Goal 11: Gluconeogenesis Flashcards
How is gluconeogenesis defined? Why do we need it?
- Making of glucose from NONCARBOHYDRATE substances
- maintain blood glucose under fasting conditions
What organs are where gluconeogenesis happens? When does one of them start to contribute more? What conditions promote this and what conditions suppress this?
- Liver: overnight fasting 90%
- Kidneys: overnight fasting 10%, but help up to 40% with PROLONGED STARVATION
- promoted when fasting and suppressed when fed
What are our body’s 3 main sources for blood glucose? When do they kick in?
- diet: during absorptive state (2-4hrs after meal)
- hepatic glycogenolysis: up to 12-18hr after previous meal is when it kicks in
- gluconeogenesis: starts 4-6hrs after previous meal
In what areas is maintaining blood sugar important?
- brain
- RBC
- anaerobic- exercising muscles
What 4 areas of the body prefer glucose for its fuel?
- kidney medulla
- lens
- cornea
- testis
What are the 4 non carbohydrates that form glucose during gluconeogenesis?
- Lactate/pyruvate
- glucogenic amino acids
- glycerol
- propionyl CoA
How is lactate turned into glucose? How many ATPs are used up?
- 3C lactate (x2)—-> 3C pyruvate (x2)—> fructose 1,6 biphosphate—> 6C Glucose
- 6 ATP
What enzyme turns lactate to pyruvate?
LDH or Lactate Dehydrogenase
Anareobicallyexercising muscles and RBC form what?
Lactate
What common amino acid can for pyruvate?
Alanine
How does lactate enter the mitochondria from the cytosol?
- By being changed into pyruvate by LDH
- pyruvate is able to move to mitochondria
In gluconeogenesis, as soon as pyruvate hits the mitochondria, what happens to it?
- pyruvate changed to oxaloacetate by Pyruvate Carboxylase.
- then oxaloacetate is changed to malate by malate dehydrogenase
In gluconeogenesis, pyruvate must change to what product to be able to EXIT the mitochondria?
Malate via malate shuttle
In gluconeogenesis, after leaving the mitochondria, what happens to the malate?
- malate turned back to oxaloacetate by malate dehydrogenase
- then oxaloacetate is turned to PEP by PEP carboxykinase
- then the glycolysis pathway is followed backwards until Fructose 1,6 biphosphate is reached.
- Fructose 1,6 biphosphate changed to fructose 6-p by Fructose 1,6 biphosphatase
- fructose 6-p changes to glucose 6-p by phosphoglucose isomerase
- then glucose 6-p is changed to glucose by Glucose 6-phosphatase
What are the 4 key enzymes that are IRREVERSIBLE in gluconeogenesis?
- Pyruvate Carboxylase
- PEP carboxykinase
- Fructose 1,6 Biphosphatase
- Glucose 6-Phosphatase
What 3 things are needed to help pyruvate to turn into oxaloacetate?
- ABC
- ATP, Biotin, CO2
During gluconeogenesis, what oxidative reaction happens? During what part of the steps does it happen?
- NAD——-> NADH + H
- happens from lactate to pyruvate
What are two ways to be deficient in Biotin?
- Biotindinase Deficiency: genetic
- consume a lot of raw eggs for a long time. Avidin is in the white part of the egg and that likes to tightly bind to Biotin to immobilize it so it can’t be absorbed
What is product formed by Beta-Oxidation of FA allosterically ACTIVATES Pyruvate Carboxylase?
Acetyl CoA
What two things does Beta Oxidation of FA provide for? What happens if there’s a defect in Beta Oxidation?
- provides Acetyl CoA for pyruvate Carboxylase
- gives ATP needed to power gluconeogenesis
- suppression of gluconeogenesis—> hypoglycemia
GTP equals how many ATP?
-1GDP/GTP = 1ATP
What 2 things induce Phosphoenolpyruvate carboxykinase (PEPCK)? Why do they alone induce this enzyme?
