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Gluconeogenesis
Glucose Synthesis
| Question | Answer |
|---|---|
| Describe Gluconeogenesis. | Its the pathway that synthesizes glucose from non-carbohydrates and releases ‘free’ glucose to fuel the brain, kidney, and RBCs. It provides energy during the fasting state, when glycogen stores are deleted, and during ‘fight and flight’ situations. |
| What is the role of Gluconeogenesis in the Cori Cycle? | Pyruvate -> Lactate(via lactate dehydrogenase) in anaerobic conditions in muscle, it then goes thru the blood to the liver where Lactate -> Pyruvate (via lactate dehydrogenase). Gluconeogenesis uses ATP to convert this Pyruvate to G6P to G. |
| Where in the body (which organs) does gluconeogenesis occur? | Mainly the liver and to a lesser extent, in the kidneys. After an overnight fast = 90% liver, 10% kidney. After prolonged fast = 60% liver, 40% kidneys. |
| Where in the cell does gluconeogenesis occur? | Malate -> OAA -> PEP -> Glyceraldehyde3P + DihydroxyacetoneP -> F1,6BP -> F6P -> G6P -> G conversion occurs in the cytosol. Pyruvate -> OAA -> Malate conversion occurs within the mitochondria. |
| What are the main substrate for gluconeogenesis? | Lactate (from/to pyruvate), glucogenic amino acids (mainly Alanine, from muscle), and glycerol (from the degradation of TAGs in fat) |
| Why can there be no net production of glucose from acetyl CoA (and compounds that give rise to acetyl CoA, like Fatty acids)? | Because of the irreversible nature of the pyruvate dehydrogenase reaction which converts Pyruvate into Acetyl CoA instead giving rise to ketone bodies. |
| Describe the gluconeogenesis pathway starting from Pyruvate. | Pyruvate -> OAA -> Malate -> OAA -> PEP -> Glyceraldehyde3P + DihydroxyacetoneP -> F1,6BP -> F6P -> G6P -> G |
| What are the irreversible reactions of gluconeogenesis? | 1) Pyruvate -> PEP (via pyruvate carboxylase to OAA, then PEP carboxykinase from OAA -> PEP), 2) F1,6BP -> F6P (via Fructose1,6Bisphosphatase), and 3) G6P -> G (via Glucose6Phosphatase) |
| Explain how carbon from other sources integrate into Gluconeogenesis. | Lactate is used to form Pyruvate (via lactate dehydrogenase), Alanine -> Pyruvate (via alanine aminotransferase), and Glycerol (from TAGs) -> Glycerol3P -> DHAP (via glycerol kinase and glycerol3P dehydrogenase) |
| What is the role of glucagon in gluconeogenesis? | Glucagon attaches to a receptor on the surface of a liver cell which signals cAMP to activate protein kinase A which in turn inactivates pyruvate kinase (via Phosphorylation) inhibiting glycolysis and activating gluconeogenesis |
| What is the role of Insulin in gluconeogenesis? | Insulin inhibits glucagon release, decreases transcription of mRNA of gluconeogenic enzymes within cells, and leads to formation of unphosphorylated PFK-2 increasing formation of F2,6,BP (all inhibiting gluconeogenesis and promoting glycolysis) |
| What regulatory role does F2,6BP play in gluconeogenesis? | increases in F2,6BP (decrease F1,6BP) inhibiting gluconeogenesis, decreases in F2,6BP (increase in F1,6BP) activate gluconeogenesis |
| How does the fed/fasted state affect which pathway (glycolysis or gluconeogenesis) is active? | Fed = glycolysis, Fasted = gluconeogenesis |
| Is gluconeogenesis a reversal of glycolysis? | No |
| Do glycolysis and gluconeogenesis take place at the same time? | No |
| What 4 substrates for gluconeogenesis are found inside the liver? | Momentary intermediates of glycolysis, 2) some lactate, 3) degradative products of amino acids that lead to pyruvate, 4) Degradative elements of gluconeogenic amino acids that lead to OAA |
| What is 3 things are continuously provided by the blood for gluconeogenesis? | 1) Lactate from the Cori cycle and RBCs, 2) Alanine and Glutamine and 3) glycerol from fat cells |
| What does low insulin/glucagon ratio do to fat cells? | It activates lipase which causes the breakdown of TAGs from fat cells |
| Do gluconeogenesis and fatty acid break down occur simultaneously? | Yes, in the liver |
