Gluconeogenesis

Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis and glycogenolysis are the 2 major ways the body produces glucose. Key enzymes for gluconeogenesis are pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Thus, gluconeogenesis becomes the main source of glycemic maintenance after glycogen stores are depleted.

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Reactions of Gluconeogenesis

Gluconeogenesis precursors include lactate, glycerol, alanine, and glutamine. This process occurs in multiple locations, beginning in the mitochondria but finishing with the shuttling of glucose into the cytoplasm via glucose transporters.

Gluconeogenesis is the opposite of glycolysis. There are 11 enzymes, or steps, required for the complete process of gluconeogenesis.

There are 3 irreversible steps that need to happen in gluconeogenesis. These steps are catalyzed by:

  • Glucose-6-phosphatase
  • Fructose-1,6-bisphosphatase
  • Phosphoenolpyruvate carboxykinase

11 steps:

  • Steps 1 and 2: pyruvate to phosphoenolpyruvate
    • Pyruvate is carboxylated to oxaloacetate via pyruvate carboxylase; this step must occur in the mitochondria.
    • The 1st step requires 1 molecule of ATP.
    • Pyruvate carboxylase is stimulated by high amounts of acetyl-CoA and inhibited by ADP and glucose.
    • Oxaloacetate is decarboxylated and phosphorylated to phosphoenolpyruvate via phosphoenolpyruvate carboxykinase (PEPCK).
    • PEPCK requires 1 molecule of guanosine triphosphate (GTP).
  • Steps 3–8: phosphoenolpyruvate to fructose-1,6-bisphosphate
    • These steps are identical, though in reverse, to the reactions that occur in glycolysis.
  • Step 9: dephosphorylation of fructose-1,6-bisphosphate to fructose-6-phosphate
    • The enzyme fructose-1,6-bisphosphatase to form fructose-6-phosphate
    • Consumes 1 molecule of water
    • Fructose-1,6-bisphosphatase is the rate-limiting step of gluconeogenesis.
  • Step 10: fructose-6-phosphate to glucose-6-phosphate via phosphoglucoisomerase
  • Step 11: glucose-6-phosphate to glucose
    • Consumes 1 molecule of water
    • Glucose-6-phosphatase is the enzyme that carries out this reaction.
    • Releases 1 inorganic phosphate
    • This step occurs in the lumen of the endoplasmic reticulum.
Gluconeogenesis Glycolysis

Gluconeogenesis as the reverse of glycolysis:
Note the key enzymes that are unique to gluconeogenesis: PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase.

Image by Lecturio. License: CC BY-NC-SA 4.0

Location of Gluconeogenesis

Gluconeogenesis occurs in organs that have high energy requirements. 

  • Gluconeogenesis happens in the human liver, kidney, muscle, and intestinal mucosa.
  • Within a cell, mitochondria convert pyruvate into oxaloacetate.
  • Oxaloacetate can convert to phosphoenolpyruvate in the mitochondria or cytoplasm.
    • If conversion occurs in the mitochondria, transport proteins carry phosphoenolpyruvate into the cytoplasm.
    • If conversion occurs in the cytoplasm, oxaloacetate must first be converted into malate for transit into the cytoplasm.
  • The cytosol houses the enzymes that convert phosphoenolpyruvate into glucose-6-phosphate.
Location of gluconeogenesis - oxaloacetate being converted into malate

Oxaloacetate must be converted into malate before transit from the mitochondrion into the cytoplasm.

Image: “First rate limiting step of gluconeogenesis” by Mertmetin96. License: CC BY-SA 4.0 cropped by Lecturio.

Stimulation and Inhibition

There are several points of regulation for gluconeogenesis.

  • 3 enzymes are key regulatory points:
    • Glucose-6-phosphatase
    • Fructose-1,6-bisphosphatase
    • PEPCK
  • Activating substrates:
    • Acetyl-CoA
    • ATP
    • Citrate
    • Glucagon: promotes phosphorylation of enzymes via protein kinase A (PKA)
  • Inhibition:
    • Insulin 
    • Metformin
  • Phosphofructokinase 2 synthesizes fructose-2,6-bisphosphate, which inhibits gluconeogenesis and promotes glycolysis. Low cAMP levels promote phosphofructokinase 2 activity.
  • In general, activators and inhibitors of gluconeogenesis serve the opposite role in the regulation of glycolysis.

Clinical Relevance

  • Galactosemia: defective metabolism of the sugar galactose. Clinical manifestations begin when milk feeding is started. Infants develop lethargy, jaundice, progressive liver dysfunction, kidney disease, cataracts, weight loss, and susceptibility to bacterial infections (especially E coli). Intellectual disability may develop if the disorder is left untreated. The mainstay of management is exclusion of galactose from the diet.
  • Hereditary fructose intolerance: deficiency of fructose-1-phosphate aldolase. Symptoms begin after ingestion of fructose (fruit sugar) or sucrose so presents later in life. Presents with failure to gain weight, vomiting, hypoglycemia, liver dysfunction, and kidney defects. Children with the disorder do very well if they avoid dietary fructose and sucrose.
  • Fructose 1,6-diphosphatase deficiency: associated with impaired gluconeogenesis. Symptoms include hypoglycemia, intolerance to fasting, and hepatomegaly. Emergent treatment of hypoglycemic episodes with glucose rich IV fluids and avoidance of fasting are the mainstays of therapy. Severe cases may require glucose supplementation to avoid hypoglycemia.
  • Glycogen storage diseases: deficiency of enzymes responsible for glycogen degradation. Depending upon which enzyme is affected, these conditions may affect the liver, muscles, or both. There are several clinically significant glycogen storage diseases with differing presentations. 
  • Glucose 6-Phosphate dehydrogenase deficiency (G6PD): a genetic disorder that occurs almost exclusively in males and mainly affects red blood cells, causing hemolysis and hemolytic anemia. Symptoms include dyspnea, fatigue, tachycardia, dark urine, palor, and jaundice. Hemolytic anemia may be triggered by infections, certain drugs (antibiotics,  antimalarials), and after eating fava beans.

References

  1. Miyamoto, T, & Amrein, H. (2017). Gluconeogenesis: An ancient biochemical pathway with a new twist, Fly, 11:3, 218–223. https://pubmed.ncbi.nlm.nih.gov/28121487/
  2. Exton, JH. (1972). Gluconeogenesis. 21(10):945–990. https://doi.org/10.1016/0026-0495(72)90028-5.
  3. Chourpiliadis, C, Mohiuddin, SS. (2020). Biochemistry, gluconeogenesis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK544346/

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