Flashcards in Lecture 26: Gluconeogenesis Deck (86)
What are the 2 main metabolic priorities of our bodies?
1. Make sure the brain has enough fuel
2. Make sure we're not breaking down to much protein in our muscles = avoiding too many AA catabolism for gluconeo
3 mechanism to maintain blood glucose levels?
2. Glycogen synthesis/breakdown
What 2 organs can perform gluconeo? % of where it happens?
1. Liver: 90%
2. Kidneys: 10%
What are the possible starting materials for gluconeo?
1. Pyruvate from lactate
2. Glycerol (small amounts during fasting state)
3. TCA cycle intermediates (which can be formed by glucogenic AAs)
How do adipocytes contribute to gluconeo?
They break down TAGs to free glycerol:
1. Can convert all the way up to DHAP but process stops there
2. Liberate a ton of it for the liver/kidneys to perform full gluconeo
How is glycerol converted to DHAP? 2 steps
1. Glycerol kinase: glycerol + ATP = glycerol-3-P + ADP (only in kidneys/liver)
2. Glycerol-phosphate dehydrogenase: glycerol-3-P + NAD+ = DHAP + NADH
What do the 3 bypasses of gluconeo accomplish?
1. Add Cs to make glucose
2. Reduce molecules to give glucose its reducing power
How much ATP does gluconeogenesis use compared to the energy created by glycolysis?
It uses up more energy than glycolysis provides (6 used vs 2 in glycolysis)
What are the 2 inhibitors of pyruvate kinase? Explain how each works.
1. Alanine: allosteric inhibition
2. Glucagon/catecholamines: cAMP/PKA phosphorylation of pyruvate kinase = decreased activity
Gluconeo Step 1: Reactant/Products? Include # of Cs.
Pyruvate (3C) + HCO3- + ATP => Oxaloacetate + ADP + Pi
Gluconeo Step 1: Reaction type? 2 answers
2. Anaplerotic because provides a TCA intermediates thereby the TCA rate
Where does the pyruvate in Step 1 of gluconeo come from?
3. Lactic acid
4. Glucogenic AAs: glutamate, aspartate among others
What are alpha keto acids? What is their purpose?
AAs without the amino group (replaced by another carboxyl group) that will feed into other pathways
How is pyruvate generated from alanine?
Alanine + alpha ketoglutarate = pyruvate + glutamate
What is the glucose-alanine cycle? 5 steps
1. Glucose converted to pyruvate in muscle
2. Pyruvate converted to alanine via aminotransferase
3. Alanine is delivered from the muscle during starvation to the liver
4. Liver converts it to glucose through gluconeo
5. Glucose goes back to muscle for protein formation and energy
What is the Cori cycle?
1. Lactate formed in muscles during anaerobic metabolism of glucose is sent to the liver
2. Liver converts it to glucose through gluconeo
3. Glucose goes back to muscle for protein formation and energy
How is lactate converted to pyruvate?
Lactate dehydrogenase: lactate + NAD+ => pyruvate + NADH
Which conversion to pyruvate is faster: AAs or lactate? Why is this a good thing?
Good to avoid muscle wasting during fasting
Gluconeo Step 1: Enzyme?
What is pyruvate carboxylase regulated by?
Acetyl CoA: high levels activate it, low levels inhibit it (allosteric regulation)
Gluconeo Step 1: Cofactors?
Gluconeo Step 2: Reactant/Products? Include # of Cs.
Oxaloacetate (4C) + NADH => Malate (4C) + NAD+
Gluconeo Step 2: Purpose?
Get oxaloacetate out of the mitosol! Malate shuttle.
Gluconeo Step 4: Reactant/Products? Include # of Cs.
Malate (4C) + NAD+ => Oxaloacetate (4C) + NADH
Gluconeo Step 3?
Malate transport from mitosol to cytosol
Gluconeo Step 5: Reactant/Products? Include # of Cs.
Oxaloacetate (4C) + GTP => Phosphoenolpyruvate (3C) + GDP + CO2
Gluconeo Step 5: Reversible or irreversible?
Where does gluconeo step 5 happen?
Can happen either in mitosol or cytosol
Gluconeo Step 5: Enzyme?
Cytosolic/Mitochondrial PEP carboxykinase
Gluconeo Step 5: Cofactor?
Where is PEPCK present?
Where is pyruvate carboxylase found?
What is the purpose of having PEPCK in muscles? When is this most useful?
Performs reverse reaction as a key anaplerotic reaction which is key in muscles during high physical activity during which energy is needed
What happens after mitochondrial PEPCK converts oxaloacetate to PEP? In which cases does this happen?
PEP can cross mito membrane
Happens when we obtained pyruvate from lactate, which already provided an NADH, so no need to use the malate shuttle
Gluconeo Step 6: Enzyme?
Gluconeo Step 6: Reactant/Products? Include # of Cs.
Phosphoenolpyruvate (3C) + H2O => 2-phosphoglycerate (3C)
Gluconeo Step 7: Enzyme?
Gluconeo Step 7: Reactant/Products? Include # of Cs.
2-phosphoglycerate (3C) => 3-phosphoglycerate (3C)
Gluconeo Step 8: Enzyme?
Gluconeo Step 8: Reactant/Products? Include # of Cs.
