Gluconeogenesis Flashcards
Gluconeogenesis is the synthesis of glucose from ….
non-carbohydrate sources.
Gluconeogenesis occurs in the ….
liver & kidney
Why is gluconeogenesis an essential metabolic pathway?
During prolonged fasting glycogen depletes and the body requires another method of receiving energy
Gluconeogenesis is not a reversible because the reactions using ____, ____, and ___ are irreversible. So, the entire process of glycolysis cannot be reversed but these three reactions can, starting in the….
Hexokinase
Phosphofructokinase
Pyruvate Kinase
Cytosol
- (GLUCONEOGENESIS/Cytosol) Glucose-6-phosphotate → Glucose
Enzyme: Glucose 6 phosphatase (In liver, not in muscle, muscle cannot perform this step of gluconeogenesis)
- (GLUCONEOGENESIS/Cytosol) Fructose 1,6 bisphosphate → fructose-6-phosphate
Enzyme: Fructose 1,6 bisphosphatase
- (GLUCONEOGENESIS/Mitochondria) Pyruvate → Oxaloacetate (1/2)
Goal: Get pyruvate back to phosphoenolpyruvate
- Enzyme: Pyruvate Carboxylase
- Requires ATP
- (GLUCONEOGENESIS/Mitochondria) Pyruvate → Oxaloacetate (1.5/2)
Oxaloacetate → Malate
Malate → Oxaloacetate (goes both ways)
Malate exported to cytosol for next step
- (GLUCONEOGENESIS/Cytosol) Malate → Oxaloacetate, Oxaloacetate → Phosphoenolpyruvate (2/2)
- Enzyme: Phosphoenolpyruvate Carboxykinase
- NAD+ → NADH + H+
- GTP (from TCA cycle) → GDP + CO2
Remember, no Glucose-6-phosphatase in the muscle
Remember, no Glucose-6-phosphatase in the muscle
Glycerol to Glucose Process
1st Glycerol → Glycerol-3-Phosphate
* Enzyme: Glycerol Kinase
* Requires ATP
2nd Glycerol-3-Phosphate → Dihydroxyacetone Phosphate
* Enzyme: Glycerol-3-Phosphate Dehydrogenase
* NAD+ → NADH + H + (same products from oxaloacetate → phosphoenolpyruvate reaction)
- Explain gluconeogenesis using propionate as the substrate
Propionate enters via TCA
(1st) Propionate → Propionyl-CoA
* Enzyme: Acyl-CoA Synthetase
* Requires ATP
(2nd) Propionyl-CoA → D-Methyl-Malonyl-CoA
* Enzyme: Propionyl-CoA carboxylase
* Requires ATP
(3rd-) D-Methyl-Malonyl-CoA → L-Methyl-malonyl-CoA
* Enzyme: Methylmalonyl-CoA Racemase (race from D to L methyl-malonyl)
(4th) L-Methyl-Malonyl-CoA → Succinyl-CoA
* Enzyme: Methylmalonyl-CoA mutase (methyl-malonyl being muted (as in no longer existing) because it’s now succinyl-CoA, we keep the CoA!)
Changes in rate of enzyme synthesis during glycogenolysis, glycolysis, and pyruvate oxidation
: During glycogenolysis, glycolysis, and pyruvate oxidation, Glycogen synthase, hexokinase, phosphofructokinase, pyruvate kinase, and pyruvate dehydrogenase are increased during feeding and decreased during fasting and diabetes.
o Glucokinase, Phosphofructokinase, and pyruvate kinase are induced by insulin (+fructose for pyruvate kinase) and repressed by glucagon.
- Induced by insulin, glucokinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)
- Induced by insulin, Phosphofructokinase-1 increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)
- Induced by insulin & fructose, Pyruvate kinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)
- Induced by insulin & fructose, Pyruvate kinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)
- Activated by CoA, NAD+, Insulin, ADP, and pyruvate, Pyruvate dehydrogenase increases activity during feeding, reduced during fasting and diabetes (inhibited by Acetyl-CoA, NADH, ATP (fatty acids, ketone bodies).
