CHAPTER 31: CARBOHYDRATE METABOLISM IN ERYTHROCYTES
Chapter 31: Carbohydrate Metabolism in Erythrocytes
The entry rate of glucose into red blood cells (RBCs) is normally greater than expected from simple diffusion. It is an example of facilitated diffusion, with the membrane transporter protein involved called a glucose transporter (GLUT), specifically GLUT 1. Other GLUT 1 transporters are found in the placenta, kidneys, intestine, and blood-brain-barrier, and all are insulin-independent.
The process of glucose entry into erythrocytes is of major importance for their survival. Although reticulocytes (i.e., developing RBCs) are nucleated with considerable quantities of ribosomal and mitochondrial RNA, mature RBCs of mammals have disposed of their intracellular organelles (i.e., nucleus, mitochondria, lysosomes, endoplasmic reticulum, and Golgi). The absence of these structures allows for membrane deformability, and it also allows more room in the cytoplasm for hemoglobin, the O2 carrier of blood. Since mature mammalian erythrocytes are missing several important intracellular organelles, they cannot synthesize nucleic acids or proteins, nor can they combust fat for energy. They must thus rely on glucose as their sole source of energy.
Birds, herptiles (amphibians and reptiles), and fish, retain a nucleus within their mature red cells; however, it is nonfunctional, and therefore these cells cannot divide. Mammals may have an advantage over these animals since enucleated erythrocytes are thought to be more flexible, and therefore more capable of navigating small capillaries. However, species with nucleated erythrocytes seem to function satisfactorily, despite the presence of these "inferior" structures.
Once glucose enters erythrocytes, it is immediately phosphorylated by hexokinase (HK), an enzyme with a low Km. Since glucose 6-phosphate (Glc-6-P) feeds back negatively on HK, decreased metabolic need will generally limit further phosphorylation. However, since glucose cannot be kept out of erythrocytes during hyperglycemia, glucose molecules may still saturate the cell. Hexokinase is believed to be the key erythrocytic enzyme whose activity fades with age. A natural result of HK senility is loss of erythrocytic capacity to utilize glucose. Next, the Na+ /K+ - and Ca++-ATPase pumps expire; then, the cytoskeleton becomes rigid and, thus, RBCs get stuck in narrow vessels (especially the spleen and liver), and are phagocytosed by reticuloendothelial (RE) cells. Other age-related changes occur in the composition of glycoproteins and glycolipids, which attract senile RBCs to lectins on membranes of RE cells.
As previously discussed, the hexose monophosphate shunt (HMS) of the mature erythrocyte produces NADPH and ribose 5-phosphate from Glc-6-P. Erythrocytes are quite dependent upon NADPH for glutathione reduction, and the ribose 5-P is utilized in nucleotide salvage (see below). Although glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency has not been clearly demonstrated in animals, several million humans demonstrate this hereditary trait, and therefore are susceptible to hemolysis, lipid peroxidation, and other oxidative stresses that may be produced by drugs (such as sulfonamides, primaquine, components of fava beans, or other oxidizing agents).
Approximately 90% of glucose is oxidized anaerobically in RBCs via the Embden Meyerhoff pathway (EMP), and the end products of metabolism (i.e., pyruvate and lactate) diffuse into plasma. Lesser amounts of Glc-6-P may pass through the HMS when needed. A second shunt, the 2,3-bisphosphoglycerate (2,3-BPG) or Rapoport-Luebering shunt, is present in the main glycolytic pathway at the step of processing 1,3-bisphosphoglycerate (1,3-BPG). Formation of 2,3-BPG (or 2,3-diphosphoglycerate (2,3-DPG)) by a mutase enzyme competes with the formation of 3-phosphoglycerate (3-PG) by a kinase, as both enzymes work on the same substrate. Once 2,3-BPG is formed, it re-enters the EMP at the level of 3- PG. Up to 15% of glucose taken up by erythrocytes may pass through this shunt, and since it effectively bypasses the ATP-producing step directly from 1,3-BPG to 3-PG, this may be economical by allowing glycolysis to proceed when the need for ATP is minimal. In primate erythrocytes, 2,3-BPG may account for over 50% of available phosphorus, and it is about equimolar in quantity with Hb. However, in several animal species studied, erythrocytic 2,3-BPG levels are known to vary considerably.
