Gluconeogenesis
High-Yield Summary
- Gluconeogenesis makes new glucose, mainly in the liver (some in kidney), becoming the dominant glucose source once liver glycogen depletes (~12-24 hrs of fasting).
- Three carbon sources: lactate (via the Cori cycle), glycerol (from triglyceride breakdown), and glucogenic amino acids. Leucine and lysine are purely ketogenic — cannot contribute. Most fatty acids can't contribute either (acetyl-CoA is a dead end); the exception is odd-chain fatty acids via propionyl-CoA.
- It is NOT glycolysis in reverse — 4 unique enzymes bypass glycolysis's 3 irreversible steps: pyruvate carboxylase + PEP carboxykinase (bypass pyruvate kinase), fructose-1,6-bisphosphatase (bypass PFK-1), glucose-6-phosphatase (bypass hexokinase/glucokinase).
- Only liver (and kidney) has glucose-6-phosphatase — muscle cannot release free glucose into blood even though it can perform glycogenolysis.
Key Terms
- Cori cycle
- Lactate from muscle/RBCs → liver → converted to pyruvate → used for gluconeogenesis.
- Pyruvate carboxylase
- Mitochondrial enzyme converting pyruvate to oxaloacetate using CO2 + ATP; activated by acetyl-CoA.
- PEP carboxykinase
- Converts oxaloacetate to PEP using GTP.
- Glucose-6-phosphatase
- ER enzyme (liver only) that removes phosphate from glucose-6-P, producing free glucose for blood release.
The Three Bypasses (Reverse Order From Pyruvate)
- 1Bypass 1 (pyruvate kinase): pyruvate → oxaloacetate (pyruvate carboxylase, mitochondria, +CO2/ATP, activated by acetyl-CoA) → malate → shuttled to cytoplasm → oxaloacetate → PEP (PEP carboxykinase, +GTP)
- 2Reversible steps shared with glycolysis run in reverse up to fructose-1,6-bisphosphate
- 3Bypass 2 (PFK-1): fructose-1,6-bisphosphate → fructose-6-phosphate (fructose-1,6-bisphosphatase; inhibited by AMP and fructose-2,6-bisphosphate)
- 4More reversible steps run in reverse up to glucose-6-phosphate
- 5Bypass 3 (hexokinase/glucokinase): glucose-6-phosphate → free glucose (glucose-6-phosphatase, liver ER only) → released to blood
Bypass Enzyme Summary
| Glycolytic Step Bypassed | Gluconeogenic Enzyme(s) / Location |
|---|---|
| Pyruvate kinase | Pyruvate carboxylase → PEP carboxykinase / mitochondria → cytoplasm |
| PFK-1 | Fructose-1,6-bisphosphatase / cytoplasm |
| Hexokinase / glucokinase | Glucose-6-phosphatase / ER (liver) |
Common MCAT Trap
- Gluconeogenesis is NOT glycolysis simply run backward — 4 unique enzymes bypass 3 irreversible glycolytic steps, using different cofactors (CO2/ATP, GTP).
- Leucine and lysine are the ONLY purely ketogenic amino acids — every other amino acid is at least partly glucogenic.
- Even-chain fatty acids cannot net-contribute carbon to gluconeogenesis (PDH is irreversible); only odd-chain fatty acids can, via propionyl-CoA → succinyl-CoA.
Quick Recall
Name the four enzymes that bypass glycolysis's irreversible steps.
Which two amino acids are purely ketogenic?
Why can't muscle perform gluconeogenesis to raise blood glucose?
What recycles lactate back into glucose?