Gluconeogenesis Flashcards
What is Gluconeogenesis?
Synthesis of Glucose using Non-Carbohydrate precursors
- Lactate, Alanine and Glycerol
- Used to make Pyruvate
- Pyruvate converted to → Glucose
Why is Gluconeogenesis Important?
- To remove blood lactate post exercise
- Form Glucose from Amino Acids/Glycerol
during fasting - Body has limited capacity to store Glucose,
Gluconeogenesis needed to sustain levels
Where does Gluconeogenesis Occur and Why?
- Kidney and Liver have Specialized Enzymes
- Enzymes overcome Irreversible steps of
Glycolysis
What Is Step 1 Of Glycolysis?
Formation of Oxaloacetate
- Acetyl CoA allosterically activates
Mitochondrial Pyruvate Carboxylase - Mitochondrial Pyruvate Carboxylase uses
ATP to convert Pyruvate → Oxaloacetate
What Is Step 2 Of Glycolysis?
Formation of Malate and Mitochondrial Exit
- Oxaloacetate → Malate (In Mitochondria)
- Malate exits Mitochondria → Cytoplasm
- Malate converted → Oxaloacetate by
formation of NADH
What Is Step 3 Of Gluconeogenesis?
Components:
Oxaloacetate (OAA)
Phosphoenolpyruvate (PEP)
Phosphoenolpyruvate Carboxykinase (PEPCK)
PEPCK uses GTP to convert OAA → PEP
Important Step Because:
It reverses irreversible pyruvate kinase reaction of glycolysis (Bypasses Glycolysis)
Energetically expensive process
What Is Step 4 Of Glycolysis?
Components:
Glyceraldehyde 3-Phosphate (G3P) Dihydroxyacetone Phosphate (DHAP)
Fructose 1,6 Biphosphate (F1,6 BP)
- Aldolase Combines G3P + DHAP to form F1,6
BP - Hydrolysis adds water molecule to F1,6 BP
- Fructose 6-Phosphate Formed + Pi Released
What Is Step 5 Of Glycolysis?
Glucose Formation
Components:
Fructose 6-Phosphate (F6P)
Glucose 6-Phosphate (G6P)
Glucose (Glu)
Isomerization:
1. Phosphohexose isomerase Converts
Fructose Backbone of F6P → Glucose Backbone
Dephosphorylation:
2. Glucose 6-Phosphatase irreversibly
Dephosphorylates G6P→ Glucose
How Is Gluconeogenesis Regulated?
- Hormonal Regulation
- Favored By High ATP + Low AMP/ADP
- Substrate Availability
How Do ATP and AMP/ADP Levels Regulate Glycolysis?
When Energy Is Needed:
1. High AMP
2. Glycolysis Activated
When ATP Is high + AMP Is low:
1. Gluconeogenesis activated
How Is Gluconeogenesis Regulated Using Substrate Availability?
Gluconeogenesis favored by Availability of Substrates for Energy Production in The Citric Acid Cycle
Citrate: Inhibits Phosphofructokinase
Acetyl CoA: Stimulates Pyruvate Carboxylase
- Acetyl-CoA Produced During Fatty Acid
Oxidation (common in fasting/starvation) - Acetyl CoA allosterically activates Pyruvate
Carboxylase, which converts pyruvate to
OA (Part 1 of gluconeogenesis)
Mechanism:
1. High acetyl-CoA signals abundant energy
(from fat breakdown)
- This enables the liver to prioritize glucose
synthesis for the brain and RBCs
How is Gluconeogenesis Regulated Using Citrate?
Citrate: Metabolic Signal
Allosteric Regulation:
- (In Cytoplasm) Citrate Inhibits PFK-1,
- PFK-1 is a key glycolytic enzyme
- Glycolysis is slowed
- Competition for substrates reduced
- Metabolism shifted toward Gluconeogenesis
Substrate Supply:
- Citrate transported from mitochondria to
cytoplasm - Citrate cleaved into acetyl-CoA and OAA
- Precursors provided for gluconeogenesis
Link To The Citric Acid Cycle:
High citrate : Indicate a well-fed state (active CAC)
During fasting: Citrate’s role shifts to balancing
glycolysis/gluconeogenesis.
How Does Insulin Regulate Gluconeogenesis?
