Gluconeogenesis Flashcards
*What is gluconeogenesis? Where does gluconeogenesis take place?
Gluconeogenesis- synthesis of glucose from non-carbohydrate precursor. (pyruvate to glucose)
Gluconeogenesis takes place in LIVER (major site) and kidney.
This process if important for FASTING or STARVATION (glucose is primary fuel for BRAIN and ONLY fuel for RBC.
*Why is gluconeogenesis not a simple reversal of glycolysis?
Not a reversal because several reactions are different in gluconeogenesis, since the equilibrium for glycolysis lies far on side pyruvate formation
In gluconeogenesis- the irreversible steps (hexokinase, PFK, pyruvate kinase) of glycolysis must be BYPASSED.\
prevent gluconeogenesis and glycolysis from occurring at the same time (need to make enzymes only active in gluconeogenesis).
*How much energy is expended in the synthesis of glucose?
Since synthezing glucose (happens twice):
you use 2 pyruvate, 4 ATP , 2 GTP and 2 NADH and 6 H20 to form glucose, 4 ADP, 2 GDP, and 6, Pi 2 NAD+
pi- high transfer phosphoryl groups.
*Understand in detail the positive and negative regulators of gluconeogenesis and glycolysis
(Figure 17.6)
glycolysis (breakdown glucose)- positive regulator (activate): F 2,6 BP and AMP (both stimulate PFK), F 1,6 BP (activate pyruvate kinase) negative regulator (inhibit): Citrate, ATP (both inhibit PFK) and ATP and Alanine (inhibit pyruvate kinase)
Gluconeogenesis- positive regulator (activate)- CITRATE (activate f 1,6 bisphosphatase), Acetyl CoA negative regulator (inhibit)- F 2,6 BP and AMP, ADP (for convert pyruvate to PEP in gluconeogenesis).
*What are the regulatory roles of phosphofructokinase 2 (PFK2) and fructose bisphosphatase 2(FBPase2)? What are the factors that regulate these enzymes?
Glucagon will stimulate Protein kinase A when blood glucose scarce. This will ACTIVATE FBPASE2 (fructobisphosphatase 2) and glycolysis is inhibited, gluconeogenesis STIMULATED.
In glucagon, protein kinase 2 will phosphorylate PFK2, inactivating it (turn off kinase), turn on phosphatase.
When you have high levels of fructose 6-phosphate (glucose abundant), it will stimulate Phosphoprotien phosphatase. PFK2 activated, GLYCOLYSIS is STIMULATED, gluconeogenesis is inhibited.
(insulin signal to dephosphorylate PFK2, turn PFK2 on., stimulate glycolysis.
*What happens to gluconeogenesis in patients suffering from Type 2 Diabetes?
Type 2 diabetes- Insulin FAILS to inhibit gluconeogenesis (insulin resistance).
So levels of enzymes in gluconeogenesis is HIGH especially PEPCK leading to high levels of blood glucose.
exercise and diet can enhance insulin sensitivity.
normally insulin inhibits gluconeogenesis.
*Understand the Cori cycle.
Cori Cycle- in the liver, Lactate converts to glucose, which then glucose passed to blood and then into skeletal muscle. Then lactate (glucose convert to lactose) produced by muscle during contraction, enters blood and is returned back to liver, start process all over again.
How is lactate made from pyruvate?
Pyruvate converts to lactate through lactate DH( NADH oxidized to form NAD+)
What process is the fed state? which one is starved state?
Glycolysis- FED state
Gluconeogenesis- STARVED state
What are the non-carb precursors that can convert into glucose? how?
- Lactate- can be produced from active muscle through lactic fermentation (pyruvate to lactate through lactate DH, reversible)
- Amino acids- made from proteins (from diet, or starvation, muscle break down proteins)
- Glycerol- made from hydrolysis of triacylglycerol in fats (make fatty acids, glycerol)
Glycerol can be metabolized (break down glucose) by glycolysis or converted into glucose by gluconeogenesis
Glycerol will convert two DHAP (dihydroxyacetone phosphate) in both pathways.
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What are the distinctive reaction and enzymes in gluconeogenesis?
1st, 2nd , 8th and last step are distinctive in gluconeogenesis.
Step 1: Pyruvate converts to oxaloacetate through PYRUVATE CARBOXYLASE (add cooh, use up ATP).
this reaction occurs in MITOCHONDRIA and enzyme requires BIOTIN (carrier of O2). This is irreversible step.
Step 2: Oxaloacetate converts to Phosphoenolpyruvate through PEPCK (phosphoenolcarboxykinase) in CYTOPLASM. Oxalo is now decarboxylated, and uses hydrolyze GTP (product: GDP, Co2)
These 2 reactions bypass irreversible reaction of pyruvate kinase in glycolysis
step 8: Fructose1,6 bisphosphate converts to fructose 6-phosphate through FRUCTOSE 1,6 BISPHOSPHATASE
(irreversible step) pi product
Step 10: Glucose 6 phosphate convert to glucose using GLUCOSE 6-PHOSPHATASE (irreversible step)
Glucose 6 phosophatase is an integral membrane enzyme of inner ER. (glucose 6 phosphate transport to lumen of ER) pi product
if normally reverse glycolysis of pyruvate to glucose it is not energetically favorable (use 2 atp). contrastingly, gluconeogesis convert pyruvate to glucose is energetically favorable (spontaneously) due to extra 4 high phosphoryl transfer potential molecules (pi)
How does oxaloacetate enter cytoplasm?
Oxaloacetate must be reduced to malate(malate DH) and transported into cytoplasm.
malate in cytoplasm is reoxidized back to oxaloacetate
and generates cytoplasmic NADH.
PEP then synthesized from oxaloacetate by PEPCK.
where is the generation of free glucose occur in gluconeogenesis?
generation of free glucose occurs only in LIVER, during last step of gluconeogenesis (G6P to glucose)
What differentiates glucose in liver vs tissues.
most tissues- do not have glucose 6 phosphatase (easily convert g6p to glucose). They have to convert G6p into glycogen (storage form of glucose)
in liver- they have glucose 6-phosphate to make free glucose.
Which bifunctional enzyme is turned on/off and determined by glucose levels?
GLUCAGON
when blood glucose is low, hormone glucagon secreted.
glucagon signaling pathway leads to phosphorylation of bifunctional enzyme that inhibits kinase and stimulates phosphatase.