The most important function of 2,3-BPG is to combine with Hb, causing a decrease in its affinity for O2 (and displacement of the oxyhemoglobin dissociation curve to the right). This effectively unloads O2 from Hb, allowing O2 to diffuse into tissues where it is needed. This is important in adaptation to high altitude, and in some species the transport of O2 from maternal to fetal blood (i.e., 2,3-BPG binds more avidly to adult Hb than it does to fetal Hb in most mammals studied, except the horse and pig, where fetal Hb has been found to be indistinguishable from adult Hb). In animals like cattle and cats, that have low erythrocytic 2,3-BPG levels, the chloride anion (Cl–) may be functioning in a similar capacity to that of 2,3-BPG.
Upon moving from sea level to high altitude, many mammalian organisms suffer from acute O2 shortage, and animals begin to hyperventilate. This leads to respiratory alkalosis, which in turn increases 2,3-BPG levels in erythrocytes by activating the mutase enzyme. This increase usually takes about 1 hour to occur, and the half-life of 2,3-BPG is about 6 hours. Hormones that increase 2,3-BPG formation, largely through increased erythropoiesis, include thyroxine, growth hormone, testosterone, and erythropoietin.
Hemolytic anemias in animals are known to result from genetically determined deficiencies in one or more of the glycolytic enzymes (e.g., pyruvate kinase (PK) or phosphofructokinase (PFK)). Since pyruvate kinase is "down-stream" from 2,3-BPG in the EMP, a deficiency in this enzyme would be expected to result in a net increase in erythrocytic 2,3-BPG levels, whereas PFK deficiency would be expected to have the opposite effect.
The developing RBC contains nucleotides in DNA and RNA. However, those in DNA are lost when the nucleus is extruded, and ribosomal RNA is normally degraded within about 24 hrs of the RBC entering the circulation. The cell, however, can use the resulting purine ribonucleotides from RNA (i.e., adenine and guanine), but pyrimidine ribonucleotides (i.e., cytosine, uracil and thymine) are unwelcome because they compete with ATP and ADP in crucial reactions, and thus interfere with cell function. Erythrocytes must maintain an adequate pool of adenine nucleotides (ATP, ADP, and AMP) to survive. Since the mature erythrocyte cannot synthesize them de novo, they are conserved and replenished through a nucleotide salvage pathway. When blood is preserved for transfusion in an adenosine and/or adenine-containing medium, erythrocytes maintain higher levels of ATP, and therefore have increased viability. A continual supply of ATP is needed to maintain membrane deformability, glucose phosphorylation, glutathione (GSH) biosynthesis, and nucleotide salvage. ATP-requiring cation pumps in the plasma membrane independently extrude Ca++, and extrude Na+ in exchange for K+ (i.e., Na+ /K+ - ATPase). Species differences exist, however, in the relative amounts of Na+ and K+ found in erythrocytes. Although most animals maintain high intracellular concentrations of K+ (and low concentrations of Na+), cats and most dogs possess low concentrations of K+ in their mature erythrocytes, due most likely to ever diminishing ATP supplies. Their reticulocytes, however, contain high concentrations of K+.
The white cells of blood, although normally fewer in number, are concerned with the body's response to injury and infection. Red blood cell metabolism accounts for about 90% of glucose used by blood cells each day, while 10% is normally accounted for by white cell metabolism. It is generally believed that a high rate of glycolysis in white blood cells is associated with their ability to grow and divide rapidly, a property they have in common with cancer cells. The rate of glycolysis in white blood cells is therefore markedly increased when the immune response is activated (e.g., due to infection).
SUMMARY
The entry rate of glucose into red blood cells (RBCs) is facilitated by a glucose transporter called GLUT 1. Mature RBCs lack intracellular organelles and rely on glucose as their sole source of energy. Birds, herptiles, and fish retain a nonfunctional nucleus in their mature RBCs. Glucose entering erythrocytes is immediately phosphorylated by hexokinase (HK). The hexose monophosphate shunt (HMS) produces NADPH and ribose 5-phosphate, which are important for glutathione reduction and nucleotide salvage, respectively. Glucose is primarily oxidized anaerobically via the Embden Meyerhoff pathway (EMP), with a smaller amount passing through the 2,3-bisphosphoglycerate (2,3-BPG) shunt. 2,3-BPG combines with hemoglobin (Hb) to decrease its affinity for oxygen, facilitating oxygen unloading in tissues. Hormones like thyroxine and erythropoietin increase 2,3-BPG formation. Hemolytic anemias can result from deficiencies in glycolytic enzymes. Erythrocytes rely on nucleotide salvage to maintain an adequate pool of adenine nucleotides. ATP is essential for various erythrocyte functions, including membrane deformability and nucleotide salvage. White blood cells have a high rate of glycolysis, especially when the immune response is activated.
