RBC metabolism

• Erythrocytes (red blood cells, RBCs)


  Primary cell in the blood, lack a nucleus, have a biconcave shape, average volume of 90 fL
• Erythrocytes


  • Biconcave shape supports deformation, enabling the circulating cell to pass smoothly through capillaries, where it readily exchanges oxygen (O2) and carbon dioxide (CO2) while contacting the vessel wall
• Hemoglobin


  Complex of globin, protoporphyrin, and iron, transports O2 from the lungs to the tissues, has four globin chains each containing a heme molecule with an iron in the ferrous state
• Erythrocyte production


  Produced through normoblastic proliferation and mature in the bone marrow, nucleus and organelles are extruded as part of the maturation process
• Without mitochondria for aerobic respiration, erythrocytes produce ATP through anaerobic glycolysis (Embden-Meyerhof pathway, EMP) for their lifetime
• Anaerobic glycolysis in erythrocytes

  • ATP drives mechanisms that slow the oxidation of proteins and iron by environmental peroxides and superoxide anions, maintaining hemoglobin's function and membrane integrity
• Oxidation eventually takes a toll, limiting the erythrocyte circulating life span to 120 days, whereupon it is disassembled into its reusable components
• Erythrocyte metabolic processes requiring energy


  • Intracellular cationic gradient maintenance
  • Maintenance of membrane phospholipid distribution
  • Maintenance of skeletal protein deformability
  • Maintenance of functional hemoglobin with ferrous iron
  • Protecting cell proteins from oxidative denaturation
  • Glycolysis initiation and maintenance
  • Glutathione synthesis
  • Nucleotide salvage reactions
• Anaerobic glycolysis (Embden-Meyerhof pathway, EMP)

  1. Glucose enters the RBC through facilitated diffusion via Glut-1

  2. Glucose catabolized to pyruvate, generating 4 ATP per glucose, net gain of 2 ATP
• Phases of glycolysis


  • Glucose phosphorylation, isomerization, and diphosphorylation to yield fructose 1,6-bisphosphate
  • Conversion of glyceraldehyde-3-phosphate to 3-phosphoglycerate
  • Conversion of 3-phosphoglycerate to pyruvate and ATP generation
• Hexose monophosphate pathway (HMP)

  Diverts glucose-6-phosphate to detoxify peroxide (H2O2), maintains hemoglobin iron in the functional, reduced, ferrous state
• Methemoglobin reductase pathway


  Reduces oxidized ferric (3+) heme iron back to the functional ferrous (2+) state
• Rapoport-Luebering pathway


  Produces 2,3-bisphosphoglycerate, which modulates hemoglobin's oxygen affinity
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited RBC enzyme deficiency worldwide, resulting in hereditary nonspherocytic anemia due to impaired ability to detoxify oxidative compounds
• Glucose catabolism: Hexose Monophosphate Pathway

  1. G6P, NADP -> 6-PG, NADPH (Glucose-6-phosphate dehydrogenase)

  2. 6-PG, NADP -> R5P, NADPH, CO2 (6-Phosphogluconate dehydrogenase)
• G6PD


  Provides the only means of generating NADPH for glutathione reduction
• In G6PD deficiency, the most common inherited RBC enzyme deficiency worldwide, the ability to detoxify is hampered, resulting in hereditary nonspherocytic anemia
• Methemoglobin Reductase Pathway


  1. Peroxide oxidizes heme iron from ferrous (2+) to ferric (3+) state (Methemoglobin)

  2. NADPH reduces methemoglobin, rendered more efficient in the presence of methemoglobin reductase (cytochrome b5 reductase)
• Rapoport-Luebering Pathway


  1. 1,3-BPG -> 2,3-BPG (Bisphosphoglycerate mutase)

  2. 2,3-BPG -> 3-PG (Bisphosphoglycerate phosphatase)
• 2,3-BPG binds between the globin chains in the hemoglobin tetramer to stabilize it in the deoxygenated state, shifting the hemoglobin-oxygen dissociation curve to the right, enhancing oxygen delivery to tissues
• The diversion of 1,3-BPG to form 2,3-BPG sacrifices the production of two ATP molecules, putting the cell into ATP deficit
• Acidic pH and low concentrations of 3-PG and 2-PG inhibit the activity of bisphosphoglycerate mutase, favoring generation of ATP by causing the conversion of 1,3-BPG directly to 3-PG and returning 2,3-BPG to 3-PG for ATP generation downstream by PK
• RBC Membrane Deformability


  • RBCs are biconcave, 7-8 μM in diameter, with 40% excess surface area compared to a sphere
  • RBCs can stretch undamaged up to 2.5 times their resting diameter as they pass through narrow capillaries and splenic pores
• RBC deformability


  Depends on RBC geometry and relative cytoplasmic (hemoglobin) viscosity
• MCHCs greater than 36% compromise deformability and shorten the RBC life span
• RBC Membrane Lipids


  • Membrane consists of ~8% carbohydrates, 52% proteins, 40% lipids (equal parts cholesterol and phospholipids)
  • Phospholipids form an impenetrable fluid barrier, providing dynamic fluidity
  • Cholesterol confers tensile strength but reduces elasticity
• The ratio of cholesterol to phospholipids remains relatively constant to maintain the balance of deformability or elasticity and strength
• Phospholipid distribution is asymmetric, with phosphatidylcholine and sphingomyelin predominating in the outer layer, and phosphatidylserine and phosphatidylethanolamine in the inner layer
• Glycolipids make up 5% of the external half of the RBC membrane, associating in clumps or rafts to anchor the glycocalyx
• RBC Membrane Proteins


  • Transmembrane proteins serve functions like transport, adhesion, and signaling
  • Cytoskeletal proteins make up 52% of the membrane structure by mass
• A proteomic study revealed there are at least 300 RBC membrane proteins, including 105 transmembrane proteins
• Phospholipids


  Constitute the principal RBC membrane structure
• Transmembrane (integral) and cytoskeletal (skeletal, peripheral) proteins

  Make up 52% of the RBC membrane structure by mass
• Some proteins have a few hundred copies per cell, and others have more than a million copies per cell
• Of the purported 300 membrane proteins, about 50 have been characterized and named
• Functions of transmembrane proteins


  • Transport sites
  • Adhesion sites
  • Signaling receptors
• Any disruption in transport protein function

  Changes the osmotic tension of the cytoplasm, which leads to a rise in viscosity and loss of deformability
• Any change affecting adhesion proteins

  Permits RBCs to adhere to one another and to the vessel walls, promoting fragmentation (vesiculation), reducing membrane flexibility, and shortening the RBC life span
• Signaling receptors


  Bind plasma ligands and trigger activation of intracellular signaling proteins, which then initiate various energy-dependent cellular activities, a process called signal transduction
• Glycosylation


  Supports surface carbohydrates, which join with glycolipids to make up the protective glycocalyx