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Questions and Answers
Iron is part of the polypeptide chain in hemoglobin.
False
Myoglobin consists of 153 amino acids and has a compact structure.
True
The haem iron in deoxy-myoglobin lies further out of plane compared to oxy-myoglobin.
True
Myoglobin is a cooperative protein that binds oxygen with a high affinity.
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Haemoglobin transports oxygen to tissues and carbon dioxide away from tissues.
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Extramedullary haematopoiesis involves cell maturation in the spleen and lymph nodes.
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One proerythroblast gives rise to about 32 mature RBCs.
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Anemia is defined as a decrease in Hb concentration below the reference range.
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The life span of a red blood cell (RBC) is approximately 180 days.
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Aerobic metabolism is less efficient than anaerobic metabolism.
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Plasma makes up 55% of the blood composition.
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The body contains approximately 3.5L of blood in a 70kg man.
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Erythropoiesis refers to the production of white blood cells.
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In adults, haematopoiesis occurs primarily in the pelvis and cranium.
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The blood's temperature is typically around 38°C.
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The formed elements of blood make up 45% of its composition.
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Platelets account for more than 50% of the formed elements in blood.
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Haemoglobin plays a role in carbon dioxide binding.
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Haemoglobin has a hyperbolic oxygen dissociation curve.
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Myoglobin can bind to a single molecule of O2.
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HbGower 1 contains two zeta chains and two epsilon chains.
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Haemoglobin dissociates at a lower partial pressure of oxygen than myoglobin.
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The a-like chains of haemoglobin are located on chromosome 11.
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Haemoglobin A is the adult form consisting of two alpha and two beta chains.
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The affinity for the fourth O2 bound to haemoglobin is lower than that of the first O2 bound.
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HbF refers to the minor form of adult hemoglobin.
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The Bohr effect indicates that O2 is released more easily at high pH or decreased pCO2.
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Increasing levels of 2,3-BPG decrease the affinity of deoxy-Hb for O2.
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The T form of hemoglobin has a higher affinity for oxygen than the R form.
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Elevated levels of 2,3-BPG help increase O2 delivery to tissues.
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Cooperativity in hemoglobin is facilitated by haem-haem interactions.
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In the lungs, the pH is lower than in peripheral tissues facilitating O2 unloading.
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2,3-BPG forms salt bridges with negatively charged residues on the alpha subunits of hemoglobin.
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Deoxy-Hb alone has a P50 value of 26 Torr.
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A single stem cell produces approximately 1 million mature cells and accounts for less than 0.1% of all cells in bone marrow.
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Erythropoiesis results in one proerythroblast giving rise to about 32 mature RBCs.
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Senescent RBCs are removed by lymphocytes in the body.
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Aerobic metabolism is considered more efficient than anaerobic metabolism.
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The components of hemoglobin are completely excreted in urine after the RBCs are removed.
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Myoglobin contains 8 helices labeled from A to H.
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Haemoglobin is a single polypeptide that binds oxygen cooperatively.
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The haem iron in oxy-myoglobin lies 0.1 Å out of plane.
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Protoporphyrin IX combined with Fe2+ forms chlorophyll.
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Myoglobin dissociates oxygen slowly due to its low affinity for O2.
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The liquid component of blood that allows cells to be suspended is known as plasma.
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Erythropoiesis is the process involved in the production of white blood cells.
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In adults, haematopoiesis primarily occurs in the liver and spleen.
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The major function of blood includes transporting hormones and nutrients to body tissues.
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The average volume of blood in a 70 kg man is approximately 7.5L.
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The formed elements in blood consist primarily of leukocytes.
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Myoglobin and hemoglobin are both responsible for binding oxygen in the bloodstream.
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Red blood cells have a significantly shorter lifespan compared to white blood cells.
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Haemoglobin can bind a total of 4 oxygen molecules due to its 4 polypeptide chains, each containing a haem group.
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Myoglobin exhibits a hyperbolic saturation curve when binding to oxygen.
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The HbF form of haemoglobin consists of two alpha and two gamma chains.
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The affinity for the first oxygen bound to haemoglobin is higher than that for the fourth oxygen.
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Haemoglobin Gower 1 consists of two alpha chains and two epsilon chains.
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The partial pressure of oxygen (pO2) is higher in the lungs than in peripheral tissues, aiding in oxygen loading.
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Oxygen dissociation from haemoglobin releases more easily at lower pH values, a phenomenon known as the Bohr effect.
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Haemoglobin A2 is the main form of haemoglobin present during embryonic development.
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The R form of hemoglobin has a lower affinity for oxygen compared to the T form.
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The Bohr effect allows for oxygen to be released more easily in tissues with higher pH levels.
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Elevated levels of 2,3-BPG lead to an increase in the affinity of hemoglobin for oxygen.
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Hemoglobin without 2,3-BPG has a P50 value that is much lower than that of deoxy-Hb with 2,3-BPG.
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The presence of 2,3-BPG stabilizes the R form of hemoglobin.
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In the lungs, oxygen loading is favored by lower acid concentrations.
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The T (tense) form of hemoglobin is more likely to bind to oxygen than the R (relaxed) form.
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Cooperativity in hemoglobin is enhanced by haem-haem interactions.
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Erythropoiesis produces red blood cells, while leucopoiesis produces white blood cells.
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The plasma component of blood constitutes approximately 45% of its volume.