OUTLINE
I. Glucose Entry into Erythrocytes
Glucose transporter (GLUT 1) facilitates glucose entry
Importance of glucose entry for erythrocyte survival
Erythrocytes rely on glucose as their sole source of energy
II. Hexokinase and Glucose Metabolism
Hexokinase phosphorylates glucose to glucose 6-phosphate (Glc-6-P)
Glc-6-P negatively regulates hexokinase activity
Decreased metabolic need limits further phosphorylation of glucose
III. Age-related Changes in Erythrocytes
Senility of hexokinase leads to loss of erythrocytic glucose utilization
Na+/K+-ATPase and Ca++-ATPase pumps expire
Changes in glycoproteins and glycolipids attract senile erythrocytes to reticuloendothelial cells
IV. Hexose Monophosphate Shunt (HMS)
HMS produces NADPH and ribose 5-phosphate from Glc-6-P
Erythrocytes depend on NADPH for glutathione reduction
Glc-6-P dehydrogenase deficiency leads to hemolysis and oxidative stress
V. Embden Meyerhoff Pathway (EMP)
90% of glucose is oxidized anaerobically via EMP
End products (pyruvate and lactate) diffuse into plasma
VI. 2,3-Bisphosphoglycerate (2,3-BPG) Shunt
Competes with EMP at the step of 1,3-bisphosphoglycerate (1,3-BPG) processing
Bypasses ATP-producing step, allowing glycolysis to proceed when ATP need is minimal
2,3-BPG combines with hemoglobin, decreasing its affinity for O2
VII. Regulation of 2,3-BPG Levels
Increase in 2,3-BPG occurs in response to hyperventilation and respiratory alkalosis
Hormones like thyroxine, growth hormone, testosterone, and erythropoietin increase 2,3-BPG formation
VIII. Hemolytic Anemias
QUESTIONS
Qcard 1:
Question: What is the process by which glucose enters red blood cells?
Answer: Facilitated diffusion, with the membrane transporter protein called a glucose transporter (GLUT 1).
Qcard 2:
Question: Why do mature mammalian erythrocytes rely on glucose as their sole source of energy?
Answer: They have disposed of their intracellular organelles, so they cannot synthesize nucleic acids or proteins, nor can they combust fat for energy.
Qcard 3:
Question: What is the function of hexokinase in erythrocytes?
Answer: Hexokinase phosphorylates glucose once it enters erythrocytes.
Qcard 4:
Question: What is the role of 2,3-BPG in erythrocytes?
Answer: 2,3-BPG combines with hemoglobin, causing a decrease in its affinity for oxygen and facilitating the unloading of oxygen in tissues.
Qcard 5:
Question: How do erythrocytes maintain an adequate pool of adenine nucleotides?
Answer: Through a nucleotide salvage pathway, as they cannot synthesize them de novo.
Qcard 6:
Question: What is the significance of a high rate of glycolysis in white blood cells?
Answer: It is associated with their ability to grow and divide rapidly, particularly during immune response activation.
Glucose Entry into Erythrocytes
Facilitated diffusion
Glucose transporter (GLUT 1)
Importance for erythrocyte survival
Energy Source for Erythrocytes
Lack of intracellular organelles
Reliance on glucose as the sole source of energy
Nucleated Erythrocytes in Non-Mammalian Species
Retention of nucleus in birds, herptiles, and fish
Functionality and advantages of nucleated erythrocytes
Glucose Metabolism in Erythrocytes
Phosphorylation of glucose by hexokinase (HK)
Age-related changes in HK activity
Role of Na+/K+-ATPase and Ca++-ATPase pumps
Hexose Monophosphate Shunt (HMS)
Production of NADPH and ribose 5-phosphate
Importance of NADPH for glutathione reduction
Glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency
Embden Meyerhoff Pathway (EMP)
Anaerobic oxidation of glucose
End products: pyruvate and lactate
2,3-Bisphosphoglycerate (2,3-BPG) Shunt
Competes with glycolysis at the step of 1,3-BPG
Bypasses ATP-producing step
Functions of 2,3-BPG in O2 transport and adaptation
Factors Affecting 2,3-BPG Levels
Increase in high-altitude adaptation
Hormones that increase 2,3-BPG formation
Hemolytic Anemias and Glycolytic Enzyme Deficiencies
Genetic deficiencies in glycolytic enzymes
Effects on erythrocytic 2,3-BPG levels
Nucleotide Salvage Pathway
Conservation and replenishment of adenine nucleotides
Importance of ATP for erythrocyte function
Species
Read and understand the introduction and importance of glucose entry into erythrocytes.
