Topic 8: Gluconeogenesis, Cori & Alanine Cycle Flashcards
What is the most important source for Carbon in gluconeogenesis?
BLOOD LACTATE
What is the main gluconeogenic organ/tissue?
LIVER!
What is the second most important source of C for gluconeogenesis?
Amino Acids:
Most can contribute to glucose –> glucogenic
Some can only to ketones –> ketogenic
What are the ketogenic only amino acids?
Leucine and Lysine
Can go into Acteyl-CoA and then Ketones
How much gluconeogenesis is from Fatty Acids?
Barely any, only the Glycerol Backbone can be used and 3 C remainder from ODD chain FA’s for proprionate.
Fatty acid chains will be used for fuel rather than gluconeogenesis considering they are utilized generally in times of fasting/starvation
What enzyme removes FA’s from the Glycerol backbone?
Lipase
What do fatty acids get used to make?
Acetyl CoA for:
ATP (TCA Cycle) or Ketones
What do even chain fatty acids make?
Carbons are cleaved 2 at a time –> copious Acetyl CoA
What do odd chain fatty acids make?
Mostly Acteyl CoA until 3 C’s are left –> Proprionate!
Proprionate can be anapleurotic in the TCA Cycle to make Succinyl CoA. This can lead to glucose formation.
What is proprionate used for in ruminants?
Main gluconeogenic substrate.
What are the 4 enzymes that are used to overcome glycolysis so that gluconeogenesis can take place?
1) Pyruvate Carboxylase and 2) PEP Carboxykinase both to overpower Pyruvate Kinase.
3) Fructose-1,6-Bisphosphatase to get past PFK
4) Glucose-6-Phosphatase to get past Hexokinase
What is the function of Pyruvate Carboxylase?
Pyruvate –> OAA in the matrix
ATP is used, CO2 is incorporated to make OAA
Requires Biotin/B7
What is the function of PEP Carboxykinase?
OAA –> PEP in the cytosol
GTP is used and CO2 is generated.
What is Step 1 of gluconeogenesis?
Pyruvate is converted via Pyruvate Carboxylase to OAA.
ATP is used and CO2 is used. Requires B7/Biotin.
OAA via the Malate-Aspartate Shuttle is moved to the cytosol. (NADH used in matrix, NADH made in cytosol)
What is Step 2 of gluconeogenesis?
OAA via PEP Carboxykinase is converted to PEP.
GTP is used and CO2 is generated
What is Step 3 of gluconeogenesis?
PEP via Enolase makes 2-Phosphoglycerate.
What is Step 4 of gluconeogenesis?
2-Phosphoglycerate via Phosphoglyceromutase moves the phosphate to make 3-Phosphoglycerate.
What is Step 5 of gluconeogenesis?
3-Phosphoglycerate via Phosphoglycerate kinase makes 1,3-bisphosphoglycerate.
ATP is used.
What is Step 6 of gluconeogenesis?
1,3-BPG via Glyceraldehyde-3-Phosphate Dehydrogenase makes Glyceraldehyde-3-Phosphate.
NADH is used, free Phosphate is yielded
What is Step 7 of gluconeogenesis?
GA-3-P (or DHAP since Aldolase does convert between the two and F-1,6-BP) via Aldolase is converted to Fructose-1,6-Bisphosphate
What is Step 8 of gluconeogenesis?
F-1,6-BP via Fructose-1,6-bisphosphatase to Fructose-6-phosphate.
H20 is used and free Pi (phosphate) is generated.
What is Step 9 of gluconeogenesis?
Fructose-6-Phosphate via Glucosephosphate isomerase is converted to Glucose-6-Phosphate.
What is Step 10 of gluconeogenesis?
Glucose-6-Phosphate via Glucose-6-Phosphatase is turned into the final product: GLUCOSE!! YAY, we did it!
Used H2O and yields a free Phosphate (Pi)
How is gluconeogenesis regulated by insulin and glucagon?
Insulin –> inhibition
Glucagon –> activation
the 4 special enzymes are up-regulated:
1) Pyruvate Carboxylase 2) PEP CarboxyKinase 3) Fructose-1,6-Bisphosphatase 4) Glucose-6-Phosphatase
What else stimulates gluconeogenesis?
Catecholamines (Epi and NorE)
AND
Glucocorticoids (cortisol)
What cells can perform Gluconeogenesis?
Mitochondria containing cells
Pyruvate carboxylase is in the mitochondrial matrix
What tissues perform gluconeogenesis the most?
LIVER of course
Kidney somewhat
Small Intestine a bit
Only tissues capable of releasing glucose to the blood.
Does the brain make glucose?
NO NO NO NO – (that means no! not nitric oxide)
How does skeletal muscle indirectly contribute to gluconeogenesis?
Lactic Acid Cycle (Cori Cycle)
AND
Glucose-Alanine Cycle
How does the Lactic Acid Cycle/Cori Cycle Work?
Lactic Acid is released from skeletal muscle in times of anaerobic metabolism. Liver takes up Lactate and Oxidizes it to form pyruvate –> TCA Cycle+ETC or Gluconeogenesis.
Glucose released is picked up, turned into pyruvate –> cycle continues
How does the Glucose-Alanine Cycle work?
When muscle has no glucose/glycogen and needs energy, AA’s are burned in muscle.
Amino group is transaminated to Pyruvate to make Alanine.
Alanine is released, liver picks up, deaminates to make pyruvate –> TCA Cycle+ETC or Gluconeogenesis.
Glucose released is picked up, turned into pyruvate –> cycle continues.
What is Cushing’s Syndrome?
Hyperadrenocorticism
What does hyperadrenocorticism do?
Excess Gluconeogenesis –> AAs begin to contribute –> skeletal muscle degrades, heart muscle degrades, collagen in tendons degrade –> why we see weak skin, hair, pendulous abdomen, and fat buildup (hyperglycemia)
Literally converting muscle to fat. Hyperglycemia brings on PU/PD from osmotic imbalance as well.
What does lactic acidosis do?
Comes from over production or under utilization of lactic acid. Happens when > 5 mM (normal is 1.2mM)
Decreased blood pH (acidosis) and HCO3
What causes lactic acidosis?
Disrupted TCA Cycle or ETC
Liver Disease (can’t utilize Lactate)
Ethanol (competition for NAD+)
Various drugs - phenformin
Why does ethanol compete for NAD+?
Ethanol metabolism takes precedence in the liver uses up NAD+. Cannot perform gluconeogenesis in presence of alcohol/ethanol since it requires NAD+ for Malate-Aspartate Shuttle and Lactate to Pyruvate.
Why do we care about alcohol poisoning in veterinary medicine?
4-Methylpyrazole (Fomepizole) used to inhibit Alcohol Dehydrogenase (enzyme that metabolizes ethanol) for:
Methanol (wood alcohol) –> Formaldehyde
Ethylene glycol (antifreeze) –> Oxalic acid –> precipitates with Ca++ in the kidney –> rapid renal failure
Why is ingesting alcohol after exercise a bad idea?
You’ve already used up your glycogen stores and built up Lactic Acid. NAD+ is used up by alcohol –> blocking gluconeogenesis = bad idea!
What vitamin is crucial for gluconeogenic enzymes to function properly? Which enzymes require it?
Vitamin B7/Biotin
Pyruvate Carboxylase (Step 1) Propionyl-CoA Carboxylase (Ruminant gluconeogenesis to make Succinyl-CoA from Proprionate)
