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Glycolysis and gluconeogenesis

Last updated: May 25, 2021

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Glycolysis is the metabolic process by which glucose is broken down, while gluconeogenesis is the metabolic process by which glucose is synthesized. In glycolysis, the breakdown of glucose molecules generates two net adenosine triphosphate (ATP) molecules, which provide a readily available source of energy for various reactions in the cell, and two pyruvate molecules, which can be further converted into lactate (used in gluconeogenesis), acetyl-CoA (used in citric acid cycle), oxaloacetate (used in citric acid cycle), and alanine (used in transamination reactions). Glycolysis, which occurs exclusively in the cytoplasm, is the sole source of ATP in cells that lack mitochondria (e.g., RBCs). In gluconeogenesis, a process that ensures euglycemia during fasting, glucose is synthesized from noncarbohydrate precursors such as glucogenic amino acids (mainly alanine and glutamine), odd-chain fatty acids, glycerol, pyruvate, and lactate. While the glycolytic pathway occurs in all cells, gluconeogenesis occurs almost exclusively in the liver. Phosphofructokinase-1 is the rate-limiting enzyme for glycolysis, while fructose 1,6-bisphosphatase is the rate-limiting enzyme for gluconeogenesis. The metabolism of glucose is mainly controlled by hormones such as insulin, which stimulates glycolysis, and glucagon, which stimulates gluconeogenesis. Glucose can also be shunted to the pentose phosphate pathway (also known as the hexose monophosphate shunt), which is a metabolic pathway that generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribose 5-phosphate from glucose 6-phosphate. The pentose phosphate pathway occurs exclusively in the cytosol and is highly active in the adrenal cortex, liver, and RBCs. Ribose 5-phosphate is required for nucleotide synthesis, while NADPH is required for cholesterol synthesis, steroid synthesis, reduction of glutathione, and respiratory burst. Hemolytic anemia is caused by glucose-6-phosphate dehydrogenase deficiency, which results in insufficient production of NADPH. NADPH is required for the reduction of glutathione, an antioxidant preventing excess hydrogen peroxide and free radicals from damaging RBC membranes.

  • Glucose breakdown and synthesis are essential processes in the human body.
  • Glucose provides the required substrates for aerobic and anaerobic metabolism. Glycolysis is the main route of metabolism for most carbohydrates (e.g., galactose and fructose).
  • RBCs, which lack mitochondria, depend entirely on glucose to function normally.
  • The metabolism of glucose is primarily controlled by hormones such as insulin and glucagon. Insulin is released in the postprandial state for anabolic metabolism, in which glucose is broken down to be transformed into storage forms (glycogen and fat).
  • Conversely, glucagon predominates in the fasting state for catabolic metabolism, in which stored products (e.g., fats, glycogen, and amino acids) are broken down into glucose to be used as an energy source.
Comparison of glycolysis and gluconeogenesis
Glycolysis Gluconeogenesis
Location

Rate limiting enzyme

Stimulation
Inhibition
Occurrence

Gluconeogenesis is more than just the reversal of glycolysis. The reactions of the key enzymes of glycolysis are irreversible due to thermodynamics and must, therefore, be reversed by different enzymes that are only active in gluconeogenesis.

Pyruvate kinase deficiency in erythrocytes causes chronic hemolytic anemia due to impaired glycolysis and a lack of ATP in the RBCs.

Glucose is composed of a 6-carbon skeleton (C6H12O6). Each glucose molecule produces 2 pyruvate molecules, which are composed of a 3-carbon skeleton.

  1. Glucose → glucose 6-phosphate (G6P)
  2. G6P fructose 6-phosphate (F6P) via G6P isomerase
  3. F6P fructose 1,6-bisphosphate
  4. 2 fructose 1,6-bisphosphate → 2 glyceraldehyde 3-phosphate (GAP) via aldolase
  5. 2 GAP → 2 1,3-biphosphoglycerate (1,3-BPG)
  6. 2 1,3-BPG → 2 3-phosphoglycerate
    • Via enzyme: phosphoglycerate kinase
    • Produces 2 ATP
  7. 2 3-phosphoglycerate → 2 2-phosphoglycerate via phosphoglycerate mutase
  8. 2 2-phosphoglycerate → 2 phosphoenolpyruvate (PEP) via enolase
  9. 2 PEP → 2 pyruvate

The net reaction for glycolysis: glucose + 2 Pi + 2 ADP + 2 NAD+ 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

In glycolysis, 2 ATP are invested to gain 4 ATP. In total, there is a net gain of 2 ATP per 1 molecule of glucose.