Focus on the role of glucose transporter (GLUT 1) in facilitated diffusion.
Take notes on the absence of intracellular organelles in mature RBCs and their reliance on glucose as the sole source of energy.
Study the differences between mammalian and non-mammalian erythrocytes in terms of nucleated cells and flexibility.
Review the process of glucose entry into erythrocytes and its immediate phosphorylation by hexokinase (HK).
Understand the feedback inhibition of HK by glucose 6-phosphate (Glc-6-P) and its implications for metabolic need.
Learn about the age-related changes in erythrocytes, including the fading activity of hexokinase and the expiration of Na+/K+- and Ca++-ATPase pumps.
Dive into the hexose monophosphate shunt (HMS) and its role in producing NADPH and ribose 5-phosphate from Glc-6-P.
Understand the importance of NADPH for glutathione reduction and the utilization of ribose 5-phosphate in nucleotide salvage.
Explore the implications of glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency in humans and its susceptibility to hemolysis and oxidative stresses.
Focus on the anaerobic oxidation of glucose in erythrocytes via the Embden Meyerhoff pathway (EMP).
Learn about the end products of metabolism (pyruvate and lactate) and their diffusion into plasma.
Study the presence of the 2,3-bisphosphoglycerate (2,3-BPG) or Rapoport-Luebering shunt in the glycolytic pathway and its role in bypassing ATP production.
Understand the function of 2,3-BPG in decreasing hemoglobin's affinity for O2 and facilitating O2 unloading in tissues.
Explore the factors influencing 2,3-BPG levels, including high altitude adaptation and hormonal regulation.
Review the impact of genetically determined deficiencies in glycolytic enzymes on erythrocytic metabolism and hemolytic anemias.
Chapter 31: Carbohydrate Metabolism in Erythrocytes
The entry rate of glucose into red blood cells (RBCs) is normally greater than expected from simple diffusion. It is an example of facilitated diffusion, with the membrane transporter protein involved called a glucose transporter (GLUT), specifically GLUT 1. Other GLUT 1 transporters are found in the placenta, kidneys, intestine, and blood-brain-barrier, and all are insulin-independent.
The process of glucose entry into erythrocytes is of major importance for their survival. Although reticulocytes (i.e., developing RBCs) are nucleated with considerable quantities of ribosomal and mitochondrial RNA, mature RBCs of mammals have disposed of their intracellular organelles (i.e., nucleus, mitochondria, lysosomes, endoplasmic reticulum, and Golgi). The absence of these structures allows for membrane deformability, and it also allows more room in the cytoplasm for hemoglobin, the O2 carrier of blood. Since mature mammalian erythrocytes are missing several important intracellular organelles, they cannot synthesize nucleic acids or proteins, nor can they combust fat for energy. They must thus rely on glucose as their sole source of energy.
Birds, herptiles (amphibians and reptiles), and fish, retain a nucleus within their mature red cells; however, it is nonfunctional, and therefore these cells cannot divide. Mammals may have an advantage over these animals since enucleated erythrocytes are thought to be more flexible, and therefore more capable of navigating small capillaries. However, species with nucleated erythrocytes seem to function satisfactorily, despite the presence of these "inferior" structures.
Once glucose enters erythrocytes, it is immediately phosphorylated by hexokinase (HK), an enzyme with a low Km. Since glucose 6-phosphate (Glc-6-P) feeds back negatively on HK, decreased metabolic need will generally limit further phosphorylation. However, since glucose cannot be kept out of erythrocytes during hyperglycemia, glucose molecules may still saturate the cell. Hexokinase is believed to be the key erythrocytic enzyme whose activity fades with age. A natural result of HK senility is loss of erythrocytic capacity to utilize glucose. Next, the Na+ /K+ - and Ca++-ATPase pumps expire; then, the cytoskeleton becomes rigid and, thus, RBCs get stuck in narrow vessels (especially the spleen and liver), and are phagocytosed by reticuloendothelial (RE) cells. Other age-related changes occur in the composition of glycoproteins and glycolipids, which attract senile RBCs to lectins on membranes of RE cells.
