Gluceoneogenesis expanded

What is gluconeogenesis?

The synthesis of glucose from noncarbohydrate precursors

What is the main purpose of gluconeogenesis?

Maintain blood glucose when dietary glucose is unavailable

Where does gluconeogenesis occur?

Primarily in the liver; also in the kidneys, especially during prolonged fasting

Which cellular compartments are involved in gluconeogenesis?

Mitochondria, cytosol, and endoplasmic reticulum

What are the main precursors for gluconeogenesis?

Lactate, glycerol, and glucogenic amino acids

What is the main starting substrate for gluconeogenesis from lactate?

Lactate

What is the starting substrate for gluconeogenesis from glycerol?

Glycerol

What is the starting substrate for gluconeogenesis from glucogenic amino acids?

Pyruvate or Krebs cycle intermediates, depending on the amino acid

Can even-chain fatty acids produce net glucose in humans?

No; acetyl-CoA cannot produce net glucose in humans

Can glycerol contribute to glucose synthesis?

Yes; it enters through DHAP

What is the main organ responsible for gluconeogenesis?

Liver

When is gluconeogenesis especially important?

Fasting, prolonged exercise, and low carbohydrate availability

What is the difference between gluconeogenesis and glycolysis?

Gluconeogenesis builds glucose; glycolysis breaks glucose down

Is gluconeogenesis simply the reverse of glycolysis?

No; three irreversible glycolysis steps require bypass reactions

What is the first gluconeogenesis intermediate when starting from pyruvate?

Oxaloacetate

What is the first step of gluconeogenesis from pyruvate?

Pyruvate is converted to oxaloacetate

What enzyme converts pyruvate to oxaloacetate?

Pyruvate carboxylase

What cofactors or energy sources does pyruvate carboxylase require?

ATP and biotin; it also requires bicarbonate

What type of reaction converts pyruvate to oxaloacetate?

Carboxylation

Where does pyruvate carboxylase operate?

Mitochondrial matrix

What activates pyruvate carboxylase?

Acetyl-CoA

What is the second step of gluconeogenesis from pyruvate?

Oxaloacetate is converted to phosphoenolpyruvate (PEP)

What enzyme converts oxaloacetate to PEP?

Phosphoenolpyruvate carboxykinase (PEPCK)

What energy source does PEPCK use?

GTP

What type of reaction does PEPCK catalyze?

Decarboxylation coupled to phosphorylation

What is the product when oxaloacetate is converted by PEPCK?

Phosphoenolpyruvate (PEP)

Why is oxaloacetate often converted to malate before leaving mitochondria?

Oxaloacetate cannot cross the inner mitochondrial membrane directly

How can oxaloacetate equivalents leave the mitochondrion?

As malate or aspartate, or PEP may be formed in mitochondria

What enzyme converts oxaloacetate to malate?

Malate dehydrogenase

What enzyme converts malate back to oxaloacetate?

Malate dehydrogenase

What happens to NADH when oxaloacetate is converted to malate?

NADH is oxidized to NAD⁺

What happens to NAD⁺ when malate is converted to oxaloacetate?

NAD⁺ is reduced to NADH

What is the next intermediate after PEP in gluconeogenesis?

2-Phosphoglycerate

What enzyme converts PEP to 2-phosphoglycerate?

Enolase

What is the next intermediate after 2-phosphoglycerate?

3-Phosphoglycerate

What enzyme converts 2-phosphoglycerate to 3-phosphoglycerate?

Phosphoglycerate mutase

What is the next intermediate after 3-phosphoglycerate?

1,3-Bisphosphoglycerate

What enzyme converts 3-phosphoglycerate to 1,3-bisphosphoglycerate?

Phosphoglycerate kinase

What energy source is used to convert 3-phosphoglycerate to 1,3-bisphosphoglycerate?

ATP

What is the next intermediate after 1,3-bisphosphoglycerate?

Glyceraldehyde-3-phosphate (G3P)

What enzyme converts 1,3-bisphosphoglycerate to G3P?

Glyceraldehyde-3-phosphate dehydrogenase

What cofactor is used when 1,3-bisphosphoglycerate becomes G3P?

NADH

What happens to NADH in this gluconeogenesis step?

NADH is oxidized to NAD⁺

What are the two triose phosphate intermediates?

Glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP)

What enzyme interconverts G3P and DHAP?

Triose phosphate isomerase

What happens when G3P and DHAP combine?

They form fructose-1,6-bisphosphate

What enzyme combines G3P and DHAP?

Aldolase

What is the next intermediate after fructose-1,6-bisphosphate?

Fructose-6-phosphate

What enzyme converts fructose-1,6-bisphosphate to fructose-6-phosphate?

Fructose-1,6-bisphosphatase

What type of reaction does fructose-1,6-bisphosphatase catalyze?

