13. Gluconeogenesis Flashcards
What is the purpose of gluconeogenesis?
It is like glycolysis with the exception of what 3 steps (state the normal)?
Why are these steps the exception?
During initial starvation, BG comes from liver glycogen stores (100g) and once run out, use gluconeogenesis to maintain BG. Also once depleted, tissues that require glucose depend on glucose synthesis from liver via gluconeogenesis. Allows you to go from pyruvate -> glucose.
1) Glucose phosphorylated by glucokinase -> glucose-6-phosphate
2) Fructose-6-phosphate phosphorylated by PFK -> fructose-1,6-bisphosphate
3) PEP -> pyruvate by pyruvate kinase
Becuase in glycolysis these steps are unidirectional under body conditions, so need alturnative route.
What are the C sources that glucose synthesis via gluconeogenesis requires?
Can fat be used?
Lactate (from glycolysis in muscle), amino acids (basis for muscle wasting in extreme starvation) and glycerol (can only use glycerol part from triglycerol - not FA)
No - we can only use our fat stores to provide energy for gluconeogenesis.
What are the ‘alturnative’ last 2 steps in gluconeogenesis that bypass the first two irreversible glycolysis steps? [backwards][NB: these are NOT the ‘reverse reaction’ of glycolysis - it’s just an alturnative route!]
1) Glycolysis: glucose -> glucose-6-phosphate via glucokinase
GNG: Glucose-6-phosphate -> glucose via glucose-6-phosphatase
2) Glycolysis: Fructose-6-phosphate -> fructose-1,6-bisphosphate via PFK
GNG: Fructose-1,6-bisphosphate -> fructose-6-phosphate via fructose-1,6-bisphosphatase
NB: need both of these enzymes to do GNG from glycerol
What is the ‘alturnative’ first step in gluconeogenesis that bypasses the last irreversible glycolysis step? [backwards]
What helps drive the reaction to produce PEP?
Get pyruvate from phosphenolpyruvate (PEP): requires a path driven by energy input (4 ATP) and carboxylation.
Glycolysis: PEP -> pyruvate via pyruvate kinase and if anaerobic: pyruvate -> lactic acid via lactate dehydrogenase
GNG: Lactate dehydrogenase reversible under cellular conditions so easily convert lactate -> pyruvate. Pyruvate kinase is unidirectional so need to go a diff way. Mechanism involves 3 enzymes and a compartment change:
1) Pyruvate transported into mitochondria. Pyruvate -> oxaloacetate via pyruvate carboxylase using ATP and a CO2 giving a 4C molecule
2) Oxaloacetate -> malate via malate dehydrogenase using NADH. Melate transported back to cytoplasm. Interacts with MDH in cytoplasm -> oxaoacetate. (“MALATE SHUTTLE”)
3) Oxaloacetate -> PEP via phosphenolpyruvate carboxykinase (PEPCK) using GTP. Lose a molecue of CO2 to get 3C PEP, which can go up into gluconeogenesis.
Loss of CO2 in the PEPCK
What are fatty acids broken down to?
What are the products used for?
Why can’t ACA make glucose?
Acetyl-coA, but this cannot be converted to glucose (only glycerol can).
Fats provide the energy for gluconeogenesis and produce reduced NAD and FAD for ETC. Levels of acetyl coA regulate the process by activating pyruvate carboxylase: large amount of ACA block conversion of pyruvate -> ACA and drive it to oxaloacetate production (i.e. towards gluconeogenesis). B/c if have lots of energy around then why not make sugar.
(NB: PDC = pyruvate dehydrogenase complex [pic])
Can’t make oxaloacetate (ACA is 2C and links to oxaloacetate in TCA but lose 2 CO2 so overall 0 net gain of C - there is no mechanism to catalyse reaction of AcoA to oxaloacetate without losing 2C, so it can’t be used in GNG)
How can pyruvate dehydrogenase be inhibited (PDC)?
What does this mean for the drive towards gluconeogenesis?
Acetyl-CoA and NADH generated by fatty acid oxidase inhibit PDC.
Compounds that can produce pyruvate will not form acetyl-coA and instead can be used for glucose formation using the energy from fatty acid oxidation (e.g. pyruvate carboxylase uses ATP)
What is the cori cycle?
Why does it need to occur?
Does this only occur anaerobically?
Allows for anaerobic metabolism in the muscle to occur, producing lactate. It’s transported in the blood (lowers blood pH) to the liver where it’s converted to glucose via gluconeogenesis. Essentially the liver puts energy in to form glucose which is then used.
If lactic acid builds up in muscle and released into blood can cause lactic acidosis so need to get rid of lactate. NB: some diabetic drugs cause this b/c block GNG.
Can occur aerobically - pyruvate does not go to TCA cycle b/c muscle switched to using fat = high levels of ACA around.
For the cori cycle to work in muscle, conversion of pyruvate -> acetyl CoA must be blocked - how is this done?
How does the body maintain BG over a longer period of time than short-term starvation?
By oxidation of fatty acids, creating more acetyl CoA.
Muscles move to fat metabolism = reduces amount of glucose they need.
How does glucose get energy from glycerol?
How does glucose get energy from amino acids?
Does gluconeogenesis only occur in the liver?
Does the body preferentially use fats or proteins to get energy?
Glycerol from triglyceride breakdown. Enters as dihydroxyacetone phosphate in middle of glycolysis/gluconeogenesis.
Alanine and glutamine are the main glucogenic AAs. Other AAs can be used, if they can produce pyruvate from breakdown.
No - a small amount in the kidney too (partly b/c use of amino parts of AAs from AA breakdown leaves glutamine which can be used in GNG to produce glucose).
Fats b/c preserves muscle and reduces overall demand for glucose (proteins = muscle breakdown).
Are all amino acids glucogenic?
What hormones control gluconeogenesis?
How does glucagon control gluconeogenesis?
How is gluconeogenesis in diabetes?
(Means can be broken down to produce pyruvate/oxaloacetate, than glucose can be synthesised from the AA). No - not leucine and lysine.
Glucagon, insulin, adrenaline
Via cAMP levels and controlling PKA and hence pyruvate dehydrogenase
Excessive b/c of increased supply of precursors (glycerol, AAs) and more FAs. Also an increase in glucagon:insulin
NB: When enzyme is phosphorylated -> GNG and when not -> glycolysis. Controlled by reciprocal actions of glucagon and insulin.