| What does the Beta-oxidation of fatty acids eventually lead to? | ATP formation from the ETC |
| How much energy does glucose synthesis from 2 pyruvate require? | 4 ATP and 2 GTP |
| What gluconeogenic enzyme does Acetyl CoA activate? | Pyruvate Decarboxylase |
| Can the carbons from Acetyl CoA itself be used for glucose synthesis? | No |
| What does inhibition of fatty acid synthesis lead too? | Hypoglycemia |
| Do gluconeogenesis and glycogen degradation occur at the same time? | Yes, both provide blood glucose |
| How long does it take to deplete the glycogen stores of the liver? | about 24 hours |
| Which occurs more quickly, glycogen degradation or gluconeogenesis? | glycogen degradation |
| How does ‘free’ glucose leave the liver? | GLUT2 |
| Where is G6Pase found? | Liver and Kidney, in the ER membrane |
| How is G6P transported into and out of the ER? | G6P translocase gets it in, G6P is then cleaved to Glucose and Pi which are transported out of the ER by separate transporters. |
| What are the first and second messengers of Gluconeogenesis? | The first messenger is Glucagon and the second messenger is cAMP |
| In ‘Flight or Flight’ scenarios how is Glycolysis turned off quickly? | Inactivation of pyruvate kinase by protein kinase A, which occurs ONLY in the liver |
| What does Pyruvate kinase normally do (glycolysis)? | cleaves PEP to pyruvate creating ATP via substrate level phosphorylation |
| Is Fructose-1,6-Bisphosphate used by glycolysis, gluconeogenesis, or both? | Gluconeogenesis |
| What does Fructose-1,6-bisphosphate do? | It circumvents the irreversible step of PFK-1 in glycolysis by performing an irreversible gluconeogenic reaction that coverts Fructose-1,6-bisphosphate to Fructose-6-phosphate and Pi |
| What does Glucose-6-phosphatase do? | It circumvents the irreversible step of Glucokinase in glycolysis by performing an irreversible gluconeogenic reaction that converts Glucose-6-phosphate to free glucose |
| Is there a single enzyme that circumvents the irreversible step of pyruvate kinase in glycolysis? | No, it’s two enzymes pyruvate carboxylase and PEP carboxykinase |
| What are the substrates for pyruvate carboxylase? | CO2 and pyruvate, it forms OAA through cleavage of ATP to ADP + Pi |
| What is the coenzyme of pyruvate carboxylase? | Biotin |
| What is the absolute activator of Pyruvate decarboxylase? | Acetyl CoA |
| What does Acetyl CoA inhibit? | The Pyruvate Dehydrogenase Complex |
| Other than Acetyl CoA, what can be used to replenish the TCA cycle? | Pyruvate carboxylase, because it makes OAA |
| Does the Acetyl CoA used as an absolute activator for pyruvate decarboxylase come from pyruvate dehydrogenase? | No, it is generated via the Beta-oxidation of fatty acids (which gives lots of Acetyl CoA and ATP) |
| What are the substrates of PEP carboxykinase? | OAA and GTP |
| What are the products of PEP carboxykinase? | PEP and GDP (through decarboxylation) |
| Where is PEP carboxykinase found (in humans)? | Both mitochondria and cytosol but the cytosolic form must transport OAA out via malate |
| How is gluconeogenesis regulated? | It is regulated via energy and substrate availability, but ultimately by the availability of F1,6BP |
| What inhibits F1,6BP? | F2,6BP and AMP |
| How and when is F2,6BP formed? | By the bifunctional enzyme at insulin ruling and high levels of F6P |
| What are the two forms of the bifunctional enzyme? | PFK2 and BPase2 |
| What is so unusual about the bifunctional enzyme? | It has two enzyme activities that counteract each other, it forms F2,6BP with its PFK2 activity and degrades F2,6BP with its BPase2 activity, and it needs to be folded in such a way that only one activity is active a time |
| How does Insulin and Glucagon/Epinephrine effect the effect the bifunctional enzyme? | Insulin leads to the unphosphorylated form that makes F2,6BP (active PFK2, inactive BPase2) and Glucagon/Epinephrine lead to the phosphorylated form that degrades F2,6BP (inactive PFK2, active BPase2) |
Created by:
sprater16