Gluconeogenesis Pathway: Introduction, Steps, Regulation, and Function

Gluconeogenesis pathway is a metabolic process in which glucose is synthesized from substrates that are not carbohydrates such as lactate, glycerol, and amino acids. This procedure is vital for maintaining normal blood glucose levels, especially to maintain homeostasis during fasting or low carbohydrate situations.

It takes place primarily in the liver and to a lesser extent in the kidneys. A series of enzyme processes transform non-carbohydrate precursors into glucose in this process.

 The overall reaction for gluconeogenesis is:

2 pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H⁺ + 4 H₂O → Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD⁺

Enzymes in gluconeogenesis

 The enzymes involved in gluconeogenesis include:

1. Pyruvate carboxylase
2. Phosphoenolpyruvate carboxykinase (PEPCK)
3. Fructose-1,6-bisphosphatase (FBPase)
4. Glucose-6-phosphatase

Co-factors in gluconeogenesis

 The co-factors required for gluconeogenesis include:

1. ATP (Adenosine triphosphate)
2. GTP (Guanosine triphosphate)
3. NADH (Nicotinamide adenine dinucleotide (NAD) + hydrogen (H))
4. H+ (Hydrogen ion)
5. Pi (inorganic phosphate)

Precursors in gluconeogenesis

 The precursors used for gluconeogenesis include:

1. Lactate
2. Glycerol
3. Amino acids (especially alanine and glutamine)

Steps of Gluconeogenesis pathway

The steps involved in the gluconeogenesis pathway are as follows:

Step 1: Conversion of Pyruvate to Oxaloacetate 

• Pyruvate carboxylase transforms pyruvate to oxaloacetate by consuming ATP and releasing ADP.
• This process occurs in the mitochondria of liver cells.

Pyruvate + ATP + HCO₃^– + H⁺ → Oxaloacetate + ADP + Pi

Step 2: Conversion of Oxaloacetate to Phosphoenolpyruvate (PEP) 

• The enzyme PEP carboxykinase converts oxaloacetate to PEP by consuming GTP and releasing GDP.
• This process occurs in the cytoplasm of liver cells.

Oxaloacetate + GTP → Phosphoenolpyruvate + CO₂ + GDP

Step 3: Conversion of Fructose-1,6-Bisphosphate to Fructose-6-Phosphate

• Fructose-1,6-bisphosphatase is a water-based enzyme that transforms fructose-1,6-bisphosphate to fructose-6-phosphate.
• This process occurs in the cytoplasm of liver cells.

Fructose-1,6-bisphosphate + H₂O → Fructose-6-phosphate + Pi

Step 4: Conversion of Glucose-6-Phosphate to Glucose 

• Glucose-6-phosphatase is a water-based enzyme that transforms glucose-6-phosphate to glucose.
• This process occurs in the endoplasmic reticulum of liver cells.

Glucose-6-phosphate + H₂O → Glucose + Pi

The resultant glucose can subsequently be delivered into the circulation to maintain appropriate blood glucose levels.

Regulation of Gluconeogenesis

The regulation of gluconeogenesis is a complicated process involving several enzymes and metabolic pathways. Hormones, substrates, and allosteric effectors have been known to modulate the pathway. 

1. Hormonal regulation: Glucagon and cortisol enhance gluconeogenesis by activating enzymes in the process. Insulin suppresses gluconeogenesis by inhibiting the activity of these enzymes.
2. Substrate availability: Gluconeogenesis can be influenced by the availability of non-carbohydrate precursors such as lactate, amino acids, and glycerol. During fasting, the levels of these precursors rise, promoting glucose synthesis.
3. Allosteric regulation: Allosteric effectors control enzymes involved in gluconeogenesis. Fructose-2,6-bisphosphate, for example, is an activator of phosphofructokinase-1, which modulates the rate of glucose consumption. This activator promotes glucose consumption while inhibiting gluconeogenesis at high doses.
4. Transcriptional regulation: Transcription factors such as CREB, FoxO1, and PGC-1 influence the expression of genes involved in gluconeogenesis. These variables influence the expression of genes involved in glucose metabolism, particularly gluconeogenesis.

Function of Gluconeogenesis 

Here are the main functions of gluconeogenesis in points:

• To synthesize glucose from noncarbohydrate precursors such as lactate, glycerol, and amino acids.
• To supply energy during fasting or periods of low carbohydrate consumption
• To utilize ATP, which is produced by the oxidation of fatty acids in the liver (-oxidation).
• To ensure a steady supply of glucose for specific organs, such as the brain, that rely on glucose for energy.
• To maintain the body’s glucose homeostasis and energy balance.
• To aid life during extended fasting or malnutrition by keeping glucose levels in the brain and other important organs stable.

Gluconeogenesis of different precursors

Gluconeogenesis of Amino acids

When glucose is unavailable, amino acids can act as gluconeogenesis precursors. Some amino acids’ carbon structure can be transformed to gluconeogenesis pathway intermediates, whilst the amino groups undergo conversion to urea and eliminated by the kidneys.

The following amino acids can be used for gluconeogenesis:

1. Alanine: Alanine is the most significant amino acid for gluconeogenesis. It is released from muscle tissue during fasting or times of minimal sugar consumption and transferred to the liver, there it is converted to pyruvate by an enzyme called alanine transaminase. Pyruvate is able to enter the gluconeogenesis process to create glucose.
2. Glutamine: Glutamine is another vital amino acid for gluconeogenesis. It is released from muscle tissue and transferred to the liver, where it is converted to glutamate and ultimately to α-ketoglutarate. α-Ketoglutarate is able to enter the gluconeogenesis pathway to generate glucose.
3. Aspartate: The enzyme aspartate transaminase converts aspartate to oxaloacetate. Oxaloacetate can then enter the gluconeogenesis pathway to create glucose.
4. Serine, glycine, and threonine: These amino acids can be transformed into 3-phosphoglycerate, a gluconeogenesis pathway intermediate.
5. Histidine, arginine, and proline: These amino acids can be transformed to glutamate, which can subsequently be converted to -ketoglutarate and enter the gluconeogenesis pathway.

Gluconeogenesis of Lactate

When glucose supply is low, lactate can be used as a substrate for gluconeogenesis to sustain glucose homeostasis. During exercise or periods of anaerobic metabolism, the muscle produces lactate. It can be delivered to the liver, where the enzyme lactate dehydrogenase converts it to pyruvate.

Pyruvate can then enter the gluconeogenesis pathway, where it can be converted to glucose. During exercise, the conversion of lactate to glucose is critical because it permits the muscle to continue energy production by using lactate as a fuel source.

Gluconeogenesis of glycerol

When glucose supply decreases, glycerol is a precursor for gluconeogenesis, which helps maintain glucose homeostasis. Glycerol is extracted from adipose tissue triglycerides and transferred to the liver, where it is transformed to dihydroxyacetone phosphate (DHAP) by the enzyme glycerol kinase.

To synthesize glucose, DHAP can next join the gluconeogenesis pathway.

Differences between Glycolysis and Gluconeogenesis

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