Glycolysis

Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors ( gluconeogenesis 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 is imported into cells by specific transport proteins. Glycolysis occurs in the cytoplasm and consists of 10 reactions, the net result of which is the conversion of 1 C6 glucose to 2 C3 pyruvate molecules. The free energy of this process is harvested to produce adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide hydride (NADH), key energy-yielding metabolites. The overall stoichiometry of the pathway is: glucose + 2 Pi + 2 ADP + 2 NAD+ > 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O (H+: hydrogen ion, Pi: phosphate ion, NAD+: nicotinamide adenine dinucleotide).

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Steps 1–5: 1st Half of Glycolysis

The 1st half of glycolysis requires an energy investment of 2 adenosine triphosphate (ATP) molecules and serves to convert the hexose glucose into 2 trioses. The process consists of 5 steps:

  1. Glucose → glucose 6-phosphate (G6P)
    • Hexokinase (HK) transfers a phosphoryl group from ATP onto the 6th carbon of glucose to form G6P.
      • Requires magnesium (Mg2+) as a cofactor 
      • Requires ATP
    • In the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, this step is catalyzed by glucokinase (an enzyme with the same function but lower glucose affinity), helping the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver serve as a blood glucose “buffer.”
  2. G6P → fructose-6-phosphate (F6P)
    • Phosphoglucose isomerase (PGI) converts G6P to F6P.
    • Isomerizes the aldose glucose to a ketose fructose
  3. F6P → fructose-1,6-biphosphate (FBP)
    • Phosphofructokinase (PFK-1) phosphorylates F6P on C1, yielding FBP.
    • Requires Mg2+ as a cofactor
    • Requires ATP
    • This is a rate-determining reaction in glycolysis, therefore a regulated step
  4. FBP → glyceraldehyde 3-phosphate (GAP) + dihydroxyacetone phosphate (DHAP)
    • Aldolase cleaves the 6-carbon FBP into 2 different 3-carbon molecules, GAP and DHAP. 
    • The reaction is an aldol cleavage with an enolate intermediate stabilized by resonance.
  5. DHAP → GAP
    • Triose-phosphate isomerase (TIM) interconverts DHAP and GAP to allow DHAP to proceed through glycolysis. 
First half of glycolysis

The first 5 steps (first half) of the glycolysis pathway

Image by Lecturio.

Steps 6–10: 2nd Half of Glycolysis

The 2nd half of glycolysis converts the triose GAP to pyruvate, with the concomitant generation of 4 ATP and 2 nicotinamide adenine dinucleotide hydride (NADH) per 2 GAP. Thus, the energy investment of steps 1–5 is paid back twice here. In certain cell types and conditions, these 5 steps are the predominant source of ATP: 

  1. GAP → 1,3-bisphosphoglycerate (1,3-BPG)
    • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the phosphorylation and oxidation of GAP, yielding 1,3-biphosphoglycerate (1,3-BPG). 
    • 1,3-BPG is the 1st high-energy intermediate in glycolysis.
    • Produces 2 NADH from nicotinamide adenine dinucleotide (NAD+) and a phosphate ion (Pi)
      • Under aerobic conditions, oxidation of NADH at the respiratory chain regenerates NAD+ and produces additional ATP.
      • Under anaerobic conditions, additional reactions are required to regenerate NAD+.
  2. 1,3-BPG → 3-phosphoglycerate
    • Phosphoglycerate kinase (PGK) converts 1,3-BPG to 3-phosphoglycerate (3PG). 
    • Requires Mg2+ as a cofactor
    • Produces ATP
    • The GAPDH and PGK reactions are coupled to allow the energetically unfavorable GAPDH reaction to be “pulled forward” by the highly favorable PGK reaction.
  3. 3PG → 2-phosphoglycerate
    • Phosphoglycerate mutase (PGM) converts 3PG to 2-phosphoglycerate (2PG) by transferring the functional group phosphate from C3 to C2.
    • Generates a 2,3-bisphosphoglycerate (2,3-BPG)–enzyme complex
  4. 2PG → phosphoenolpyruvate (PEP)
    • Enolase dehydrates 2PG to phosphoenolpyruvate (PEP). 
    • PEP is the 2nd high-energy intermediate formed in glycolysis.
  5. PEP → pyruvate
    • Pyruvate kinase (PK) converts PEP to pyruvate (Pyr), releasing a large amount of energy, which is used to drive the synthesis of ATP.
    • Produces ATP

Net reaction: glucose + 2 Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

Second half of glycolysis

The last 5 steps (last half) of the glycolysis pathway.

