U01.01.095 Gluconeogenesis, irreversible enzymes

Gluconeogenesis is the metabolic pathway that generates glucose from non-carbohydrate precursors. It occurs mainly in the liver and to a lesser extent in the kidneys and intestinal epithelium. This process is essential for maintaining euglycemia (normal blood glucose levels) during fasting. Several key enzymes in this pathway are irreversible, and they are regulated to ensure proper glucose production.

Key Irreversible Enzymes in Gluconeogenesis

These enzymes catalyze the critical steps that make gluconeogenesis irreversible:

Enzyme	Location	Reaction	Co-factors/Regulation
Pyruvate Carboxylase	Mitochondria	Pyruvate → Oxaloacetate	Requires biotin, ATP; activated by acetyl-CoA
Phosphoenolpyruvate Carboxykinase	Cytosol	Oxaloacetate → Phosphoenolpyruvate	Requires GTP
Fructose-1,6-bisphosphatase	Cytosol	Fructose-1,6-bisphosphate → Fructose-6-phosphate	Inhibited by AMP, fructose-2,6-bisphosphate; activated by citrate
Glucose-6-phosphatase	Endoplasmic Reticulum (ER)	Glucose-6-phosphate → Glucose	N/A

Pathway Overview

Pyruvate to Oxaloacetate:
- The first step in gluconeogenesis involves the enzyme pyruvate carboxylase, which converts pyruvate to oxaloacetate in the mitochondria. This step requires biotin as a cofactor and ATP for energy. Acetyl-CoA activates this enzyme.
Oxaloacetate to Phosphoenolpyruvate:
- In the cytosol, phosphoenolpyruvate carboxykinase catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (PEP), requiring GTP for energy.
Fructose-1,6-bisphosphate to Fructose-6-phosphate:
- Fructose-1,6-bisphosphatase catalyzes the dephosphorylation of fructose-1,6-bisphosphate to fructose-6-phosphate. This step is regulated by citrate (activator) and inhibited by AMP and fructose-2,6-bisphosphate.
Glucose-6-phosphate to Glucose:
- Finally, glucose-6-phosphatase, located in the ER, dephosphorylates glucose-6-phosphate to release free glucose into the bloodstream. This step is crucial for maintaining blood glucose levels.

Additional Points

Tissue Specificity:
- Gluconeogenesis occurs primarily in the liver and also in the kidneys and intestinal epithelium.
Hypoglycemia Risk:
- A deficiency in any of the key gluconeogenic enzymes leads to impaired glucose production and hypoglycemia. Muscle tissue cannot contribute to gluconeogenesis because it lacks glucose-6-phosphatase.
Fatty Acid Contribution:
- Odd-chain fatty acids can contribute to gluconeogenesis by yielding propionyl-CoA, which enters the TCA cycle and can be converted to succinyl-CoA for glucose production.
- Even-chain fatty acids, on the other hand, can only produce acetyl-CoA, which cannot contribute to new glucose production.

Points to Remember

Gluconeogenesis is the process of generating glucose from non-carbohydrate sources.
It occurs mainly in the liver and kidneys, and serves to maintain blood glucose during fasting.
Key irreversible enzymes include pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase.
Odd-chain fatty acids can support gluconeogenesis, while even-chain fatty acids cannot.

Understanding the regulation and enzymes of gluconeogenesis is crucial for USMLE Step 1, especially in the context of metabolic disorders and fasting physiology.

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