Gluconeogenesis is a process in which glucose or glycogen is produced from non-carbohydrate sources. The Gluconeogenesis pathway would have simply been a reversal of Glycolysis but it is not so because of the 3 irreversible steps of Glycolysis that need to be bypassed using different enzymes.

Gluconeogenesis Definition

Gluconeogenesis can be defined as energy-requiring process of converting pyruvate (that is derived from other sources other than carbohydrates) to glucose that occurs during prolong fasting or starvation. Other sources of pyruvate can be derived from amino acids and fats.

What is Gluconeogenesis?

Gluconeogenesis is a term that describes the synthesis of Glucose from non-carbohydrate sources such as lipids and proteins. This is necessary because in the absence of dietary intake of carbohydrate, the liver glycogen can meet the need for glucose for only 10 to 18 hours after which the glycogen stores of the liver become depleted such as in prolonged fasting; this causes the production of glucose from precursors such as lactate, pyruvate, glycerol and keto acids through Gluconeogenesis.

Bypassed Reactions of Gluconeogenesis

1. Conversion of pyruvate to phosphoenolpyruvate by pyruvate carboxylase
2. Conversion of fructose-1,6-bisphosphate to fructose-6-phosphate by fructose-1,6-bisphosphatase
3. Conversion of glucose-6-phosphate to glucose + P_i by glucose-6-phosphatase (this enzyme is only found in the liver and renal cortex)

Where does Gluconeogenesis occur?

Gluconeogenesis occurs in cells of the Liver and Kidneys in humans and other mammals because they possess the full complement of enzymes necessary for gluconeogenesis. About 90% of gluconeogenesis occurs in the liver; the kidneys provide 10% of newly synthesized glucose molecules thereby playing a minor role in gluconeogenesis except in prolonged starvation when kidneys become major glucose producing organs.

Gluconeogenesis Pathway (Gluconeogenesis Steps)

1. In gluconeogenesis, the first reaction is the conversion of pyruvate to oxaloacetate pyruvate Carboxylase (pyruvate carboxylase is found in the mitochondria of liver and kidneys, but not in muscle).
2. Oxaloacetate is then converted to Phosphoenolpyruvate (PEP) by the action of Phosphoenolpyruvate carboxykinase.
3. Phosphoenolpyruvateto2-Phosphoglyceratecatalysed byEnolase enzyme
4. 2-Phosphoglycerate to 3-Phosphoglyceratecatalysed byPhosphoglycerate mutase enzyme
5. 3-Phosphoglycerate to 1,3-Bisphosphoglycerate catalysed byPhosphoglycerate kinaseenzyme
6. 1,3-Bisphosphoglycerate to Glyceraldehyde-3-phosphate catalysed byGlyceraldehyde-3-phosphate dehydrogenaseenzyme
7. Glyceraldehyde-3-phosphate to Dihydroxyacetone phosphatecatalysed byTriosephosphate isomeraseenzyme
8. Dihydroxyacetone phosphate to Fructose-1,6-bisphosphatecatalysed byAldolase enzyme
9. Fructose-1,6-bisphosphate to Fructose-6-phosphatecatalysed byFructose-1,6-bisphosphataseenzyme
10. Fructose-6-phosphate to Glucose-6-phosphatecatalysed byPhosphoglucoisomerase enzyme
11. Conversion ofGlucose-6-phosphate to Glucosecatalysed byGlucose-6-phosphataseenzyme

These reactions are the reversed of glycolysis except with numbers 1, 2 and 11.

Gluconeogenesis Cycle

Gluconeogenesis Pathway/Cycle showing the enzymes. Highlighted enzymes signify the enzymes that bypass glycolysis

Substrates for Gluconeogenesis

1. Glucogenic amino acids: these are amino acids that form glucose ( pyruvate forming amino acids) and those that produce intermediates of TCA cycle. Examples include oxaloacetate and -ketoglutarate. See complete list of amino acids below
2. Lactates and pyruvates
3. Glycerol: Obtained from lipolysis of fats
4. Propionic acid (important in ruminants). In human beings, propionyl-CoA is formed in metabolic pathways, which can form glucose.