As previously discussed, the hexose monophosphate shunt (HMS) of the mature erythrocyte produces NADPH and ribose 5-phosphate from Glc-6-P. Erythrocytes are quite dependent upon NADPH for glutathione reduction, and the ribose 5-P is utilized in nucleotide salvage (see below). Although glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency has not been clearly demonstrated in animals, several million humans demonstrate this hereditary trait, and therefore are susceptible to hemolysis, lipid peroxidation, and other oxidative stresses that may be produced by drugs (such as sulfonamides, primaquine, components of fava beans, or other oxidizing agents).
Approximately 90% of glucose is oxidized anaerobically in RBCs via the Embden Meyerhoff pathway (EMP), and the end products of metabolism (i.e., pyruvate and lactate) diffuse into plasma. Lesser amounts of Glc-6-P may pass through the HMS when needed. A second shunt, the 2,3-bisphosphoglycerate (2,3-BPG) or Rapoport-Luebering shunt, is present in the main glycolytic pathway at the step of processing 1,3-bisphosphoglycerate (1,3-BPG). Formation of 2,3-BPG (or 2,3-diphosphoglycerate (2,3-DPG)) by a mutase enzyme competes with the formation of 3-phosphoglycerate (3-PG) by a kinase, as both enzymes work on the same substrate. Once 2,3-BPG is formed, it re-enters the EMP at the level of 3- PG. Up to 15% of glucose taken up by erythrocytes may pass through this shunt, and since it effectively bypasses the ATP-producing step directly from 1,3-BPG to 3-PG, this may be economical by allowing glycolysis to proceed when the need for ATP is minimal. In primate erythrocytes, 2,3-BPG may account for over 50% of available phosphorus, and it is about equimolar in quantity with Hb. However, in several animal species studied, erythrocytic 2,3-BPG levels are known to vary considerably.
The most important function of 2,3-BPG is to combine with Hb, causing a decrease in its affinity for O2 (and displacement of the oxyhemoglobin dissociation curve to the right). This effectively unloads O2 from Hb, allowing O2 to diffuse into tissues where it is needed. This is important in adaptation to high altitude, and in some species the transport of O2 from maternal to fetal blood (i.e., 2,3-BPG binds more avidly to adult Hb than it does to fetal Hb in most mammals studied, except the horse and pig, where fetal Hb has been found to be indistinguishable from adult Hb). In animals like cattle and cats, that have low erythrocytic 2,3-BPG levels, the chloride anion (Cl–) may be functioning in a similar capacity to that of 2,3-BPG.
Upon moving from sea level to high altitude, many mammalian organisms suffer from acute O2 shortage, and animals begin to hyperventilate. This leads to respiratory alkalosis, which in turn increases 2,3-BPG levels in erythrocytes by activating the mutase enzyme. This increase usually takes about 1 hour to occur, and the half-life of 2,3-BPG is about 6 hours. Hormones that increase 2,3-BPG formation, largely through increased erythropoiesis, include thyroxine, growth hormone, testosterone, and erythropoietin.
Hemolytic anemias in animals are known to result from genetically determined deficiencies in one or more of the glycolytic enzymes (e.g., pyruvate kinase (PK) or phosphofructokinase (PFK)). Since pyruvate kinase is "down-stream" from 2,3-BPG in the EMP, a deficiency in this enzyme would be expected to result in a net increase in erythrocytic 2,3-BPG levels, whereas PFK deficiency would be expected to have the opposite effect.
The developing RBC contains nucleotides in DNA and RNA. However, those in DNA are lost when the nucleus is extruded, and ribosomal RNA is normally degraded within about 24 hrs of the RBC entering the circulation. The cell, however, can use the resulting purine ribonucleotides from RNA (i.e., adenine and guanine), but pyrimidine ribonucleotides (i.e., cytosine, uracil and thymine) are unwelcome because they compete with ATP and ADP in crucial reactions, and thus interfere with cell function. Erythrocytes must maintain an adequate pool of adenine nucleotides (ATP, ADP, and AMP) to survive. Since the mature erythrocyte cannot synthesize them de novo, they are conserved and replenished through a nucleotide salvage pathway. When blood is preserved for transfusion in an adenosine and/or adenine-containing medium, erythrocytes maintain higher levels of ATP, and therefore have increased viability. A continual supply of ATP is needed to maintain membrane deformability, glucose phosphorylation, glutathione (GSH) biosynthesis, and nucleotide salvage. ATP-requiring cation pumps in the plasma membrane independently extrude Ca++, and extrude Na+ in exchange for K+ (i.e., Na+ /K+ - ATPase). Species differences exist, however, in the relative amounts of Na+ and K+ found in erythrocytes. Although most animals maintain high intracellular concentrations of K+ (and low concentrations of Na+), cats and most dogs possess low concentrations of K+ in their mature erythrocytes, due most likely to ever diminishing ATP supplies. Their reticulocytes, however, contain high concentrations of K+.
