Definition and Function
Definition
The pentose phosphate pathway generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate through a series of reactions and occurs parallel to glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis.
Location
The pentose phosphate pathway occurs in the cytoplasm of cells.
Function
The pentose phosphate pathway generates intermediates that are utilized for multiple purposes:
- NADPH:
- Glutathione reduction (prevents oxidative damage)
- Fatty acid and cholesterol biosynthesis
- Ribose-5-phosphate: an important precursor for nucleotide biosynthesis
- Erythrose-4-phosphate: used for aromatic amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism
- Other metabolites may be used for:
- Glycolysis
- 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
Pentose phosphate pathway intermediates:
Image by Lecturio.
Glucose-6-phosphate (G-6-P), fructose-6-phosphate (F-6-P), and glyceraldehyde-3-phosphate (GLYAL-3-P) are intermediates from glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis. Ribose-5-phosphate (R-5-P) is used in the synthesis of nucleotides, whereas erythrose-4-phosphate (E-4-P) is used in the synthesis of aromatic amino acids. The bottom row depicts sugars that are either rarely, or never, found outside the pentose phosphate pathway.
The pentose phosphate pathway acts as a junction point for numerous pathways.
Image by Lecturio.
Image showing the multiple entrance and exit points for metabolites, including nucleotide synthesis, aromatic amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids synthesis, glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis, and gluconeogenesis
NADPH: nicotinamide adenine dinucleotide phosphate
P: phosphate
G: glucose
PG: phosphogluconate
L: lactone
Ru: ribulose
R: ribose
Xu: xylulose
S: sedoheptulose
GLYAL: glyceraldehyde
Oxidative and Nonoxidative Phases
There are 2 major phases that comprise the pentose phosphate pathway:
- Oxidative phase (irreversible)
- Nonoxidative phase (reversible)
Oxidative phase
The oxidative phase is an irreversible, 3-step process.
Initial molecules:
- Glucose-6-phosphate
- 2 NADP+
- H2O
Reactions:
- Dehydrogenation at the C1 atom of glucose-6-phosphate → 6-phosphogluconolactone
- Catalyzed by glucose-6-phosphate dehydrogenase (G6PD)
- Rate-limiting step
- NADP+ is reduced → NADPH
- 6-Phosphogluconolactonase hydrolyzes 6-phosphogluconolactone → 6-phosphogluconate
- Oxidative decarboxylation of 6-phosphogluconate by 6-phosphogluconate dehydrogenase → ribulose-5-phosphate:
- NADP+ is reduced → NADPH
- CO2 is produced.
Products:
- 2 NADPH
- 1 CO2
- Ribulose-5-phosphate
The oxidative phase converts glucose-6-phosphate (1) into ribulose-5-phosphate (4), forming 2 molecules of NADPH in the process.
NADPH: nicotinamide adenine dinucleotide phosphate
Nonoxidative phase
The nonoxidative phase is reversible, utilizing isomerases to form sugar intermediates that are used in glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis and nucleotide biosynthesis.
- Ribulose-5-phosphate ⇆ either:
- Xylulose-5-phosphate (by ribulose-5-phosphate epimerase) or
- Ribose-5-phosphate (by ribose-5-phosphate isomerase)
- Xylulose-5-phosphate + ribose-5-phosphate ⇆ glyceraldehyde-3-phosphate + sedoheptulose-7-phosphate
- Catalyzed by transketolase
- The reaction requires thiamine pyrophosphate.
- Transaldolase transfers an aldehyde group from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate ⇆ erythrose-4-phosphate + fructose-6-phosphate
- Additionally, the following reaction occurs: erythrose-4-phosphate + xylulose-5-phosphate ⇆ fructose-6-phosphate + glyceraldehyde-3-phosphate
- Catalyzed by transketolase
- The reaction requires thiamine pyrophosphate.
- Creates intermediates for glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis and gluconeogenesis
Rearrangement within the nonoxidative phase of the pentose phosphate pathway:
Image by Lecturio.
Transketolase transfers 2 carbons from xylulose-5-phosphate (Xu-5-P) to ribose-5-phosphate (R-5-P) to yield sedoheptulose-7-phosphate (S-7-P) and glyceraldehyde-3-phosphate (GLYCAL-3-P).
Rearrangement within the nonoxidative phase of the pentose phosphate pathway:
Image by Lecturio.
Transaldolase transfers a carbon from sedoheptulose-7-phosphate (S-7-P) to glyceraldehyde-3-phosphate (GLYCAL-3-P) to yield erythrose-4-phosphate (E-4-P) and fructose-6-phopshate (F-6-P).
Rearrangement within the nonoxidative phase of the pentose phosphate pathway:
Image by Lecturio.
Transketolase transfers 2 carbons from xylulose-5-phosphate (Xu-5-P) to erythrose-4-phosphate (E-4-P) to yield fructose-6-phosphate (F-6-P) and glyceraldehyde-3-phosphate (GLYAL-3-P).
Pentose Phosphate Pathway Regulation
- The key regulatory step of the pentose phosphate pathway is the rate-limiting reaction catalyzed by G6PD:
- Stimulated by:
- NADP+
- Glucose-6-phosphate
- Inhibited by:
- NADPH (key negative feedback mechanism)
- Acetyl coenzyme A (CoA)
- Stimulated by:
- However, note that alternative movements through the pathway are possible due to:
- Multiple entry and exit points
- Multiple possible intermediates
- Reversible reactions (particularly in the nonoxidative phase)
Clinical Relevance
- G6PD deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency: a type of intravascular 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 inherited in an X-linked recessive manner. A deficiency in G6PD results in an insufficient amount of NADPH, without which glutathione cannot be reduced in RBCs. Red blood cells are not protected from oxidative stressors, resulting in damage and hemolysis.
- Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria: an infectious parasitic disease caused by the Plasmodium genus. A deficiency in G6PD can potentially protect individuals from malaria (parasites require NADPH).
- Transaldolase deficiency: an extremely rare congenital condition that affects metabolism and can lead to hydrops fetalis, 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, congenital heart disease, and dysmorphic facial features. Genetic testing confirms the diagnosis. There is no treatment; however, 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 transplantation may benefit some individuals.
- Glycolysis: a central metabolic pathway that is 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-6-phosphate, fructose-6-phosphate, and glyceraldehyde-3-phosphate are utilized in both glycolysis 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) and is imported into cells by specific transport proteins. Glycolysis and the pentose phosphate pathway.
References
- Jin, L., Zhou, Y. (2019). Crucial role of pentose phosphate pathway in malignant tumors. Onc Letters. 4213-4221. https://www.spandidos-publications.com/10.3892/ol.2019.10112
- Berg, J.M., Tymoczko, J.L., Stryer, L. (2002). 20.3 The Pentose Phosphate Pathway Generates NADPH and Synthesizes Five-Carbon Sugars. In Biochemistry. 5th edition. New York: W H Freeman. https://www.ncbi.nlm.nih.gov/books/NBK22416/
- Patra, K.C., Hay, N. (2014). The pentose phosphate pathway and cancer. Trends in Biochemical Sciences. 39, 347-354. https://doi.org/10.1016/j.tibs.2014.06.005
