Gluconeogenesis Flashcards
What are the main carbon precursors of gluconeogenesis?
Lactate
AAs (((alanine)
Glycerol
What role does gluconeogenesis have in the clearance of lactate?
Lactate is constantly being produced, even in times of inactivity. So, we need to have a way to clear it. The way we do this is by converting it to glucose via gluconeogenesis.
What organ/s is/are responsible for gluconeogenesis?
Liver does 90%
Kidney dies 10% - only really during excessive starvation
- Muscle does NOT play a role in gluconeogenesis
What is different with regards to the location of glycolysis vs gluconeogenesis?
Glycolysis - muscle and brain mostly
Gluconeogenesis - mainly in the liver
What are the unique enzymes involved in gluconeogenesis?
Pyruvate Carboxylase (mitochondrial)
Phosphoenol Carbboxykinase (PEPCK) (cytoplasmic and mitochondrial)
Fructose 1,6-bisphosphatase (cytoplasmic)
Glucose 6-phosphate are (ER)
Pyruvate Carboxylase
So essentially we need to go backwards from what we did in glycolysis. So we had lactate, which can reversible go back to Pyruvate. From Pyruvate, we need to convert it into Oxaloacetate.
- It used biotin as a cofactor and uses 1 ATP.
- Acetyl CoA upregulates this reaction
- Avidin, found in egg whites, can bind to biotin and disrupt this enzyme.
- This occurs in the mitochondria
Phosphoenolpyruvate Carbboxykinase (PEPCK)
Oxaloacetate is brought into the cytosol and is converted into phosphoenolpyruvate via PEPCK (although on the slide it says that this can be mitochondrial also).
- Consumes a GTP.
- releases a CO2
In what circumstances will PEPCK occur in the cytosol vs mito?
Mito - if straight up lactate is the precursor then. It. Will be in the mito.
Cytosol - if Pyruvate is the precursor then it is in the cytosol.
What happens after the PEPCK step?
5 reversible reactions until we finally form fructose 1,6-bispphosphate
- remember, we need two molecules of PEP to make 1 molecule of fructose 1,6-bisphosphate
Fructose 1,6-bisphosphatase-1 (FBP-1)
Removes the phosphate on carbon #1 of fructose 1,6-bisphosphate to produce fructose-6-phosphate
What happens after we have fructose-6-phosphate?
It is isomerized into glucose-6-phosphate
Glucose-6-phosphatase
Glucose-6-phosphate is transported from the cytosol into the ER where it interacts with Glucose-6-phosphatese.
- It is An ER membrane bound complex of proteins in the ER.
- It converts Glucose-6-phosphate into free glucose and releases it into the cytosol along with Pi.
- Not In the muscle, only in the liver
- —- therefore uses GLUT2
Is gluconeogenesis a energy consuming or generating Process?
Consuming
- 6 total ATP
Regulation of gluconeogenesis
Hormonal: glucagon will activate gluconeogenesis
Allosteric - Acetyl CoA will activate Pyruvate carboxylase
What regulates FBP-1
AMP and Fructose 2,6 bisphosphate
- both of these things indicate a low energy state
- they turn on glycolysis
Affects of insulin/glucagon on PFK-1/FBP-1 in the liver? - on a molecular level
1) A high glucagon:insulin ratio causes elevated cAMP–>PKA
2) PKA will phosphorylates PFK2/FBP2
3) Phosphorylated PFK2 is inactive and FBP2 is active. This impedes formation of fructose 2,6-bisphosphate
4) Decreased levels of fructose 2,6-bisphosphate decreases the inhibition of FBP-1, which leads to an increase in gluconeogenesis.
Fructose-1,6-bisphosphatase deficiency
- usually hypoglycemic and have lactic acidosis within the first few days of life.
- frequent feeding with carbs prevents further problems.
- This enzyme deficiency prevents glucose formation f rom all gluconeogenic precursors. Therefore, normal glucose levels are dependent purely on glucose intake and breakdown of glycogen.
WHt would fructose-1,6-bisphosphate se deficiency cause lactic acidosis?
Because gluconeogenesis is responsible for clearing lactate from the body.
Which are the two amino acids that do not play a role in gluconeogenesis? In other words, which two AAs are ketogenic?
Leucine and Lysine
WHat are the essential AAs
PVT TIM HALL
Cori Cycle
Liver uptake of lactate and conversion into glucose
Alanine’s. Role - Chaill cycle
When you are starving, skeletal muscle will break down. Alanine is used to soak up toxic ammonia from urea and bring It back to the liver.
Why do we often see hypoglycemia in neonate so?
- during uterine development he was in a hyperglycemia environment. Therefore, he adapted by increasing endogenous insulin production - this has a growth hormone like activity, which results in being overweight.
- at birth, when placental delivery of glucose ceases, he has normal blood glucose but prior to birth he had hyperinsulinemia, which brings blood glucose down.
- hyperinsulinemia will also suppress gluconeogenic enzymes.
What is gluconeogenesis?
Synthesis of new glucose from simple Caron precursors.
- remember, there are parts of the body that red glucose at all time. While we do get glucose from the diet, what happens if we fast? Then we dip into our liver glycogen stores. However, those stores are fully depleted into 24 hours, which is why gluconeogenesis is so important.