The white cells of blood, although normally fewer in number, are concerned with the body's response to injury and infection. Red blood cell metabolism accounts for about 90% of glucose used by blood cells each day, while 10% is normally accounted for by white cell metabolism. It is generally believed that a high rate of glycolysis in white blood cells is associated with their ability to grow and divide rapidly, a property they have in common with cancer cells. The rate of glycolysis in white blood cells is therefore markedly increased when the immune response is activated (e.g., due to infection).
SUMMARY
The entry rate of glucose into red blood cells (RBCs) is facilitated by a glucose transporter called GLUT 1. Mature RBCs lack intracellular organelles and rely on glucose as their sole source of energy. Birds, herptiles, and fish retain a nonfunctional nucleus in their mature RBCs. Glucose entering erythrocytes is immediately phosphorylated by hexokinase (HK). The hexose monophosphate shunt (HMS) produces NADPH and ribose 5-phosphate, which are important for glutathione reduction and nucleotide salvage, respectively. Glucose is primarily oxidized anaerobically via the Embden Meyerhoff pathway (EMP), with a smaller amount passing through the 2,3-bisphosphoglycerate (2,3-BPG) shunt. 2,3-BPG combines with hemoglobin (Hb) to decrease its affinity for oxygen, facilitating oxygen unloading in tissues. Hormones like thyroxine and erythropoietin increase 2,3-BPG formation. Hemolytic anemias can result from deficiencies in glycolytic enzymes. Erythrocytes rely on nucleotide salvage to maintain an adequate pool of adenine nucleotides. ATP is essential for various erythrocyte functions, including membrane deformability and nucleotide salvage. White blood cells have a high rate of glycolysis, especially when the immune response is activated.
OUTLINE
I. Glucose Entry into Erythrocytes
Glucose transporter (GLUT 1) facilitates glucose entry
Importance of glucose entry for erythrocyte survival
Erythrocytes rely on glucose as their sole source of energy
II. Hexokinase and Glucose Metabolism
Hexokinase phosphorylates glucose to glucose 6-phosphate (Glc-6-P)
Glc-6-P negatively regulates hexokinase activity
Decreased metabolic need limits further phosphorylation of glucose
III. Age-related Changes in Erythrocytes
Senility of hexokinase leads to loss of erythrocytic glucose utilization
Na+/K+-ATPase and Ca++-ATPase pumps expire
Changes in glycoproteins and glycolipids attract senile erythrocytes to reticuloendothelial cells
IV. Hexose Monophosphate Shunt (HMS)
HMS produces NADPH and ribose 5-phosphate from Glc-6-P
Erythrocytes depend on NADPH for glutathione reduction
Glc-6-P dehydrogenase deficiency leads to hemolysis and oxidative stress
V. Embden Meyerhoff Pathway (EMP)
90% of glucose is oxidized anaerobically via EMP
End products (pyruvate and lactate) diffuse into plasma
VI. 2,3-Bisphosphoglycerate (2,3-BPG) Shunt
Competes with EMP at the step of 1,3-bisphosphoglycerate (1,3-BPG) processing
Bypasses ATP-producing step, allowing glycolysis to proceed when ATP need is minimal
2,3-BPG combines with hemoglobin, decreasing its affinity for O2
VII. Regulation of 2,3-BPG Levels
Increase in 2,3-BPG occurs in response to hyperventilation and respiratory alkalosis
Hormones like thyroxine, growth hormone, testosterone, and erythropoietin increase 2,3-BPG formation
VIII. Hemolytic Anemias
QUESTIONS
Qcard 1:
Question: What is the process by which glucose enters red blood cells?
Answer: Facilitated diffusion, with the membrane transporter protein called a glucose transporter (GLUT 1).
