insulin/glucagon ratio (fed state): reduced glycogenolysis and gluconeogenesis and instead favours anabolic reactions e.g. muscle synthesis and storage.
- Low insulin/glucagon ratio (fast state): favours glycogenolysis and gluconeogenesis
- Epinephrine also promotes gluconeogenesis
15
Q
Glycolytic specific enzymes
A
- Phosphofructokinase-1 (PFK-1)
- Pyruvate kinase
16
Q
Gluconeogenic specific enzymes
A
- Glucose 6-phosphatase
- Fructose bisphosphatase -1 (FBP-1)
- Phosphoenolpyruvate carboxykinase
- Pyruvate carboxylase
17
Q
Effects of glucagon in fasting state
A
- High levels produced during fasting state
- Activates adenylate cyclase which synthesise cAMP
- cAMP activates Protein Kinase A (PKA)
- PKA targets & modulates several enzymes involved in gluconeogenesis + glycolysis
- PKA phosphorylates Pyruvate Kinase, inactivating it
- Prevents Phosphoenolpyruvate being converted to pyruvate and therefore favours gluconeogenesis
18
Q
Increase in Fructose 2, 6 bisphosphate
A
- ↑ PFK1 activity and so activates glycolysis
- ↓ FBP1 activity and so inhibits gluconeogenesis
19
Q
Decrease in Fructose 2, 6 bisphosphate
A
- ↓PFK1 activity and so inhibits glycolysis
- ↑FBP1 activity and so activates gluconeogenesis
20
Q
What controls PFK-2/FBPase-2 activities?
A
- Phosphorylation: ↓ kinase activity of PFK-2 ↑phosphatase activity of FBPase-2 - Dephosphorylation: ↑ kinase activity of PFK-2 ↓ phosphatase activity of FBPase-2
21
Q
Phosphorylation of PFK-2/FBPase-2
A
- PKA is activated by high glucagon.
- PKA phosphorylates PFK-2/FBPase-2: P decreases activity of PFK-2 and increases FBPase-2 – this impedes the synthesis of fructose 2,6-bisP
- So fructose 2,6-bisP ↓: gluconeogenesis ↑, Glycolysis ↓
- Increases synthesis of glucose
22
Q
Dephosphorylation of PFK-2/FBPase
A
- PKA is not activated in high insulin
- favours dephosphorylation of PFK-2/FBPase-2: increases activity of PFK-2 and decreases FBPase-2 – this increases the synthesis of fructose 2,6-bisP
- So fructose 2,6-bisP ↑: gluconeogenesis ↓, glycolysis ↑
- Prevents synthesis of glucose