Regulation of glycolysis enzymes
Enzyme Hexokinase Glucokinase (hexokinase IV) Phosphofructokinase-1 (PFK-1) Pyruvate kinase
Reaction
  • Converts glucose to G6P
  • All tissues, except liver and β-cells of the pancreas
  • Low Km (i.e., ↑ affinity compared to glucokinase) → sequestration of glucose in tissues even when blood glucose levels are low
  • Low Vmax (i.e., ↓ capacity)
  • Converts glucose to G6P
  • Liver and β-cells of the pancreas
  • High Km (i.e., ↓ affinity compared to hexokinase) → sequestration of glucose in the liver only when blood glucose levels are high
  • High Vmax (i.e., ↑ capacity)
Stimulation
  • -
Inhibition
  • G6P (feedback inhibition)


Phosphofructokinase-1 is the rate-limiting enzyme in glycolysis.

Fructose 2,6-bisphosphate (feed-forward regulation)

The activity of FBPase is increased during fasting: Fasting Boosts its Power.
The activity of PFK is increased after eating: PFK Prefers a Full stomaK.

Pyruvate characteristics

LDH is found in almost every cell of the body. Elevated LDH levels without exercise may indicate cell injury due to cancer (e.g., germ cell tumors), hemolytic anemia, myocardial infarction, infection, kidney, or liver disease.

Pyruvate dehydrogenase complex

Products of pyruvate metabolism

Overview of the products of pyruvate metabolism
Product Reaction Location Function Regulation
Lactate
Acetyl-CoA
Oxaloacetate
Alanine

Tender Loving Care For Nancy: Thiamine, Lipoic acid, CoA, FAD, and NAD+ are the five cofactors of the pyruvate dehydrogenase complex.

Arsenic inhibits lipoic acid, which prevents the production of acetyl-CoA and inhibits the TCA cycle.

Pyruvate dehydrogenase complex deficiency results in impaired conversion of pyruvate to acetyl-CoA, reduced production of citrate, and, therefore, impairment of the TCA cycle, leading to severe energy deficits (especially in the CNS). Long-term treatment includes a ketogenic diet (high fat, low carbohydrate, glucogenic amino acids, e.g., valine) and cofactor supplementation with thiamine and lipoic acid.

Overview

Primary substrates

All amino acids, except for leucine and lysine, can be used as substrates for gluconeogenesis.

Gluconeogenesis reactions and regulation

Enzyme 1. Pyruvate carboxylase 2. Phosphoenolpyruvate carboxykinase 3. Fructose 1,6-bisphosphatase 4. Glucose 6-phosphatase
Reaction
  • Converts G6P to glucose
Location
Stimulated by
  • G6P (feed-forward regulation)
Inhibited by

Overview

In the pentose phosphate pathway, no ATP is produced or used up.

G6PD deficiency is the most common human enzyme deficiency. It results in insufficient NADPH production, which is required for reduction of the antioxidant glutathione to prevent excess hydrogen peroxide and free radicals from damaging RBC membranes (and causing hemolytic anemia).

Sequence of reactions (2 phases)

Oxidative phase (irreversible)

Net reaction in 3 steps: G6P + 2 NADP+ + H2O → ribulose 5-phosphate + 2 NADPH + 2 H+ + CO2

  1. G6P 6-phosphogluconolactone
  2. 6-phosphogluconolactone6-phosphogluconate
    • Enzyme: 6-phosphogluconolactonase
    • Requires 1 H2O
  3. 6-phosphogluconate → ribulose 5-phosphate

Nonoxidative phase (reversible)

Net reaction: 3 ribulose 5-phosphateribose 5-phosphate + 2 xylulose 5-phosphate2 fructose 6-phosphate + glyceraldehyde 3-phosphate

  1. van Schaftingen E, Gerin I. The glucose-6-phosphatase system. Biochem J. 2002; 362 (Pt 3): p.513-32.
  2. Anemaet IG, González JD, Salgado MC, et al. Transactivation of cytosolic alanine aminotransferase gene promoter by p300 and c-Myb. J Mol Endocrinol. 2010; 45 (3): p.119-132. doi: 10.1677/jme-10-0022 . | Open in Read by QxMD