gluconeogenesis

Definition

Target type: biologicalprocess

The formation of glucose from noncarbohydrate precursors, such as pyruvate, amino acids and glycerol. [MetaCyc:GLUCONEO-PWY]

Gluconeogenesis is a metabolic pathway that generates glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids. This process occurs primarily in the liver and, to a lesser extent, in the kidneys. It is essential for maintaining blood glucose levels, particularly during periods of fasting or starvation, when glucose supply from dietary sources is limited. The process can be divided into several steps, each catalyzed by specific enzymes.

**1. Conversion of Pyruvate to Phosphoenolpyruvate (PEP)**
Pyruvate, derived from glycolysis or other sources, is transported into the mitochondria where it is carboxylated by pyruvate carboxylase to form oxaloacetate. This reaction requires biotin as a cofactor and is driven by high levels of acetyl-CoA, which is generated from the breakdown of fatty acids during fasting.
Oxaloacetate is then transported back to the cytoplasm where it is decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase (PEPCK). This step requires GTP and is the rate-limiting step in gluconeogenesis.

**2. Conversion of PEP to Fructose 1,6-bisphosphate**
PEP is converted to 2-phosphoglycerate by enolase, then to 3-phosphoglycerate by phosphoglycerate mutase, and finally to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase. The latter step is catalyzed by the same enzyme as in glycolysis, but the reaction proceeds in the opposite direction.
Dihydroxyacetone phosphate, an intermediate in glycolysis, can also enter the gluconeogenic pathway at this point.
Fructose 1,6-bisphosphatase, an enzyme specific to gluconeogenesis, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, releasing inorganic phosphate.

**3. Conversion of Fructose 6-phosphate to Glucose 6-phosphate**
Glucose 6-phosphate isomerase, an enzyme shared by glycolysis and gluconeogenesis, converts fructose 6-phosphate to glucose 6-phosphate.

**4. Conversion of Glucose 6-phosphate to Glucose**
Glucose 6-phosphatase, present mainly in the liver and kidneys, catalyzes the final step of gluconeogenesis, hydrolyzing glucose 6-phosphate to glucose, which is released into the bloodstream.

**Regulation of Gluconeogenesis**
Gluconeogenesis is tightly regulated to ensure that blood glucose levels are maintained within a narrow range. The main factors regulating gluconeogenesis include:
* **Hormonal regulation:** Glucagon, a hormone released by the pancreas in response to low blood glucose levels, stimulates gluconeogenesis. Insulin, on the other hand, suppresses gluconeogenesis.
* **Substrate availability:** The availability of precursors like pyruvate, lactate, glycerol, and glucogenic amino acids directly influences the rate of gluconeogenesis.
* **Allosteric regulation:** Certain enzymes involved in gluconeogenesis are subject to allosteric regulation by metabolites such as ATP, AMP, and fructose 2,6-bisphosphate.

**Clinical Significance of Gluconeogenesis**
Gluconeogenesis is essential for survival, especially during periods of fasting or starvation. It provides the brain, red blood cells, and other tissues with a constant supply of glucose when dietary intake is limited.
Deficiencies in enzymes involved in gluconeogenesis can lead to various metabolic disorders, such as glycogen storage diseases and pyruvate carboxylase deficiency.

**Gluconeogenesis is a complex process with several unique features:**
* **It is energetically expensive:** Gluconeogenesis requires ATP and GTP for the conversion of pyruvate to glucose.
* **It is irreversible:** Although some enzymes involved in gluconeogenesis are also used in glycolysis, the overall process is irreversible due to the presence of specific enzymes like PEPCK and fructose 1,6-bisphosphatase.
* **It is tightly regulated:** Gluconeogenesis is finely tuned by hormones, substrates, and allosteric effectors to ensure a stable blood glucose concentration.

In summary, gluconeogenesis is a critical metabolic pathway that generates glucose from non-carbohydrate sources, ensuring glucose availability for energy production, especially during times of fasting or starvation.'
"

Proteins (25)

Compounds (203)