Q3
LONG ANSWER
10M
★ High-yield
Define gluconeogenesis. Describe its substrates, the key enzymes bypassing glycolysis, and its regulation.
Definition
Gluconeogenesis = the synthesis of glucose from non-carbohydrate precursors.
| Feature | Detail |
|---|---|
| Site | Liver (90%) and kidney cortex (10%); the renal share rises to 40% in prolonged starvation |
| Cell location | Mainly cytosol; first step in mitochondria, last in the endoplasmic reticulum |
| When active | Fasting, starvation, prolonged exercise, diabetes |
| Cost | 6 high-energy bonds (4 ATP + 2 GTP) per glucose |
Substrates
| Substrate | Source | Enters as |
|---|---|---|
| Lactate | Muscle and RBC (Cori cycle) | Pyruvate |
| Glucogenic amino acids | Muscle protein breakdown; alanine is the chief one | Pyruvate or TCA intermediates |
| Glycerol | Triglyceride breakdown in adipose tissue | DHAP |
| Propionate | Odd-chain fatty acids | Succinyl-CoA |
CLINICAL PEARL
Fatty acids (even-chain) cannot make glucose. Acetyl-CoA cannot be converted to pyruvate, because the pyruvate dehydrogenase reaction is irreversible. Only glycerol from the triglyceride can.
The Four Key Enzymes — Bypassing Glycolysis
| Glycolytic step (irreversible) | Gluconeogenic bypass | Notes |
|---|---|---|
| Pyruvate kinase (PEP → pyruvate) | 1. Pyruvate carboxylase (pyruvate → OAA)2. PEPCK (OAA → PEP) | Carboxylase is mitochondrial, needs biotin and ATP, activated by acetyl-CoA. PEPCK uses GTP |
| Phosphofructokinase-1 | 3. Fructose-1,6-bisphosphatase | Cytosolic; inhibited by amp and fructose-2,6-bisphosphate |
| Hexokinase / glucokinase | 4. Glucose-6-phosphatase | In the endoplasmic reticulum of liver and kidney only — which is why muscle cannot release free glucose |
The Oxaloacetate Shuttle
Pyruvate enters mitochondrion → Pyruvate carboxylase → Oxaloacetate → OAA cannot cross the inner mitochondrial membrane → Reduced to malate (malate dehydrogenase) → Malate crosses into the cytosol → Re-oxidised to OAA → PEPCK → PEP
- This shuttle also carries NADH into the cytosol, which is needed at the G3P dehydrogenase step of gluconeogenesis
- When lactate is the substrate, NADH is generated in the cytosol already, so aspartate may be used instead of malate
Regulation
| Regulator | Gluconeogenesis | Glycolysis |
|---|---|---|
| Glucagon (fasting) | ↑↑ | ↓ |
| Insulin (fed) | ↓ | ↑ |
| Cortisol | ↑ (induces PEPCK) | ↓ |
| Acetyl-CoA | ↑ (activates pyruvate carboxylase) | ↓ (inhibits PDH) |
| Fructose-2,6-bisphosphate | ↓ | ↑ |
| Amp | ↓ | ↑ |
| ATP, citrate | ↑ | ↓ |
Fructose-2,6-bisphosphate — the master switch
Glucagon → ↑ cAMP → protein kinase A → Phosphorylates the bifunctional enzyme PFK-2 / FBPase-2 → Kinase activity off, phosphatase ON → ↓ Fructose-2,6-bisphosphate → ↓ PFK-1 and ↑ fructose-1,6-bisphosphatase → glycolysis off, gluconeogenesis ON
- This reciprocal control prevents a futile cycle in which glucose would be simultaneously made and broken down, wasting ATP as heat
Significance
- Maintains blood glucose during fasting, once liver glycogen is exhausted after about 18–24 hours
- Supplies the brain (120 g glucose/day) and the RBC, which are obligate glucose users
- Clears lactate produced by muscle and RBC (Cori cycle), preventing acidosis
- Clears glycerol from fat breakdown and propionate
Comparison with Glycolysis
| Feature | Glycolysis | Gluconeogenesis |
|---|---|---|
| Direction | Glucose → pyruvate | Pyruvate → glucose |
| Site | Cytosol, all cells | Liver and kidney only |
| Energy | Yields 2 ATP | Consumes 6 ATP |
| Active in | Fed state | Fasting |
| Hormone | Insulin | Glucagon, cortisol |
| Key enzymes | Hexokinase, PFK-1, pyruvate kinase | Pyruvate carboxylase, PEPCK, F-1,6-BPase, G-6-Pase |
- The two are reciprocally regulated so that they never run at full speed together — that would be a futile cycle, wasting ATP as heat
Applied Aspects
- Von Gierke disease (type I glycogen storage disease) — glucose-6-phosphatase deficiency → neither glycogenolysis nor gluconeogenesis can release glucose → severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hepatomegaly
- Alcohol causes hypoglycaemia — its oxidation raises the NADH:NAD+ ratio, driving pyruvate to lactate and oxaloacetate to malate, so both gluconeogenic substrates are depleted. Dangerous in a fasting drinker
- Metformin reduces hepatic gluconeogenesis — its chief action in type 2 diabetes
- Biotin deficiency impairs pyruvate carboxylase and hence gluconeogenesis
- Cortisol excess (Cushing) → excess gluconeogenesis → steroid diabetes
- Hereditary fructose intolerance — aldolase B deficiency; fructose-1-phosphate accumulates and inhibits gluconeogenesis → severe hypoglycaemia after fructose
All questions in Carbohydrate Metabolism I: Glycolysis, TCA & Gluconeogenesis
- Q1Define glycolysis. Describe its reactions, energetics and regulation. Add a note on its significance in the red blood cell. ★
- Q2Describe the reactions of the TCA cycle with its energetics and regulation. Explain its amphibolic role and add a note on anaplerotic reactions. ★
- Q3Define gluconeogenesis. Describe its substrates, the key enzymes bypassing glycolysis, and its regulation. ★
- Q4Describe the sources and fates of blood glucose. Explain the hormonal regulation of blood glucose in the fed and fasting states. ★
- Q5Describe the pyruvate dehydrogenase complex with its components, coenzymes and regulation. Explain its metabolic significance. ★
- SN1Describe the Cori cycle and its significance. Add a note on the glucose–alanine cycle. ★
- SN2Describe the Rapoport–Luebering shunt and the significance of 2,3-BPG. ★
- SN3Define substrate-level phosphorylation. Give the reactions and compare it with oxidative phosphorylation. ★
- SN4Define anaplerotic reactions. Give examples and explain their importance. ★
- SN5Classify the glycogen storage diseases. Describe Von Gierke and McArdle disease. ★
- SN6Define lactic acidosis. Describe its biochemical basis and classify its causes. ★
- SN7Describe the glucose transporters with their sites and functions.