Metabolism 4: Gluconeogenesis Flashcards
What are the major gluconeogenic precursors?
Lactate, glucogenic amino acids, glycerol
Where does gluconeogenesis predominantly take place?
Liver and kidney
When using gluconeogenic amino acids as precursors, why is additional ATP needed?
To dispose the amino groups via ureagenesis
Do glycolysis and gluconeogenesis use the same set of enzymes?
No, they require separate enzymes
Does ethanol ingestion inhibit gluconeogenesis?
Yes and it can lead to hypoglycemia
Explain the process after consuming carbs?
Insulin dependent glucose transports to adipose, heart, skeletal muscle -> insulin independent glucose transports to liver and other tissues -> glycolysis is active -> PDH active in tissue with mitochondria t -> produce AcetylCoA -> Acetyl CoA metabolized/oxidized by CAC
What glycolytic enzyme genes does insulin promote the expression of in the liver in the fed state?
Glucokinase, PFK1, Pyruvate Kinase
What happens in a fasted/starved state?
Decrease glycolysis, increase gluconeogenesis and increase glycogenolysis (glycogen breakdown)
What role does glucagon/epinephrine play in glycolysis?
Block glycolysis by inhibiting pyruvate kinase and indirectly blocking PFK-1 by inhibiting PFK-2
Decrease transcription of glucokinase, PFK-1, pyruvate kinase
Promote glucose mobilization by glycogenolysis
What role does glucagon/epinephrine play in gluconeogenesis?
Promote it by increasing transcription and synthesis of key gluconeogenic enzymes
What are the 2 pathways necessary for glucose homeostasis and where do they take place?
Glycogenolysis
Gluconeogenesis
Liver
Why is G6P Phosphatase important in gluconeogenesis?
Need this enzyme to remove phosphate from G6P (generated from both gluconeogenesis and glycogenolysis paths) and create glucose. Without it, can end up with more glycogen
What stimulates gluconeogenesis?
low blood glucose via glucagon
How many ATP is required in gluconeogenesis?
6
Why is oxaloacetate important in gluconeogenesis?
Pyruvate is convereted to PEP in a 2 step process via oxaloacetate (“activated” form of pyruvatE)
What is required to form the “activated form” of pyruvate (oxaloacetate)?
Bicarb and cofactor biotin
Why is there a risk of hypoglycemia in neonates?
They are very dependent on glucose via glycogenolysis and gluconeogenesis, but it takes a few hours to induce PEP carboxykinase which is necessary to generate glucose from lactate or alanine
What is the sequence for glucoeneogenesis from lactate?
lactate -> pyruvate ->oxaloacetate -> PEP ——-> G6P ->glucose
What is the sequence for gluconeogenesis from alanine
alanine -> pyruvate ->oxaloacetate -> PEP ——-> G6P ->glucose
What is the sequence for gluconeogenesis from muscle protein?
Muscle protein -> aspartic acid -> oxaloacetate -> PEP —–> G6P ->glucose
What is the sequence for gluconeogenesis from triacylglycerol?
Triacylglycerol -> glycerol -> DHP —> G6P -> glucose
What does the cori cycle do?
Convert lactate from RBCs and skeletal muscles to glucose in liver
What does the alanine cycle do?
convert alanine (mostly from skeletal muscle) to glucose in the liver
releases ammonia during this gluconeogenic process
What is the conversion of fructose into lactate called?
fructolysis. the lactate can then be used in gluconeogenesis
What is the sequence for fructolysis
fructose -> F1P -> DHAP + Glyceraldehyde 3 phosphate
Glyceraldehyde 3 phosphate -> lactate
Why is galactose important for gluconeogenesis?
Can get you G6P which can be converted into glucose or used in glycolysis pathway
During an overnight fast, what serves as the major source of ATP for gluconeogenesis?
Oxidation of fatty acids
Can Acetyl-CoA undergo gluconeogenesis?
No. It has 2 C and we need a 3C compound. Will undergo either fatty acid synthesis of TCA
What is glycerol a precursor for the synthesis of?
Triacylglycerols and phospholipids in the liver and adipose tissue
What must glycerol be converted into before entering glycolysis or gluconeogenesis?