Hydrolysis; removes a phosphate group

Does fructose-1,6-bisphosphatase use ATP?

No; it hydrolyzes the phosphate bond and releases inorganic phosphate

What is the next intermediate after fructose-6-phosphate?

Glucose-6-phosphate

What enzyme converts fructose-6-phosphate to glucose-6-phosphate?

Phosphoglucose isomerase

What is the final intermediate before free glucose is produced?

Glucose-6-phosphate

What enzyme converts glucose-6-phosphate to glucose?

Glucose-6-phosphatase

What type of reaction does glucose-6-phosphatase catalyze?

Hydrolysis; removes the phosphate group

Where is glucose-6-phosphatase located?

Endoplasmic reticulum

Why can the liver release free glucose into the blood?

It has glucose-6-phosphatase to remove the phosphate from glucose-6-phosphate

Why can't skeletal muscle directly release free glucose from glucose-6-phosphate?

Skeletal muscle lacks glucose-6-phosphatase

What are the three irreversible glycolysis steps bypassed by gluconeogenesis?

Pyruvate kinase, phosphofructokinase-1, and hexokinase/glucokinase

What enzyme bypasses pyruvate kinase in gluconeogenesis?

Pyruvate carboxylase and PEP carboxykinase

What enzyme bypasses phosphofructokinase-1?

Fructose-1,6-bisphosphatase

What enzyme bypasses hexokinase/glucokinase?

Glucose-6-phosphatase

What is the first bypass reaction?

Pyruvate to oxaloacetate to PEP

What is the second bypass reaction?

Fructose-1,6-bisphosphate to fructose-6-phosphate

What is the third bypass reaction?

Glucose-6-phosphate to glucose

Why can't gluconeogenesis simply reverse glycolysis?

The three irreversible glycolysis reactions require different enzymes and energy inputs

What is the mnemonic for the three gluconeogenesis bypasses?

Pyruvate uses two enzymes; F-1,6-BP uses a phosphatase; G-6-P uses a phosphatase

How many ATP are consumed to make one glucose from two pyruvate?

4 ATP

How many GTP are consumed to make one glucose from two pyruvate?

2 GTP

How many NADH are consumed to make one glucose from two pyruvate?

2 NADH

What is the total energy cost of gluconeogenesis from two pyruvate?

4 ATP, 2 GTP, and 2 NADH

How many high-energy phosphate bonds are used per glucose made from two pyruvate?

6 high-energy phosphate bonds

Why does gluconeogenesis require energy?

Building glucose from smaller precursors is energetically unfavorable

Does gluconeogenesis produce ATP overall?

No; it consumes ATP, GTP, and NADH

What is the net carbon balance when two pyruvate molecules form one glucose?

Six carbons are retained to form one six-carbon glucose

How many pyruvate molecules are needed to make one glucose?

2 pyruvate

How many oxaloacetate molecules are formed from two pyruvate?

2 oxaloacetate

How many PEP molecules are needed to make one glucose?

2 PEP

How many molecules of G3P and DHAP combine to form one glucose?

One G3P and one DHAP combine to form fructose-1,6-bisphosphate

What is the role of biotin in gluconeogenesis?

It carries CO₂ during pyruvate carboxylation

What is carboxylation?

Addition of a carboxyl group, often using CO₂

What is decarboxylation?

Removal of a carboxyl group as CO₂

What is phosphorylation?

Addition of a phosphate group

What is dephosphorylation?

Removal of a phosphate group

What is hydrolysis?

Breaking a bond using water

What is isomerization?

Rearrangement of a molecule into an isomer

What is oxidation?

Loss of electrons

What is reduction?

Gain of electrons

What is the role of NADH in gluconeogenesis?

Provides reducing power for the conversion of 1,3-bisphosphoglycerate to G3P

What is the role of GTP in gluconeogenesis?

Provides energy for PEP formation from oxaloacetate

What is the role of ATP in gluconeogenesis?

Provides energy for pyruvate carboxylation and 3-phosphoglycerate phosphorylation

What stimulates gluconeogenesis during fasting?

Glucagon and increased availability of gluconeogenic precursors

What hormone generally inhibits gluconeogenesis after a meal?

Insulin

What does glucagon do to fructose-2,6-bisphosphate levels in the liver?

Decreases them

What does insulin do to fructose-2,6-bisphosphate levels in the liver?

Increases them

How does fructose-2,6-bisphosphate affect glycolysis?

Activates phosphofructokinase-1

How does fructose-2,6-bisphosphate affect gluconeogenesis?

Inhibits fructose-1,6-bisphosphatase

What happens to gluconeogenesis when glucagon is high?

Gluconeogenesis generally increases

What happens to gluconeogenesis when insulin is high?

Gluconeogenesis generally decreases