- Activated by CoA, NAD+, Insulin, ADP, and pyruvate, Pyruvate dehydrogenase increases activity during feeding, reduced during fasting and diabetes (inhibited by Acetyl-CoA, NADH, ATP (fatty acids, ketone bodies).
(Gluconeogenesis Regulation) : Changes in rate of enzyme synthesis during gluconeogenesis
- Pyruvate carboxylase, phosphoenolpyruvate, and glucose-6-phosphate are decreased during feeding, increased during fasting. They are induced by glucocorticoids, glucagon, and epinephrine. Repressed by insulin (when fed).
o Makes sense when you consider that gluconeogenesis is increased during the fasting state as the body must make glucose from non-CHO sources due to a lack of glucose in the body.
o Pyruvate Carboxylase activated by Acetyl-CoA, inhibited by ADP.
o Phosphoenolpyruvate activated by glucagon.
(Gluconeogenesis Regulation) : Covalent modification by reversible phosphorylation
Glucagon & Epinephrine
- Inhibit glycolysis; stimulate gluconeogenesis via ↑ cAMP → cAMP-dependent protein kinase activated → inactivation of pyruvate kinase.
(Gluconeogenesis Regulation) : Allosteric effects of Acetyl-CoA
o (Gluconeogenesis) Pyruvate Carboxylase → (pyruvate → oxaloacetate)
Needs Acetyl-CoA (Acetyl-CoA is the allosteric activator, it activates pyruvate carboxylase) - ACTIVATOR
o Glycolysis (Fed) Pyruvate dehydrogenase → (pyruvate (NOT CONVERTED TO) acetyl CoA)
Needs Acetyl-CoA (Acetyl-CoA is the allosteric inactivator, it inhibits pyruvate dehydrogenase) - INHIBITOR
____ inhibits glycolysis and stimulates gluconeogenesis
B-oxidation, alters metabolic fate of pyruvate with changes in CHO oxidation
(Gluconeogenesis Regulation) : Allosteric effects of Phosphofructokinase
Phosphofructokinase
o Inhibited by citrate, normal intracellular concentrations of ATP
o Activated by 5’ AMP
(Gluconeogenesis Regulation) : Allosteric effects of 5’AMP
5’ AMP indicator of energy status of cell
o 2 ADP ATP + 5’ AMP
o Small ↓ ATP = Large ↑ AMP
o AMP stimulates phosphofructokinase (glycolysis), glycogen phosphorylase (glycogenolysis)
(Gluconeogenesis Regulation) : Allosteric effects of fructose 1,6-bisphosphate (can DECREASE or INCREASE gluconeogenesis by altering glucose metabolism)
- Activates phosphofructokinase & increases affinity for fructose-6-phosphate.
- Inhibits fructose 1,6-bisphosphatase.
- ↑ glucose → ↑ fructose 2,6-bisphosphate = ↑ glycolysis & ↓ gluconeogenesis
If increased F 2,6 bisphosphate has the affect then the opposite is …
* ↓ Fructose 2,6-bisphophate = inactivates phosphofructokinase & stimulates fructose 1,6-bisphosphatase
- Fasting (↓ glucose) → ↓ Fructose 2,6-bisphophate = ↑ gluconeogenesis & ↓ glycolysis
- Describe the sources of glucose to maintain blood glucose homeostasis
- Galactose & fructose → glucose (liver)
- Lactate goes through Cori cycle → glucose (liver, kidney)
- Process of converting lactate → glucose = cori cycle
- Alanine (muscle) goes through glucose-alanine cycle → glucose (liver)
- In summary the sources of glucose are galactose & fructose, lactate through the cori cycle, and alanine in the muscle through the glucose-alanine cycle.
