Gluconeogenesis Flashcards
T or F. Gluconeogenesis is the pathway for synthesizing glucose from carbohydrate precursors
F. It is the pathway from non-carbohydrate precursors
What kinds of the non-carbohydrate precursors are the basis of gluconeogenesis?
lactate, pyruvate, glycerol, amino acids
Where does gluconeogenesis primarily occur?
liver
2-3 hrs after a meal, where is BG coming from?
glycogenolysis
16-24 hrs after a meal, where is BG coming from?
gluconeogenesis
What is the secondary site of gluconeogenesis?
kidney
What are the three main carbon sources for gluconeogenesis?
lactate, amino acids (alanine), and glycerol
Where does the glycerol for gluconeogenesis come from?
adipose lipolysis
Where do the amino acids (alanine) for gluconeogenesis come from?
glycolysis and amino acid metabolism
Where does the lactate for gluconeogenesis come from?
muscle and RBC glycolysis
What are the irreversible enzymes of glycolysis?
glucokinase, PFK-1, pyruvate kinase, pyruvate dehydrogenase
What does pyruvate dehydrogenase do?
converts pyruvate into acetyl CoA in glycolysis
T or F. Gluconeogenesis occurs under conditions where glucokinase, PFK-1, and pyruvate kinase are under low activity
T. This minimizes glycolysis
What is the first step of gluconeogenesis?
pyruvate is concerted to oxaloacetate
What enzyme is involved with conversion of pyruvate to oxaloacetate?
pyruvate carboxylase (using ATP)
Where does the conversion of pyruvate to oxaloacetate occur?
inside the mitochondria
What must oxaloacetate be converted to before leaving the mitochondria and why?
either malate or aspirate (using NADH and making NAD+) because oxaloacetate in not diffusible across the membrane
What happens to malate and aspartate after leaving the mitochondria?
they are reconverted to oxaloacetate
NOTE: malate does this using NAD+ and making NADH as a bi-product
What happens to oxaloacetate in the cytosol?
it is converted to PEP by phosphenol-pyruvate carboxykinase (PEPCK) by using GTP (and giving off GDP and CO2 as bi-products)
What is pyruvate carboxylase activated by?
Acetyl CoA (coming from FA oxidation)
What does pyruvate carboxylase require to work?
biotin and CO2
What else does pyruvate carboxylase do cells?
responsible for maintaining OAA concentrations for the TCA cycle
Is pyruvate carboxylase active in both fed and fasting cycles? Why?
Yes. because it is responsible for maintaining OAA concentrations for the TCA cycle during fed state and responsible for the conversion of pyruvate to oxaloacetate during fasting stages
Is pyruvate carboxykinase found in the cytosol or the mitochondria or both?
mitochondria only
Is phosphenol-pyruvate carboxykinase (PEPCK) found in the cytosol or the mitochondria or both?
both
Can oxaloacetate be converted to PEP both in the mitochondria and in the cytosol? How?
Yes.
In the mitochondria, if there are mitochondria PEPCKs present, they will convert OAA directly to PEP (without intermediates). PEP is diffusable and can cross the mitochondrial membrane to the cytosol
Another way is to convert OAA to malate and aspartate to move out of the mitochondria, reconvert to OAA, and be converted to PEP by PEPCK
How is PEP converted to glyceraldehyde-3-p?
reversible of the steps of glycolysis (conversion would require 2 ATPs and a GTP)- know where from
What would be the steps needed to use glycerol as a pre-cursor of gluconeogenesis?
1) glycerol kinase would convert glycerol to glycerol-3-p using glycerol kinase (using hydrolysis of ATP)
2) glycerol-3-p would be converted to DHAP using NAD+ (and giving off NADH as a bi-product)
Why would using glycerol as a pre-cursor for gluconeogenesis be energy saving vs using pyruvate?
it only uses 1 ATP vs pyruvate conversion using 2 ATPs and a GTP
Do glucose-6-phosphatase and fructose-1,6-bisphosphatase step-for-step reverse the actions of glucokinase and PFK-1?
No. glucokinase and PFK-1 use hydrolysis of ATP while glucose-6-phosphatase and fructose-1,6-bisphosphatase do not give off ATP and release a free glucose and an inorganic phosphate group, respectively
When does gluconeogenesis occur?
fasting, prolonged exercise, stress, high protein diet
What factors promote gluconeogenesis?
availability of substrates (glycerol, AAs, lactate)
What steps of gluconeogenesis are regulated?
pyruvate -> PEP
fructose-1,6-bisphosphatase -> F-6-P
G-6-phosphatase -> glucose
How is pyruvate dehydrogenase regulated?
1) during fasting, adipose TAG is broken down and FA are released and sent to the liver where they undergo B-oxidation to Acetyl CoA, NADH, and ATP.
2) As a consequence, ADP levels decrease and pyruvate dehydrogenase is phosphorylated to its inactive form
3) Thus, acetyl CoA is not formed from pyruvate
What activates pyruvate carboxylase?
acetyl CoA produced from the oxidation of FA
How does acetyl CoA regulate gluconeogeneis?
1) activates pyruvate carboxylase
2) inhibits pyruvate dehydrogenase
How is PEPCK upregulated?
glucagon activates adenylyl cyclase which makes cAMP (from ATP), which then activates PKA.
PKA stimulates the transcription of the PEPCK gene
What activates adenylyl cyclase during fasting?
glucagon
What activates adenylyl cyclase during exercise?
epinephrine
How is pyruvate kinase regulated?
PKA induced from glucagon inactivates it
What regulates the activity of fructose-1,6-bisphosphatase?
fructose-2,6-bisphosphate levels (high levels will reduce the activity of fructose-1,6-bisphosphatase and will increase the activity of PFK-1)
What enzyme is responsible for the production of fructose-2,6-bisphosphate?
PFK-2
What does the kinase domain of PFK-2 do and what up regulates it? When is it active
F6-p converted to f-2,6-bisphosphate
high f6-p levels
active when PFK-2 is de-phosphorylated
What does the phosphatase domain of PFK-2 do and what up regulates it?
converts f-2,6-bisphosphate to f6-p
cAMP activated PKA activates it by phosphorylating it (aka when PFK-2 is phosphylated, its undergoing gluconeogenesis)
active when PFK-2 is phosphorylated
How many ATPs and GTPs are need to make glucose from glycerol?
2 ATPs, no GTP
How many ATPs and GTPs are need to make glucose from pyruvate?
4 ATPs, 2 GTPs
Where does the energy (aka ATPs and GTPs) needed for gluconeogenesis come from?
oxidation of fatty acids and lactate