3-phosphoglycerate (3C) + ATP => 1,3BPG (3C) + ADP
Gluconeo Step 9: Enzyme?
Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH)
Gluconeo Step 9: Reactant/Products? Include # of Cs.
1,3-bisphosphoglycerate (3C) + NADH + H+ => GAP (3C) + Pi + NAD+
Gluconeo Step 10: Enzyme?
Gluconeo Step 10: Reactant/Products? Include # of Cs.
DHAP (3C) => GAP (3C)
Gluconeo Step 11: Enzyme?
Gluconeo Step 11: Reactant/Products? Include # of Cs.
DHAP (3C) + GAP (3C) => F1,6BP (6C)
Gluconeo Step 12: Enzyme?
Gluconeo Step 12: Reactant/Products? Include # of Cs.
F1,6BP (6C) => F6P (6C) + Pi
What is fructose-1,6-bisphosphatase stimulated by?
1. Absence of F26BP
What do we call F-2,6-BP in regards to its effect on fructose-1,6-bisphosphatase?
An allosteric effector
How are levels of F-2,6-BP downregulated?
Glucagon/epi activate PKA to phosphorylate Fructose-2 bisphosphatase (FBPase-2), activating it, which dephosphorylates F-2,6-BP
Explain how PFK2 is regulated when blood glucose is high?
Insulin stimulates dephosphorylation of PKA (inactive) and phosphoprotein phosphatase (active) --> PP-1 dephosphorylates PFK2 --> activates it --> converts F-6P to F-2,6-BP --> stimulates PFK
Explain how PFK2 is regulated when blood glucose is low?
Glucagon phosphorylates PKA (active) --> PKA phosphorylates PFK2 (inactive) --> activating the FBPase2 --> dephosphorylates F-2,6-BP to F-6P --> PFK not activated
Gluconeo Step 13: Reactant/Products? Include # of Cs.
F6P (6C) => G6P (6C)
Gluconeo Step 13: Enzyme?
Gluconeo Step 14: Reactant/Products? Include # of Cs.
G6P (6C) => Glucose (6C) + Pi
Gluconeo Step 14: Enzyme?
Where does the NADH and ATP/GTP for gluconeo come from? What happens when this runs out?
TAGs => FFAs => Beta oxidation => Acetyl-CoA + Increased rate of TCA because of intermediates formed by gluconeo => NADH/ATP/GTP
When TCA cannot keep up: ketogenesis!
AA catabolism Step 1: Reactant/Products?
AA + alpha-ketoglutarate => alpha keto acid + glutamate
How does starvation affect the rate of step 1 of AA catabolism? What is the purpose of this?
TCA cycle rate increased => less alpha-ketoglutarate available to accept amino group => lower rate of AA catabolism
Purpose: avoid muscle wasting during starvation
AA catabolism Step 1: Enzyme?
AA catabolism Step 1: Cofactor? Role?
Pyridoxal phosphate (PLP) (VB6 derivative): conduit to accept amino group
What is the precursor to pyridoxal phosphate?
AA catabolism Step 2: Reactant/Products?
Glutamate + H2O + NADP/NAD+ => alpha-ketoglutarate + NADPH/NADH + NH4+
AA catabolism Step 2: Enzyme?
Gluconeo Step 2: Enzyme?
Gluconeo Step 4: Enzyme?
Other than glutamate, what is another good nitrogen donor? Describe the reaction. Where is this enzyme found?
Glutaminase: glutamine + H2O => glutamate + NH4+
Liver and kidney
Which steps of gluconeo happen in the mitochondria?
1 and 2
Optional: 4 and 5
Why else is malate transport from mitosol to the cytosol important (other than transporting oxaloacetate out)?
It transports NADH out which is needed for gluconeo!
Under what conditions do steps 4 and 5 of gluconeo happen in the mitosol?
When the pyruvate source is lactate because NADH has already been generated in the cytosol by lactate dehydrogenase
Where is the enzyme glucose-6-phosphatase found in the liver cells?
What is the deamination of AAs limited by? Purpose of this?
The availability of alpha-ketoglutarate, which is a TCA intermediate
Starvation: low TCA intermediates so slows down AA degradation: PREVENTS MUSCLE WASTING
AA catabolism Step 2: Cofactor?
NADP OR NAD+ (rare enzyme that can use both)
AA catabolism Step 1: Reactant/Products?
Amino acid + alpha-ketoglutarate => alpha-keto acid + glutamate
Can FAs be used for gluconeogenesis?
Odd numbered ones can because propionyl-CoA converted to succinyl-CoA
Where does AA catabolism happen?
What are the 2 types of malate dehydrogenases and what are they used for?
1. Mitochondrial: TCA cycle AND gluconeogenesis (oxaloacetate to malate)
2. Cytosolic: gluconeogenesis
Where does the conversion of oxaloacetate to malate happen?
Where does the conversion of malate to oxaloacetate happen?
Both cytosol and mitosol
What is the exact definition of a cofactor?
Substance (other than the substrate) whose presence is essential for the activity of an enzyme
What is fructose-1,6-bisphosphatase inhibited by?
2. High levels of fructose-2,6-BP
What is the major source for gluconeo during the fasting state?
When is glycerol used in gluconeo?
What is the main anaplerotic enzyme in the kidney?