Gluconeogenesis Flashcards
When does glycogenolysis happen? When does gluconeogenesis happen?
When blood glucose starts running lower, the liver performs glycogenolysis mostly.
When glycogen storage starts running low (e.g. sleep), then glycogenolysis falls and gluconeogenesis rises.
Gluconeogenesis
Formation of glucose from non-carbohydrate precursors
Reverses glycolysis
____ is performed in the cytosol of every cell of our body.
___ mainly occurs in hepatocytes, but also kidney and intestinal epithelium.
Glycolysis in every cell
Gluconeogenesis in liver, kidney, and intestine
How does gluconeogenesis reverse the pyruvate kinase rxn? Where?
- Pyruvate –<strong><em>pyruvate carboxylase, ATP, biotin</em></strong>–> oxaloacetic acid
- Ligase rxn
- Oxaloacetic acid –<strong>PEP carboxykinase (PEPCK), GTP, CO2</strong> –> PEP
both occur int he mitochondria + cytosol
How to reverse the PFK-1 rxn? Where?
F16BP –FBPase-1 +Pi<strong><em> </em></strong>–> F6P
Cytosol
How to reverse the hexokinase reaction? Where?
Glucose-6-phosphate –glucose-6-phosphatase + Pi–> Glucose
Occurs in the ER
Muscle cells perform ___, but it doesn’t affect BLOOD glucose because it’s used internally.
Muscle cells CANNOT perform ___
Can perform glycogenlysis
CANNOT perform gluconeogenesis
Which two gluconeogenesis-specific enzymes do adipose cells have that allow them to perofrm glyceroneogenesis??
Pyruvate carboxylaes
PEPCK
Reaction of gluconeogenesis
2 pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 2H2O
–>
Glucose + 4ADP + 2GDP + 6Pi + 2NAD+
2 ATP were consumed in the pyruvate carboxylase rxn and 2 GTP were consumed in the following PEPCk reaction.
What about the other 2 ATP used in gluconeogenesis?
What about the 2 NADH that got used?
2ATP comes from reversing the phosphoglycerate kinase reaction (which generated 2 ATP in glycolysis)
2NADH comes from reversing the the glyceraldehyde 3-phosphate dehydrogenase reaction (generated 2NADH in glycolysis)
Gluconeogenic precursors:
Ala (most common)
Glycerol
Other aa (e.g. Asp)
Lactic acid
- Ala -> pyruvate
- Glycerol -> DHAP
- Other aa (e.g. Asp) -> oxaloacetate
- (Bypasses ATP hydrolyis of pyruvate carboxylase)
- Lactic acid -> pyruvate
How to hormones mediate changes to enzymes?
Protein covalent modifications
Allosteric control mechanisms
Glucose-6-phosphatase and hexokinase are both active in hepatic cells. How do liver cells regulate their opposing pahtways?
Glucokinase is in the cytosol
Glucose-6-phosphatase is in the ER
When glucose is low, where is glucokinase? where is glucose 6phosphatase?
Glucokinase is sequestered to the nucleus
Glucose 6-phosphtase is active in the ER lumen
When [glucose 6 phosphate] rises in the cell
It’s transported into the ER by a glucose 6-phosphate transporter to be hydrolyzed by the phosphatase to produce glucose.
Transported back to the cytosol, then out to the blood if blood glucose is lower than cytosol
Both PFK-1 (glycolysis) and FBPase-1 (gluconeogenesis) are regulated how?
Allosteric regulation by Fructose 2,6-bisphosphate, which
Stimulates PFK-1
Inhibits FBPase-1
___ catalyzes the production of F2,6BP from fructose-6-phosphate
PFK-2
__ catalyzes the hydrolyzes the cabron-2 phosphate from F2,6BP to regenerate Fructose 6-phosphate
FBPase-2
The bifuncitonal enzyme is
PFK-2 & FBPase2
Hormonal signals in response to blood glucose determine which of the opposing enzymatic activities is stimualted or repressed.
If blood glucose is high, what happens to the bifunctional enzyme?
What if blood glucose is low?
