Pentose Phosphate Pathway

Definition and Function

Definition

The pentose phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway generates nicotinamide adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids dinucleotide phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (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 Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway occurs in the cytoplasm of cells.

Function

The pentose phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway generates intermediates that are utilized for multiple purposes:

• NADPH:
  • Glutathione reduction (prevents oxidative damage)
  • Fatty acid and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology
• Ribose-5-phosphate: an important precursor for nucleotide biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology
• 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 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
  • 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

Oxidative and Nonoxidative Phases

There are 2 major phases that comprise the pentose phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway:

• Oxidative phase (irreversible)
• Nonoxidative phase (reversible)

Oxidative phase

The oxidative phase is an irreversible, 3-step process.

Initial molecules:

• Glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis
• 2 NADP⁺
• H₂O

Reactions:

1. Dehydrogenation at the C1 atom of glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis → 6-phosphogluconolactone
   • Catalyzed by glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis dehydrogenase (G6PD)
   • Rate-limiting step
   • NADP⁺ is reduced → NADPH
2. 6-Phosphogluconolactonase hydrolyzes 6-phosphogluconolactone → 6-phosphogluconate
3. Oxidative decarboxylation Decarboxylation The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. Catabolism of Amino Acids 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

Nonoxidative phase

The nonoxidative phase is reversible, utilizing isomerases Isomerases A class of enzymes that catalyze geometric or structural changes within a molecule to form a single product. The reactions do not involve a net change in the concentrations of compounds other than the substrate and the product. Basics of Enzymes 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 Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology.

1. Ribulose-5-phosphate ⇆ either:
   • Xylulose-5-phosphate (by ribulose-5-phosphate epimerase) or
   • Ribose-5-phosphate (by ribose-5-phosphate isomerase)
2. Xylulose-5-phosphate + ribose-5-phosphate ⇆ glyceraldehyde-3-phosphate + sedoheptulose-7-phosphate
   • Catalyzed by transketolase
   • The reaction requires thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies pyrophosphate.
3. Transaldolase transfers an aldehyde group from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate ⇆ erythrose-4-phosphate + fructose-6-phosphate Fructose-6-phosphate Glycolysis
4. Additionally, the following reaction occurs: erythrose-4-phosphate + xylulose-5-phosphate ⇆ fructose-6-phosphate Fructose-6-phosphate Glycolysis + glyceraldehyde-3-phosphate
   • Catalyzed by transketolase
   • The reaction requires thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies 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 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 Regulation

• The key regulatory step of the pentose phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway is the rate-limiting reaction catalyzed by G6PD:
  • Stimulated by:
    • NADP⁺
    • Glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis
  • Inhibited by:
    • NADPH (key negative feedback Negative feedback Hypothalamic and Pituitary Hormones mechanism)
    • Acetyl coenzyme A (CoA)
• 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 X-Linked Recessive Duchenne Muscular Dystrophy manner. A deficiency in G6PD results in an insufficient amount of NADPH, without which glutathione cannot be reduced in RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology. Red blood cells Red blood cells Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology 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. Plasmodium/Malaria: an infectious parasitic disease caused by the Plasmodium Plasmodium A genus of protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are plasmodium falciparum; plasmodium malariae; plasmodium ovale, and plasmodium vivax. Species causing infection in vertebrates other than man include: plasmodium berghei; plasmodium chabaudi; p. Vinckei, and plasmodium yoelii in rodents; p. Brasilianum, plasmodium cynomolgi; and plasmodium knowlesi in monkeys; and plasmodium gallinaceum in chickens. Antimalarial Drugs genus. A deficiency in G6PD can potentially protect individuals from 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. Plasmodium/Malaria (parasites require NADPH).
• Transaldolase deficiency: an extremely rare congenital condition that affects metabolism and can lead to hydrops Hydrops Cholecystitis 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: Anatomy dysfunction, congenital heart disease, and dysmorphic facial features. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. There is no treatment; however, liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases may benefit some individuals.
• 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: a central metabolic pathway that is responsible for the breakdown of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance and plays a vital role in generating free energy Free energy Enzyme Kinetics for the cell and metabolites for further oxidative degradation. Glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis, fructose-6-phosphate Fructose-6-phosphate Glycolysis, 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 Phosphate Inorganic salts of phosphoric acid. Electrolytes pathway.