L6. Gluconeogenesis, Proteolysis and Ketone Body Synthesis Flashcards
LO
- Summarise the substrates available for de novo gluconeogenesis
- Explain why using lactate as a substrate does not increase the circulating glucose pool via gluconeogenesis
- Describe the overall structure and strategy of gluconeogenesis
- Frame the overarching principles of amino acid processing
- Outline the general flow of nitrogenous compounds in starvation
- Understand how ketone bodies are formed and how they help to address the shortfall on glucose demanded by the brain during long-term starvation
- Predict the source of inefficiencies in energy metabolism induced by the ketotic state
- Summarise the patterns of fuel selection and mobilisation in late starvation
- Construct flow diagrams to encapsulate the movement, source and fate of fuels during extended starvation
- Explain the role played by glucagon in extended starvation
Proteolysis
- After a few hours of having blood glucose below ~5mM, pancreatic beta cells stop insulin production stimulating lipolysis
- Hyoinsulemia then leads to proteolysis
- Release of amino acids from tissues (mainly muscle)
- Many amino acids ‘carbon skeletons’ are used for gluconeogenesis and the amine groups go to the liver to be detoxified into urea
Processing amino acids
Proteins broken down into 20 different AA.
These AA are broken into amine groups and ‘carbon skeletons’
The amine groups are channelled to 3 amino acids
- Alanine (from pyruvate)
- Glutamate (from α-Ketoglutarate, krebs cycle)
- Aspartate (from Oxaloacetate, krebs cycle)
Amino-transferase enzyme transfers the anime group to either:
- Pyruvate (turns into Alanine)
- α-Ketoglutarate (turns into Glutamate)
- Oxaloacetate (turns into Aspartate)
Resulting α-Keto acids used in gluconeogenesis
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Fate of amino groups
The urea cycle in the liver:
The 3 amino acids can entre the urea cycle and drop off amine group
- Uses lots of ATP
Gluconeogenesis
Essentialy reverse of glycolysis except for 3 irriversible reactions
- Hexokinase = Glucose-6-Phosphate
- Phosphofructokinase = Fructose 1,6-Bisphosphate
- Pyruvate Kinase = Pyruvate Carboxylase & PEP Carboxykinase
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Gluconeogenesis substrates
Lactate:
- Entres as pyruvate
Glycerol:
- Entres as dihydroxyacetone phosphate (3C)
Amino Acid:
- Entres various places
Not all AA ‘skeletons’ can make glucose
- If skeleton can ONLY be turned into ac-CoA, it will end up as CO2 and NOT contribute to new glucose
- If it can be made into pyruvate or any krebs cycle intermediate, it can be made into glucose
- Only ~2g protein = 1g glucose
Lipolysis and Beta Oxidation
After ~2-3 days of starvation, the rate of lipolysis is at a maximum
- FA released into blood increasing the [bloodFA], therefore there is more than needed due to NO high demands for ATP and krebs cycle.
Beta oxidation in liver
Liver can do beta oxidation despite low demands for ATP
- CoA can be regenerated from ac-CoA by creating ketone bodies
- If ac-CoA doesn’t entre the krebs cycle, we cannot get CoA back, beta oxidation needs CoA to create 2C.
Ketone body formation
- Uses ac-CoA built up, rather than having the krebs cycle work with no demands
- 2x ac-CoA entre and create acetoacetyl-CoA, releasing a CoA
- A third ac-CoA beinds to acetoacetyl-CoA and forms HMG-CoA, releasing an acetyl-CoA
- Acetoacetate is then formed which is one of the ketone bodies
- Acetoacetate can be used by the brain for energy
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Fate of Acetoacetate
Acetoacetate is Interconvertible with ‘β-Hydroxybutyrate’ through REDOX reactions
- both can be used by the brain
Acetoacetate is split in the mitochondria to 2x ac-CoA to be used in the krebs cycle
- Ac-CoA inhibits PDH and stimulates PDH-Kinase
- Therefore acetoacetate releives use of glucose by the brain, taking stress off proteolysis
Inefficiency of the ketone body mechanism
Nothing innefficent BUT:
- Ketone bodies get lost in urine due to high charges and are small
- Ketone bodies can spontaneously decarboxylate to beceome acetone
- Acetone is a dead end product, is sweated, breathed and urinated out.
Demand from other tissue is not sustainable
- Proteins lost from all tissues (inactive muscles preferentially degraded)
- Equilibrium will be reached in demand and supply (loss of body protein and functions)