- glycogen and glucocorticoids (like cortisol)
- both of these hormones stimulate the transcription of the gene that makes PEPCK
In gluconeogenesis, when you make it to PEP from oxaloacetate the process goes upward to reverse the glycolysis instead of going down to pyruvate again? Under what conditions can PEP go to pyruvate?
- Pyruvate kinase is INHIBITED by glucagon!!
- in presence of insulin, PEP will go to pyruvate
Fructose 1,6 biphosphatase is allosterically inhibited by what 2 things?
- fructose 2,6 biphosphate and AMP
- In the case of glycolysis, this same product allosterically stimulates PFK1
What two hormones activate Fructose 2,6 biphosphatase 2?
-Glucagon and epinephrine
Where in the cell is Glucose 6-phosphatase found? Because of this, what enzyme moves the product briefly to this location and back? What happens in this location?
- ER
- Glucose 6-phosphate translocase moves G6P briefly from cytosol to ER
- G6P is hydrolysis by G6 phosphatase to make free glucose and then released into the blood
What conditions induced Glucose 6-Phosphatase?
Fasting conditions
All 20 amino acids EXCEPT WHAT TWO AMINO ACIDS can be degraded to pyruvate or one of the TCA intermediates?
-Leucine and Lysine
What amino acids can be turned directly into pyruvate? What amino acid turns into pyruvate indirectly?
- direct- alanine, serine, cysteine
- indirect: tryptophan must turn into alanine to become pyruvate
What amino acids can give rise to Fumarate of the TCA cycle?
Phenylalanine and Tyrosine
What amino acids give rise to oxaloacetate?
Aspartate
What amino acids and fatty acid enter the TCA cycle by giving rise to succinyl CoA? What are the steps to get to succinyl CoA?
- VOMIT: Valine, Odd chain fatty acids, methionine, isoleucine, threonine
- VOMIT—> propionyl CoA (utilize ABC’s)—-> methymalonyl CoA (need Vitamin B12)—-> succinyl CoA
Where in the cell does TCA cycle happen?
Mitchochondria
TAGs enter gluconeogenesis how?
-TAG—> glycerol —-> glycerol 3p—-> DHAP
What happens if you’re deficient with Vitamin B12? What signs and symptoms do you see?
- megaloblastic anemia: bone marrow produces unusually large and structurally abnormal immature red blood cells
- see methylmalonic acidemia (a lot of methylmalonic acid in blood) and methylmalonic aciduria (in the urine)
What is the Cori Cycle? What’s compared and what’s the difference of what’s compared?
-cycle between anaerobic glycolysis in skeletal muscle and gluconeogenesis in the liver
-liver (gluconeogenesis to make glucose)—> glucose sent to blood to be utilized by muscle (glycolysis done to breakdown glucose to energy) —-> lactate sent to blood for liver to utilize for gluconeogenesis and so on
FORVER CONTINUOUS
What blood tests is raised in a problem with the liver?
-ALT and AST
What does the glucose alanine cycle show us? Under what conditions is this cycle most needed?
- same as Cori cycle but instead of lactate involved, it’s alanine utilized; continuous cycle
- helps during fasting conditions to give glucose from alanine
What NAD and NADH ratio is preferred? Which is bad?
- good: high NAD and low NADH
- bad: low NAD and high NADH
Alcohol metabolism causes excessive formation of what in the cytosol of the liver?
- too much NADH
- think alcohol (ethanol) uses up energy so there’s is a lot of NAD—>NADH
What causes lactic acidosis?
Pyruvate —-> lactate
What two reactions are unfavorable to gluconeogenesis? Why is this?
- pyruvate—> lactate
- oxaloacetate—>malate
- both these reactions have low NAD and high NADH. You need energy to generate gluconeogenesis
Methanol toxicity can be corrected by treating with what? Why?
- Ethanol
- ethanol acts as competitive inhibitor of alcohol dehydrogenase so it saturates the enzyme
Why are patients that are in the starved state advised NOT to consume alcohol?
- breakdown of alcohol uses up energy (NAD). If there’s no energy storage to begin with, consuming alcohol keeps using up energy your body doesn’t have
- SEVERE HYPOGLYCEMIA