Released By Pancreatic β Cells
Main Effects:
- Promotes Glucose Uptake
- Promotes Glycolysis + Glycogenolysis
- Inhibits Gluconeogenesis
Mechanism:
- Insulin activates Protein Phosphatases
- Key Enzymes Dephosphorylated
- Increase In F2,6BP
- This Activates PFK-1 (Glycolysis Accelerator)
- Inhibits Fructose-1,6-Bisphosphatase
- Suppresses transcription of Gluconeogenic
enzymes e.g. Glucose 6 Phosphate
How Does Glucagon Regulate Gluconeogenesis?
Glucagon: Produced by Pancreatic α-Cells
- Stimulates Gluconeogenesis
- Stimulates Glycogenolysis
- Inhibits Glycolysis
Mechanism:
- Glucagon binds to liver receptors
- This Activates cAMP/PKA pathway
- PKA phosphorylates enzymes
- This Inactivates Pyruvate Kinase
(Slowing Glycolysis) - It also Activates PEP Carboxykinase
(Promoting Gluconeogenesis) - F2,6BP levels reduced
- Glycolysis stimulation and gluconeogenesis
Inhibition removed - Transcription of Gluconeogenic Enzymes
increased
How Does Fructose 2,6 Biphosphate Act as a Molecular Switch?
Insulin Triggers High Conc of F2,6 BP:
Activating Glycolysis
Inhibiting Gluconeogenesis
Gluconeogenesis Causes F2,6 BP Conc to Drop
Inhibiting Glycolysis
Activating Gluconeogenesis
How is F2,6 BP Acquired?
Fructose 6-Phosphate + ATP → Fructose 2,6 Biphosphate
What is The Cori Cycle?
Metabolic Partnership Between Muscles and Liver To Prevent Lactic Acid Buildup
Prevents Lactic Acidosis during exercise
Recycles Energy
Describe The Stages of The Cori Cycle.
- Muscles Rapidly Break Down Glucose
(Glycolysis) During Intense Exercise - Lactate produced in Anaerobic Conditions
as byproduct - Lactate diffuses into bloodstream and
travels to liver - Liver converts Lactate → Glucose
(Via gluconeogenesis, requires ATP) - Newly Synthesized Glucose released into
Bloodstream + Transported back to muscles. - Muscles take up Glucose and fuel further
activity, completing the cycle.
What Is The Cost Of The Cell Cycle?
Gluconeogenesis uses 6 ATP to make 1 Glucose from 2 lactate molecules
Glycolysis produces 2 ATP
“ATP debt” Repaid by Liver to Support Muscle Activity
What is The Glucose Alanine Cycle?
Metabolic Partnership Between Muscles and the Liver
Recycles Glucose (During Fasting/Starvation)
Transports Nitrogen → Liver
(For Disposal as Urea)
Describe The Glucose Alanine Cycle?
During Fasting/Exercise:
- Protein Breakdown Releases Amino Acids.
- Pyruvate reacts with glutamate via Alanine
Aminotransferase (ALT): - Alanine released into bloodstream and
Transported → Liver - (In Liver) Alanine converted back → Pyruvate
(Using Aminotransferase) - Pyruvate enters Gluconeogenesis →
Synthesized into glucose - Glucose released into blood, used by
Muscles and other tissues - Amino group from Glutamate (Generated in
Liver) enters Urea Cycle → converted to Urea
and excreted in urine.
How Is Glucose Generated From Glycerol?
Body breaks down Triglycerides in Adipose Tissue (Lipolysis) → Glycerol + Fatty Acids
- Glycerol Kinase uses Pi from ATP to
Phosphorylate Glycerol
Products: Glycerol-3-phosphate + ADP(Most Tissues Lack Glycerol Kinase, Process
Primarily Occurs in Liver) - G3P Oxidized → Dihydroxyacetone
Phosphate using G3P Dehydrogenase(DHAP Key intermediate
Glycolysis/Gluconeogenesis) - DHAP Converted → Glyceraldehyde 3-
Phosphate via Isomerization
x2 Glyceraldehyde 3-Phosphate Combine, forms F1,6 BP
F1,6 BP proceeds through Gluconeogenesis → Glucose
What Happens During A Sprint?
- Muscle Cells produce Lactate from Glucose
- Cardiac Cells convert Lactate → Pyruvate
- Gluconeogenesis in Liver keeps Muscle Cells supplied
with Glucose
