Biochemistry-Gluconeogenesis Flashcards
Precursors for gluconeogenesis
AAs, Lactate/pyruvate, glycerol and TCA cycle intermediates
Where does gluconeogenesis take place?
1) Liver 2) Renal Cortex (dumps glucose into blood w/severe liver damage)
What is the purpose of gluconeogenesis?
Maintain blood glucose levels during fasting and prolonged exercise. Recycle lactate.
What is the Cori cycle?
Glucose -> Lactate -> Liver takes up lactate and sends glucose back into the blood. Note that the majority of the energy needed to make this transformation comes from oxidation of fatty acids.
What reactions in gluconeogenesis differ from glycolysis?
1) Glucokinase in glycolysis 2) PFK-1 in glycolysis and 3) Pyruvate kinase are all irreversible reactions in glycolysis. These steps are bypasses in gluconeogenesis.
Alanine finally makes it from the muscle to the liver. It gets hit by a transaminase to become pyruvate and pyruvate enters the mitochondria. How does gluconeogenesis proceed from here?
1) ATP + pyruvate carboxylase converts pyruvate to oxaloacetate 2) Oxaloacetate enters the malate aspartate shuttle and is transported to the cytosol 3) PEPCK (phosphoenolpyruvate carboxykinase) converts oxaloacetate to PEP in the cytosol.
Malate aspartate shuttle transferring oxaloacetate with malate dehydrogenase
Oxaloacetate + NADH -> Malate. Malate then crosses the mitochondrial membrane and is oxidized by malate dehydrogenase to oxaloacetate.
Malate aspartate shuttle transferring oxaloacetate with a transaminase.
Oxaloacetate + transaminase -> Aspartate. Aspartate then crosses the mitochondrial membrane where it meets transaminase and goes back to oxaloacetate.
How is gluconeogenesis related to the urea cycle?
The urea cycle utilizes the aspartate that was oxaloacetate in the mitochondria.
What is the main source of cytosolic NADH?
Malate dehydrogenase making NADH from NAD in the reaction going from malate to oxaloacetate.
What is the main source of energy utilized for gluconeogenesis?
Fatty acid oxidation.
Why is lactate a better precursor in gluconeogenesis?
You don’t need NADH to convert lactate to glucose. In the cytosol lactate is converted to pyruvate by lactate dehydrogenase. Then pyruvate enters the mitochondria where it becomes oxaloacetate. Then mitochondrial PEPCK makes PEP from oxaloacetate, PEP exits into the cytosol and is then made into glucose.
Mechanism of pyruvate conversion to oxaloacetate
Pyruvate carboxylase + biotin. Biotin carries CO2 to pyruvate and sticks it on.
Mechanism of oxaloacetate conversion to phosphoenolpyruvate.
PEPCK + GTP -> PEP and GDP. Losing CO2 creates a decarboxylated intermediate that drives this unfavorable reaction forward.
How much energy does it take to go from pyruvate to PEP?
Two high energy bonds (GTP and ATP)
How does the third bypass reaction of gluconeogenesis occur? Why is this reaction so important?
G6P->Free glucose by glucose-6-phosphatase. G6P cannot exit the liver, it must be converted to free glucose before exiting.
When you add them all up, how many high energy bonds are required to convert 2 pyruvate glucose-6-P?
6
Which enzyme do you not want pyruvate to interact with in the mitochondrial matrix when gluconeogenesis needs to happen? How does this happen?
Pyruvate dehydrogenase, this will convert pyruvate to acetyl CoA. During the starved state, beta-oxidation is on full blast. This means acetyl CoA and NADH will accumulate in the mitochondrial matrix. Acetyl CoA activates pyruvate carboxylase and NADH inhibits pyruvate dehydrogenase.
What prevents a futile cycle?
When gluconeogenesis is running, you need to shut down glycolysis. Pyruvate kinase is inactivated by glucagon sending cAMP to phosphorylate pyruvate kinase, now PEP will not be converted back to pyruvate. Absence of F-2,6-BP during the fasted state leaves PFK-1 inactivated. In a fasted state glucokinase is not present in high amounts.