Image by Lecturio.

Regulation of Glycolysis

  • Glycolysis operates continuously in most tissues, with a varying rate according to the needs of the cell.
  • Factors that induce glycolysis repress gluconeogenesis 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 (the reverse of glycolysis) and vice versa because gluconeogenesis 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 is reciprocally regulated. 
  • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin and glucagon are the main hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview that control the fluxes of glycolysis and gluconeogenesis 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.
  • Optimal pathway regulation is achieved by controlling reactions with a large negative free energy change, of which there are 3 in glycolysis.
Regulation of glycolysis

An overview of the regulation of glycolysis. Activators of hexokinase (HK), phosphofructokinase-1 (PFK-1), or pyruvate kinase (PK) are marked in green. Metabolites that inhibit these enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are marked in red.

Image by Lecturio.

Hexokinase (HK)

  • Regulates step 1 of the pathway
  • Negatively regulated by excess G6P
  • Not relevant when glucose is derived from glycogen, as glucose is released from glycogen as G6P

Phosphofructokinase

  • PFK-1 is the primary flux control point for glycolysis; regulates step 3
  • FBPase catalyzes the reverse step to PFK-1 in gluconeogenesis 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 the 2 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are reciprocally regulated.
    • When PFK-1 is inhibited and FBPase is activated, flux is shifted from glycolysis to gluconeogenesis 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.
  • PFK-1 is allosterically inhibited by ATP, an indicator of energy abundance.
  • PFK-1 is allosterically activated by adenosine monophosphate (AMP) and adenosine diphosphate (ADP), indicators of energy scarcity.
  • PFK-1 is allosterically inhibited by citrate.
  • PFK-1 is potently allosterically activated by fructose-2,6-bisphosphate (F2,6P).
    • F2,6P has the opposite effect on the opposing step in gluconeogenesis 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.
    • F2,6P is synthesized and degraded by a bifunctional enzyme called PFK-2/FBPase-2, whose activity is controlled by many allosteric effectors and hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview.
    • F6P promotes F2,6P synthesis, activating glycolysis.
    • In the fed state: insulin stimulates PFK-2/FBPase-2 dephosphorylation → increasing F2,6P levels → increasing glycolytic flux
  • Catecholamines (via cyclic AMP) inhibit glycolytic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes HK, PFK-1, PFK-2 (which produces fructose 2,6 bisphosphate), and PK. 
    • Inducing synthesis of pyruvate carboxylase, PEP carboxykinase, FBPase, and G6Pase

Pyruvate kinase (PK)

  • Regulates step 10 (last) of the pathway
  • Allosterically activated by FBP, indicating accumulation of upstream glycolytic intermediates: results in “pulling” through the glycolytic pathway
  • Allosterically inhibited by ATP, indicating plentiful energy supply
  • In the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, allosterically inhibited by alanine, a precursor for gluconeogenesis 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

Clinical Relevance

  • Galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia: defective metabolism of the sugar galactose. Clinical manifestations begin when milk feeding is started. Infants develop lethargy, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, progressive liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 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. Symptoms include hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, intolerance to fasting, and hepatomegaly. Emergent treatment of hypoglycemic episodes with glucose rich IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids and avoidance of fasting are the mainstays of therapy. Severe cases may require glucose supplementation to avoid hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia.
  • Glycogen storage diseases: deficiency of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes responsible for glycogen degradation. Depending upon which enzyme is affected, these conditions may affect the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. Symptoms include dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fatigue, tachycardia, dark urine, palor, and jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice. Hemolytic anemia may be triggered by infections, certain drugs (antibiotics,  antimalarials), and after eating fava beans.

The following are enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of the glycolysis pathway that may be involved in congenital enzymatic defects:

  • Pyruvate kinase deficiency (most common)
  • Erythrocyte hexokinase
  • Glucose phosphate isomerase
  • Phosphofructokinase

These congenital enzymatic defects produce hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia.

Hemolytic anemia: a group of anemias that are due to destruction or premature clearance of RBCs. Intrinsic abnormalities of the RBC lead to splenic clearance (extravascular hemolysis). The chronic destruction of RBCs can present as jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, cholelithiasis Cholelithiasis Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis, hematuria, and symptoms of anemia (shortness of breath, fatigue, syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, and tachycardia).

References

  1. Voet D., Voet J. G., Pratt C. W. (2016) Voet’s Principles of Biochemistry Global Edition.
  2. Allen, G. K. (2020). First Aid for the USMLE Step 1.

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