Lecture 12 - Regulation of Glycolysis and Gluconeogenesis Flashcards
Why is hexokinase important in the regulation of glycolysis?
Step one - Glucose to Glucose-6-phosphate (Hexokinase)
Hexokinase is inhibited by G6P product inhibition
This has two functions:
1. Ensures that if a cell has sufficient G6P then phosphorylation of glucose will decrease
Glucose in blood becomes available to liver glucokinase. This enzyme has a lower affinity for glucose than hexokinase and is not inhibited by G6P
How is pyruvate kinase invovled in the regulation of glycolysis?
Step 10 - Phosphoenolpyruvate to pyruvate (Pyruvate kinase)
The activity of PK is controlled by a number of allosteric regulators:
Decrease in activity to conserve glucose - ATP, Citrate, Alanine and long-chain fatty acids
Increase in activity to stimulate glycolysis - Phosphoenolpyruvate and fructose-1,6-bisphosphate Positive feedforward control
* There are several isozymic forms of PK - liver has L type and muscle has M type both respond to allosteric regulators by the liver isoform is also regulated by phosphorylation
The phosphorylation of L isoform is controlled by hormonal regulation (glucagon and insulin)
What is the role of PFK in glycolysis regulation?
PFK is the Key Enzyme
PFK is the first committed step
Flucose-6-phosphate formed by step 1 of glycolysis is not uniquely a glycolytic intermediate. It can also be used in the synthesis of glycogen or it can be oxidised in the pentose phospate pathway to produce NADPH. It has many possible fates within the cell
Glycolysis is regulated at more than one point as it is a biosynthetic pathway which means it produces intermediates which are precursors to other compounds, particularly lipids and amino acids.
What is the amount of glucose stored in the liver, How are muscle stores different?
Liver and muscle have significant glycogen sores. Total liver glycogen is about 50-120g
The stored glucose in muscle is not available to the body as muscle does not possess glucose-6-phosphatease
Therefore liver glycogen is the glucose store for the body
Our carbohydrate stores are sufficient for a day or so without food
For survival in periods of starvation, glucose must be synthesised form non-carbohydrate sources - Glyconeogenesis.
What is gluconeogenesis?
Glucose can be synthesised by cells under certain conditions.
1. The availability of precursors
2. Spare energy, i.e. ATP and GTP
3. The enzymes needed to catalyse the reactions in the sequence
Gluconeogenesis is not a direct reversal of glycolysis. The glycolytic pathway has three irreversible steps. Glyconeogenesis gets around these steps (1, 3, and 10) through additional reactions.
Requires 6 high energy phosphate bonds in form of 4ATP and 2GDP
How does the reversal of step 10 of glycolysis occour for gluconeogenesis?
Reversal of step 10
(Pyruvate - Phosphoenolpyruvate)
Pyruvate - oxaloacetate - malate - oxaloacetate - PEP
Oxaloacetate is formed in the mitochondria but only malate can be transported out
Reactions catalysed by:
1. Pyruvate carboxylase
2. Mitochondrial malate dehydrogenase
3. Cytoplasmic malate dehydrogenase
4. Phosphoenolpyruvate carboxykinase
The consumed GTP is produced in the citric acid cycle
How is PEP converted to fructose-1,6-bisphosphate in gluconeogenesis?
The conversion of PEP to fructose-1,6-bisphosphate involves the straight forward reversal of the glycolytic steps 9 to 4 but requires the input of energy
ATP in step 7
NADH in step 6
How does the reversal of steps 1 and 3 of glycolysis occour for gluconeogenesis?
Step 1: Fructose-1,6-bisphosphatase catalyzes the conversion of Fructose 1,6-bisphosphate to fructose-6-phosphate.
Step 2: Fructose-6-phosphate is converted to glucose-6-phosphate. This conversion is facilitated by the enzyme glucose-6-phosphate isomerase.
Step 3: Glucose-6-phosphate is further converted to glucose. This final step occurs primarily in the liver and kidneys and is catalyzed by the enzyme glucose-6-phosphatase.
How do hormones regulate glycolysis and gluconeogenesis? What is the role of Fructose bisphosphate 2 ( phosphofructokinase 2)
Overview:
Fructose bisphosphate 2 and phosphofructokinase 2 are the same protein, constituting a bifunctional enzyme.
The enzyme’s activity is modulated by the phosphorylation status of the protein.
Regulation by Phosphorylation:
* Phosphorylated Protein:
Results in Fructose bisphosphate 2 activity.
Stimulates gluconeogenesis.
Converts Fructose-2,6-bisphosphate to Fructose-6-phosphate.
* Non-phosphorylated Protein:
Leads to phosphofructokinase 2 activity.
Stimulates glycolysis.
Converts Fructose-6-phosphate to Fructose-2,6-bisphosphate.
Regulatory Factors:
* Glucagon Activation:
Activates cyclic-AMP dependent protein kinase.
Phosphorylates the protein.
Leads to gluconeogenesis stimulation.
* Insulin Activation:
Activates protein phosphatase 2a.
Dephosphorylates the protein.
Leads to glycolysis stimulation.
What is the cori cycle
The lever and skeletal muscle cooperate metabolically. Contracting skeletal muscle supplies lactate to the liver which uses it to synthesise and release glucose. Glucose produces lactate as waste product in muscle.
