All of the following are gluconeogenic substrates that can be converted to glucose-6-phosphate EXCEPT:

Question

Accepted Answer

A. Acetyl-CoA via pyruvate carboxylase. ## Gluconeogenic Substrates and Their Pathways

**Key Point:** Gluconeogenesis requires substrates that can be converted to oxaloacetate or phosphoenolpyruvate (PEP), which then proceed to glucose-6-phosphate. Acetyl-CoA cannot serve as a net gluconeogenic substrate in mammals.

### Why Acetyl-CoA Is NOT Gluconeogenic

Although acetyl-CoA enters the TCA cycle and is oxidized, the two carbons lost as CO₂ in the cycle mean there is **no net synthesis of oxaloacetate** from acetyl-CoA. The carbons that enter as acetyl-CoA are released as CO₂ during isocitrate dehydrogenase and α-ketoglutarate dehydrogenase steps. Therefore, acetyl-CoA cannot be converted to glucose-6-phosphate in mammals.

**High-Yield:** This is a classic NEET PG trap — students often confuse "acetyl-CoA enters the TCA cycle" with "acetyl-CoA is gluconeogenic." It is not.

### Valid Gluconeogenic Substrates

| Substrate | Enzyme(s) | Pathway |
|-----------|-----------|----------|
| **Lactate** | Lactate dehydrogenase → pyruvate carboxylase | Lactate → pyruvate → oxaloacetate → PEP → glucose-6-phosphate |
| **Glycerol** | Glycerol kinase → glycerol-3-phosphate dehydrogenase | Glycerol → glycerol-3-phosphate → DHAP → glucose-6-phosphate |
| **Amino acids** | Transaminases, deaminases | Amino acids → pyruvate or TCA intermediates → oxaloacetate → glucose-6-phosphate |
| **Odd-chain fatty acids** | β-oxidation | Propionyl-CoA → succinyl-CoA (TCA intermediate) → oxaloacetate |

**Clinical Pearl:** During prolonged fasting or starvation, lactate (from muscle glycolysis), glycerol (from adipose triglyceride breakdown), and amino acids (from muscle proteolysis) become the primary gluconeogenic substrates to maintain blood glucose.

### Why Even-Chain Fatty Acids Cannot Be Gluconeogenic

Even-chain fatty acids yield only acetyl-CoA upon β-oxidation, which cannot be converted to glucose in mammals (though plants and bacteria can via the glyoxylate cycle).

**Mnemonic:** **GLAD** — Gluconeogenic substrates are **G**lycerol, **L**actate, **A**mino acids, and odd-chain **D**icarboxylic fatty acids (via propionyl-CoA).

Answer

B. Lactate via the Cori cycle

Answer

C. Glycerol via glycerol-3-phosphate dehydrogenase

Answer

D. Amino acids via transamination and deamination

All of the following are gluconeogenic substrates that can be converted to glucose-6-phosphate EXCEPT:

Explanation

Gluconeogenic Substrates and Their Pathways

Why Acetyl-CoA Is NOT Gluconeogenic

Valid Gluconeogenic Substrates

Why Even-Chain Fatty Acids Cannot Be Gluconeogenic

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Substrate	Enzyme(s)	Pathway
Lactate	Lactate dehydrogenase → pyruvate carboxylase	Lactate → pyruvate → oxaloacetate → PEP → glucose-6-phosphate
Glycerol	Glycerol kinase → glycerol-3-phosphate dehydrogenase	Glycerol → glycerol-3-phosphate → DHAP → glucose-6-phosphate
Amino acids	Transaminases, deaminases	Amino acids → pyruvate or TCA intermediates → oxaloacetate → glucose-6-phosphate
Odd-chain fatty acids	β-oxidation	Propionyl-CoA → succinyl-CoA (TCA intermediate) → oxaloacetate