Pyruvate forming glucogenic amino acids

1. Glycine
2. Alanine
3. Serine
4. Cysteine
5. Cystine
6. Threonine

Oxaloacetate forming glucogenic amino acids

1. Aspartic acid

-Oxoglutarate forming glucogenic amino acids

1. Glutamate
2. Glutamine
3. Proline
4. Arginine
5. Histidine
6. Lysine

Gluconeogenesis from Glycerol (Conversion of glycerol to glucose)

Glycerol is a product of metabolism of adipose tissue and is produced by lipolysis. Tissues which possess the activating enzyme Glycerokinase can utilize glycerol. Glycerokinase enzyme is present in liver, kidneys, heart muscle, lactating mammary gland and intestinal mucosa but absent in adipose tissue.

Because glycerol cannot enter metabolic pathway directly, it has to be activated to -glycero-phosphate. The reaction is catalyzed by the enzyme Glycerokinase and requires ATP and mainly occurs in Liver and Kidneys.

The -Glycero-phosphate formed is then oxidized to dihydroxyacetone-phosphate in presence of the enzyme Glycerol-3-phosphate-dehydrogenase and NAD⁺ .

Dihydroxyacetone-phosphate can be converted to glyceraldehyde-3-phosphate by triose phosphate isomerase. This pathway thus connects with the triose-phosphate stages of the glycolytic pathway and triose-Phosphate can enter reverse glycolysis after conversion to fructose-1,6-biphosphate. Then it can form glucose by completing the gluconeogenesis pathway as explained above.

Gluconeogenesis Enzymes

1. Glucose-6 phosphatase
2. Phosphoglucoisomerase
3. Fructose-1,5-biphosphatase
4. Aldolase
5. Triosephosphate isomerase
6. Glyceraldehyde-3-phosphate dehydrogenase
7. Phosphoglycerate kinase
8. Phosphoglycerate mutase
9. Enolase
10. Phosphoenol pyruvate carboxykinase

The above named enzymes catalyze gluconeogenesis, it can be observed that 7 of these enzymes are the same and catalyze the same reactions as in Glycolysis but the 3 enzymes in bold are different from those in glycolysis; this signifies the differences between glycolysis and gluconeogenesis. The enzymes in bold are called gluconeogenic enzymes because they help to bypass the irreversible reactions of glycolysis making it possible to form glucose.

Gluconeogenesis Regulation

Regulation of Gluconeogenesis occurs through 4 key enzymes which are: Pyruvate carboxylase, Phosphoenol Pyruvate carboxykinase, Fructose-1,6-biphosphatase and Glucose-6-phosphatase.

Regulatory enzymes of Gluconeogenesis

1. Fructose-1,6-Biphosphatase: this enzyme is strongly and allosterically inhibited by AMP, but is activated by citrates. An increase in the levels of ATP and citrates will therefore increase gluconeogenesis but there is decreased gluconeogenesis when Fructose-1,6-Biphosphatase is inhibited whenever the liver cells are rich in AMP and low in citrate concentration
2. Phosphoenol pyruvate carboxykinase: This enzyme is induced by Glucagon in starvation, thus increasing gluconeogenesis. Insulin reduces gluconeogenesis by depressing the enzyme.
3. Pyruvate carboxylase: This is the key enzyme in the gluconeogenesis pathway. The enzyme is activated allosterically by acetyl-CoA which then binds with the allosteric site of the enzyme thereby bringing a conformational change at tertiary level, so that the affinity of the enzyme for CO₂ increases.
4. Glucose-6-phosphatase: this enzyme is induced by the hormones glucagon and glucocorticoids, which are secreted during starvation thus enhancing gluconeogenesis. Insulin represses the enzyme.

Importance of Gluconeogenesis (Significance of Gluconeogenesis)

1. Gluconeogenesis supplies glucose in the body when carbohydrates are not available in sufficient amounts from the diet. Even when fat is used as a source of energy, certain cells such as nervous tissues and erythrocytes (Red blood cells) still need glucose as source of energy.
2. Glucose is needed as a precursor of milk sugar (lactose) for lactating mammary gland

Gluconeogenic mechanisms are required in the clearance of the products of metabolism of other tissues from the blood such as the clearance of lactic acid produced by muscles and erythrocytes; and the clearance of glycerol which is continuously produced by adipose tissue by lipolysis of triacyl glycerol.