Dephosphorylation -> increases PFK-2 and decreases FBPase-2 -> glycolysis
Phosphorylation -> decreases PFK-2 and increases FBPase-2 –> gluconeogenesis
Effect of glucagon
- Phosphorylate the bifunctional enzyme to inhibit PFK-2 and activate FBPase-2.
-
Phosphorylation & inactivation of pyruvate kinase
- –> Accumulates PEP to use directly in gluconeogenesis (saves ATP)
- Stimulate transcription of Glucose-6-phosphatase, FBPase-1, PEPCK
- Inhibit transcription of glucokinase, PFK-1, and pyruvate kinase
3 ways acetyl CoA may build up
Indicates a well-fed state; produced from either
- Pryuvate metabolism
- B oxidation of fatty acids
- Breakdown of ketogenic aa (Leu & Lys)
What does acetyl CoA activate? Why?
Acetyl CoA activates pyruvate carboxylase because it’s a sign that more oxaloacetic acid is required for gluconeogenesis
Also remember that it was an inhibitor for pyruvate kinase.
Adipocytes can’t perform gluconeogenesis. What is glyceroneogenesis?
Process by which glycerol-3-phosphate is generated from pyruvate in liver and adipose cells.
High serum fatty acids correlate with ___ed insulin sensitivity
High serum FA –> reduced insulin sensitivity
Why do some diabetes drugs stimulate glyceroneogenesis?
It re-esterifies fatty acis back into triglycerides among adipocytes to increase insulin sensitivity
When glucagon is high, what do adipose tissues do?
Hydrolyze triglyceride fat stores into glycerol and free FA, released into the blood stream
- Glycerol goes to liver as a precursor for gluconeogenesis
- Free FAs are taken up by other tissues (like muscle) to be oxidized for energy to CO2
Free fatty acids that aren’t metabolized go to the liver, where they get
Re-esterified to glycerol-3-phosphate from pyruvate during glyceroneogenesis to produce new triglycerides. These triglycerides are exported to the liver to provide FFAs to the fat cells, where new TGs can be synthesized and stored.
Glyceroneogenesis uses pyruvate as a precursor and involves the enzymes pyruvate kinase and PEPCK; however, it doesn’t include F1,6BPase-1 or Glucose-6-phosphatase, so ___ backs up and is reduced to ___ by ____.
DHAP backs up and is reduced to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase.
gly 3 p is the final product of glyceroneogenesis
Adipocytes lack ___, which is why glycerol from hydrolysis of TGs must travel to the liver in order to be phosphorylated to glycerol 3-phosphate.
glycerol kinase
Rosiglitazone
Diabetes drug
Stimulates transcription PEPCK and thus induces glyceroneogenesis –> marked decrease in FFA release from adipose tissue (which usually happens in T2D)
Can your body make glucose from fatty caids? Can i tmake it from triglycerides?
B-oxidation of FA yields only acetyl-CoA
Wheras, triglycerides’ glycerol can be converted to glucose
“Second wind” of long-distance runners / Cori cycle
- Muscles require ATP from glycogen breakdown.
- When oxygen is low, the pyruvate of glycolysis is converted to lactate to regenerate NAD+.
- Lactate is taken up by the liver, which converts it to glucose that goes back to the muscle to replenish glycogen supplies.
What are teh energy requirements to make one glucose from 2 pyruvates? From 2 lactate molecules?
From 2 pyruvates: 4ATP + 2GTP + 2NADH
From 2 lactates: 4ATP + 2GTP
Cortisol stimulates
Gluconeogenesis in the liver by increasing PEPCK synthesis and increasing protein breakdown for glucose synthesis.
Why is it important to coordinately control glycolysis and gluconeogenesis?
Gluconeogenesis is energetically expensive, so your liver & kidneys shouldn’t be breaking down glucose via glycolysis when it’s needed to supply the brain.
The liver & other tissues can use FA for energy generation, but the brain can’t because BBB
Pyruvate kianse is inactivated by glucagon-stimulated cAMP-dependent protein kinase. Why?
It takes 2 enzymes, an ATP, and a GTP to convert pyruvate back to PEP. When you have low blood sugar, inactivating pyruvate kinase makes the process of gluconeogenesis instead more energetically favorable
Where dose glyceroneogenesis occur
adipose and liver tissue