Glycerol-3-phosphate by glycerol kinase
How is propionyl CoA formed
As a product of beta oxidation of odd chain fatty acids, isoleucine, valine, and alpha ketobutyric acid
Why is propionyl CoA important
Good precursor for gluconeogenesis
Propionyl CoA -> Oxaloacetate -> glucose
What are the 4 enzymes necessary to reverse the 3 irreversible steps of glycolysis?
Pyruvate Carboxylase (Mitochondria)
PEP Carboxykinase (Cytosol)
Fructose 1,6 bisphosphatase (cytosol)
Glucose-6-phosphatase (cytosol)
What does mitochondrial pyruvate carboxylase do?
Convert 1 molecule of pyruvate to oxaloacetate using biotin
Activated by Acetyl-CoA
What happens with pyruvate carboxylase deficiency?
Accumulation of pyruvate which gets converted to lactate by LDH leading to increased lactic acid
Also get increasing levels of alanine in serum as well
What does PEP Carboxykinase do?
Convert Oxaloacetate into phosphoenolpyruvate using GTP
What does Fructose 1,6 bisphosphatase do?
Removes 1phosphate from Fructose-1,6-bisphosphate to produce Fructose 6 phosphate
What is Fructose 1,6 bisphosphatase inhibited by?
Fructose 2,6 bisphosphate, AMP
What does Glucose 6 phosphatase do?
Remove phosphate from G6P to create glucose
Is glucose 6 phosphatase present in skeletal muscle?
No. Can’t synthesize glucose here. Only use glucose or synthesize lacatate and send to liver
How do we go from fructose 6 phosphate to glucose 6 phosphate in gluconeogenesis?
phosphoglucoisomerase
Where is glucose 6 phosphatase located?
In the ER of liver, kidneyes, and intestines. G6P enters the luminal surface of the ER and gets converted by this enzyme to produce glucose
What can result in accumulation of glycogen in the liver?
Genetic defect in either the G6P transproter or the G6Phophatase
What happens with glucose 6 phosphatase deficiency?
Glycogen Storage Disease (Von Gierke)
Can’t convert G6P to glucose -> accumulate glycogen and fat in liver as well as elevated serum uric acid and elevated serum lactate
What are some sx of G6phosphatase deficiency?
poor tolerance to fasting, growth retardation, hepatomegaly
What are the control points in glycolysis and their reciprocal in gluconeogenesis?
Glucokinase:: Glucose 6phosphatase
Phosphofructokinase:: Fructose 1,6 bisphosphatase
Pyruvate Kinase:: Pyruvate Carboxylase/PEP Carboxykinase
What regulates glucokinase?
+: insulin, glucose
What regulates glucose 6 phosphatase?
+: glucagon
-: insulin, glucose
What regulates phosphofructokinase?
+ F2,6bisphosphate, AMP
-: ATP, Citrate
What regulates Fructose-1,6 bisphosphatase?
-: F2,6bisphosphate, AMP
What regulates pyruvate kinase?
+: F1,6bisphosphate, glucose
-: glucagon, ATP
What regulates PEP Carboxykinase?
+:glucagon
-: insulin
What regulates pyruvate carboxylase?
+: Acetyl-CoA
What generally increases the levels./synthesis of the glycolytic enzymes?
Increased insulin and glucose
Decreased cAMP due to decreased glucagon/epi
What generally increases the levels./synthesis of the gluconeogenic enzymes?
Increased glucagon/epi
Starved/fasting
Increased cAMP
Less available energy (ATP)
How does glucagon exert its gluconeogenic effect?
Alters the transcription of genes
Glucagon binds to receptor G protein -> AC -> increase cAMP -> inc PKA ->phosphorylate CREB -> upregulate transcription of enzymes
How does ethanol metabolism cause hypoglycemia?
Increased NADH/H ratio -> promotes conversion of pyruvate and oxaloacetate into lactate and malate, thus removing them from the pool of gluconeogenic precursors
Different NADH levels lead to what?
Increased NADH -> increased lactate formation
Decreased NADH -> decreased lactate formation
What is the reaction for ethanol metabolism leading to hypoglycemia?
Ethanol + NAD -> Acetaldehyde + NADH + H+
Pyruvate + NADH + H -> Lactate + NAD+
Oxaloacetate + NADH + H -> Malate + NAD+