Qcard 2:
Question: Why do mature mammalian erythrocytes rely on glucose as their sole source of energy?
Answer: They have disposed of their intracellular organelles, so they cannot synthesize nucleic acids or proteins, nor can they combust fat for energy.
Qcard 3:
Question: What is the function of hexokinase in erythrocytes?
Answer: Hexokinase phosphorylates glucose once it enters erythrocytes.
Qcard 4:
Question: What is the role of 2,3-BPG in erythrocytes?
Answer: 2,3-BPG combines with hemoglobin, causing a decrease in its affinity for oxygen and facilitating the unloading of oxygen in tissues.
Qcard 5:
Question: How do erythrocytes maintain an adequate pool of adenine nucleotides?
Answer: Through a nucleotide salvage pathway, as they cannot synthesize them de novo.
Qcard 6:
Question: What is the significance of a high rate of glycolysis in white blood cells?
Answer: It is associated with their ability to grow and divide rapidly, particularly during immune response activation.
Glucose Entry into Erythrocytes
Facilitated diffusion
Glucose transporter (GLUT 1)
Importance for erythrocyte survival
Energy Source for Erythrocytes
Lack of intracellular organelles
Reliance on glucose as the sole source of energy
Nucleated Erythrocytes in Non-Mammalian Species
Retention of nucleus in birds, herptiles, and fish
Functionality and advantages of nucleated erythrocytes
Glucose Metabolism in Erythrocytes
Phosphorylation of glucose by hexokinase (HK)
Age-related changes in HK activity
Role of Na+/K+-ATPase and Ca++-ATPase pumps
Hexose Monophosphate Shunt (HMS)
Production of NADPH and ribose 5-phosphate
Importance of NADPH for glutathione reduction
Glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency
Embden Meyerhoff Pathway (EMP)
Anaerobic oxidation of glucose
End products: pyruvate and lactate
2,3-Bisphosphoglycerate (2,3-BPG) Shunt
Competes with glycolysis at the step of 1,3-BPG
Bypasses ATP-producing step
Functions of 2,3-BPG in O2 transport and adaptation
Factors Affecting 2,3-BPG Levels
Increase in high-altitude adaptation
Hormones that increase 2,3-BPG formation
Hemolytic Anemias and Glycolytic Enzyme Deficiencies
Genetic deficiencies in glycolytic enzymes
Effects on erythrocytic 2,3-BPG levels
Nucleotide Salvage Pathway
Conservation and replenishment of adenine nucleotides
Importance of ATP for erythrocyte function
Species
Read and understand the introduction and importance of glucose entry into erythrocytes.
Focus on the role of glucose transporter (GLUT 1) in facilitated diffusion.
Take notes on the absence of intracellular organelles in mature RBCs and their reliance on glucose as the sole source of energy.
Study the differences between mammalian and non-mammalian erythrocytes in terms of nucleated cells and flexibility.
Review the process of glucose entry into erythrocytes and its immediate phosphorylation by hexokinase (HK).
Understand the feedback inhibition of HK by glucose 6-phosphate (Glc-6-P) and its implications for metabolic need.
Learn about the age-related changes in erythrocytes, including the fading activity of hexokinase and the expiration of Na+/K+- and Ca++-ATPase pumps.
Dive into the hexose monophosphate shunt (HMS) and its role in producing NADPH and ribose 5-phosphate from Glc-6-P.
Understand the importance of NADPH for glutathione reduction and the utilization of ribose 5-phosphate in nucleotide salvage.
Explore the implications of glucose 6-phosphate dehydrogenase (Glc-6-PD) deficiency in humans and its susceptibility to hemolysis and oxidative stresses.
Focus on the anaerobic oxidation of glucose in erythrocytes via the Embden Meyerhoff pathway (EMP).
Learn about the end products of metabolism (pyruvate and lactate) and their diffusion into plasma.
Study the presence of the 2,3-bisphosphoglycerate (2,3-BPG) or Rapoport-Luebering shunt in the glycolytic pathway and its role in bypassing ATP production.
Understand the function of 2,3-BPG in decreasing hemoglobin's affinity for O2 and facilitating O2 unloading in tissues.
Explore the factors influencing 2,3-BPG levels, including high altitude adaptation and hormonal regulation.
Review the impact of genetically determined deficiencies in glycolytic enzymes on erythrocytic metabolism and hemolytic anemias.
