Gluconeogenesis

Gluconeogenesis is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. Gluconeogenesis is the process by which new glucose molecules are formed in the body. Unlike glucose derived from the breakdown of stored glycogen, gluconeogenesis creates glucose from non-carbohydrate sources. It mainly occurs in the liver, but smaller amounts can also happen in the kidneys and small intestine. The primary purpose of gluconeogenesis is to maintain blood sugar levels (glucose homeostasis). It ensures that our body has a steady supply of glucose even when we’re not consuming enough carbohydrates. By generating glucose from non-carbohydrate precursors, gluconeogenesis helps prevent hypoglycemia (low blood sugar) in humans and other animals. In this article we will see pathway and significance of gluconeogenesis.

Table of Contents

Pathway

Substrates

Gluconeogenesis begins with various substrates, including:

Lactate: Produced during intense exercise or fasting.
Pyruvate: Derived from glycolysis or other sources.
Glycerol: Converted to dihydroxyacetone phosphate (DHAP), an intermediate in gluconeogenesis.
Certain amino acids: These can be transformed into glucose.

Conversion of Pyruvate to Phosphoenolpyruvate (PEP)

Pyruvate carboxylase converts pyruvate (from lactate or other sources) into oxaloacetate.
ATP and biotin serve as cofactors for this conversion.
Next, phosphoenolpyruvate carboxykinase (PEPCK) transforms oxaloacetate into phosphoenolpyruvate (PEP)1.

PEP to Fructose-1,6-bisphosphate

A series of enzymatic reactions convert PEP to fructose-1,6-bisphosphate, avoiding the irreversible steps of glycolysis.
PEP is first changed by PEP carboxykinase into oxaloacetate, which then becomes malate and exits the mitochondria.
In the cytoplasm, malate is converted back to oxaloacetate and phosphorylated to create PEP.

Fructose-1,6-bisphosphate to Glucose

The subsequent steps mimic the anti-glycolytic responses.
Fructose-1,6-bisphosphate is further processed to eventually yield glucose.

Energetics

Gluconeogenesis is an endergonic process (requires energy input). Surprisingly, it occurs when the body is already low on energy. To minimize energy expenditure, some steps of gluconeogenesis differ from those of glycolysis (the breakdown of glucose). These adaptations allow the process to proceed efficiently despite the energy constraints.

For example, the conversion of pyruvate to glucose-6-phosphate involves ATP and GTP, but the overall payoff is worth it when glucose enters cells and contributes to ATP production.

Comparison with Glycogenolysis

Glycogenolysis is another process used to raise blood glucose levels when they are low. It involves breaking down stored glycogen into glucose.

The key difference is,

Glycogenolysis: Glucose formed from glycogen (a glucose polymer).
Gluconeogenesis: Glucose formed from non-glucose sources (e.g., lactate, amino acids).

Glycogenolysis is exergonic (releases energy), while gluconeogenesis requires energy input.

Significance

Gluconeogenesis plays a crucial role in maintaining our body’s energy balance, especially during times of fasting or limited carbohydrate intake. Which includes,

Energy Source When Carbohydrates Are Scarce

Gluconeogenesis ensures that our body can produce glucose even when dietary carbohydrates are insufficient.
When we’re not eating enough carbs or during extended fasting, gluconeogenesis kicks in to create glucose from non-carbohydrate sources like lactate, pyruvate, glycerol, and certain amino acids.
This newly synthesized glucose serves as a vital respiratory substrate for energy production.

Liver and Kidneys as Key Players

The liver is the primary site for gluconeogenesis. It contains essential enzymes for this process.
The kidneys also contribute, albeit to a lesser extent.
During prolonged fasting or increased energy demands, these organs ensure a steady supply of glucose for the body.

Steps of Gluconeogenesis

Gluconeogenesis involves several steps:

Substrates: Precursors like lactate, pyruvate, glycerol, and amino acids are used.
Conversion of Pyruvate to PEP: Enzymes transform pyruvate into phosphoenolpyruvate (PEP).
PEP to Fructose-1,6-bisphosphate: Further enzymatic processes convert PEP to fructose-1,6-bisphosphate.
Fructose-1,6-bisphosphate to Glucose: The final stages mimic anti-glycolytic responses.

Metabolic Homeostasis

Gluconeogenesis helps maintain blood glucose levels within a normal range.
It ensures that glucose-dependent tissues (including the brain) receive a steady supply of energy.
Without gluconeogenesis, our body would struggle to function during periods of low carbohydrate availability.

Summary

In summary, gluconeogenesis ensures that our body can produce glucose even when dietary carbohydrates are scarce. It’s a remarkable adaptation that allows us to maintain stable blood sugar levels and keep our cells energized during challenging times.