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Haemopoiesis primarily occurs in the liver and spleen in adults.
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The average blood temperature in the human body is approximately 38°C.
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Platelets make up more than 1% of the formed elements in blood.
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The lifespan of a red blood cell is approximately 120 days.
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Whole blood, when allowed to clot, separates into plasma and serum, with serum containing coagulation factors.
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In children, haematopoiesis occurs primarily in the marrow of long bones such as the femur and tibia.
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The interior of myoglobin is predominantly hydrophilic with the exception of histidines E7 and F8.
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Haemoglobin consists of a single polypeptide chain and is cooperative in its oxygen binding.
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A conformational change in myoglobin occurs when it transitions from deoxy to oxy form.
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Protoporphyrin IX combined with Fe2+ produces haem, essential for myoglobin function.
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Myoglobin and hemoglobin both have equal capabilities in oxygen transport and storage due to similar structures.
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Extramedullary haematopoiesis takes place exclusively in the liver.
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The average life span of a red blood cell (RBC) is approximately 120 days.
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Anaemia is characterized by an increase in Hb concentration above the reference range.
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an example of an inherited haemolytic anaemia.
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Haemoglobin components are completely recycled before being excreted in bile.
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Hb Gower 1 is comprised of two alpha chains and two beta chains.
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The oxygen dissociation curve of hemoglobin is hyperbolic in shape.
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In adults, the minor form of hemoglobin is known as Hb Gower 1.
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Myoglobin has a lower affinity for oxygen compared to hemoglobin.
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The structural changes in hemoglobin are initiated by the binding of the first oxygen molecule.
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The chains of hemoglobin are primarily held together by covalent bonds.
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The partial pressure of oxygen (pO2) significantly affects the saturation of hemoglobin.
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HbF consists of two alpha chains and two gamma chains.
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The Bohr effect indicates that O2 is released more easily at low pH and increased pCO2.
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2,3-BPG increases the affinity of deoxy-Hb for O2, thereby enhancing oxygen delivery in tissues.
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The presence of 2,3-BPG shifts the oxygen dissociation curve to the left, indicating a lower P50 value.
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The T (tense) form of hemoglobin has a low affinity for oxygen compared to the R (relaxed) form.
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Increased levels of 2,3-BPG enhance the oxygen affinity of hemoglobin at low oxygen concentrations.
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The differential pH gradient between the lungs and peripheral tissues facilitates the unloading of O2 in tissues.
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Deoxy-Hb has a P50 of 1 Torr when 2,3-BPG is not bound to it.
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2,3-BPG interacts with the alpha subunits of hemoglobin, forming salt bridges that stabilize the T conformation.
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Study Notes
Blood Composition
- Blood circulates throughout the body via the heart, arteries, veins, and capillaries.
- 70 kg man ≈ 5.6 L of blood (7-8% of body weight)
- Blood temperature ≈ 38 °C
- Blood pH is slightly alkaline, 7.35-7.45
- Blood is composed of plasma (55%) and formed elements (45%)
- Plasma is the liquid component containing dissolved substances like gases, salts, proteins, carbohydrates, and lipids.
- Formed elements include red blood cells (99%), platelets (<1%), and white blood cells (<1%).
- Serum is the remaining fluid after blood clotting, devoid of coagulation factors.
Functions of Blood
- Transports oxygen, nutrients, hormones, water, solutes, and heat to body tissues.
- Transports waste matter, carbon dioxide away from tissues.
Haemopoiesis
- Refers to the production and development of new blood cells.
- Erythropoiesis: Production of red blood cells (RBCs)
- Leucopoiesis: Production of white blood cells (WBCs)
- Thrombopoiesis: Production of platelets
- Number of circulating RBCs is >500 times higher than WBCs.
Sites of Haemopoiesis
- In children, haemopoiesis largely occurs in the marrow of long bones (femur, tibia).
- In adults, primary sites are the pelvis, cranium, vertebrae, and sternum.
- Extramedullary haemopoiesis occurs when the liver, thymus, and spleen resume their haematopoietic function, a response to need.
- Spleen and lymph nodes support maturation, activation, and some proliferation of lymphoid cells.
Key Features of Haemopoiesis
- A single stem cell generates >10^6 mature cells, accounting for <0.1% of all cells in bone marrow.
- Stem cells grow and divide within the bone marrow.
- Loss of Cell Adhesion Molecules (CAMs) allows cells to leave the marrow and enter circulation.
- Haemopoiesis requires growth factors:
- Erythropoietin
- Colony stimulating factors
- Interleukins
- Thrombopoietin
Erythropoiesis
- Typically, one proerythroblast gives rise to approximately 16 mature RBCs.
Erythrocytes (RBCs)
- Anucleate (lacking a nucleus) and discoid shaped.
- Average lifespan ≈ 120 days.
- 1% destroyed per day.
Anaemia
- A decrease in haemoglobin concentration below the reference range for age and sex.
- Female: 11.5-16.0 g/dL
- Male: 13.5 - 17.5 g/dL
Inherited Haemolytic Anaemias
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency: An enzyme deficiency impacting red blood cell survival, leading to premature breakdown.
- Sickle cell anaemia: A genetic disorder where abnormal haemoglobin causes red blood cells to become sickle-shaped, leading to complications like blockages.
Life Cycle of RBCs
- Typical lifespan of an RBC is ~120 days.
- Senescent (aging) RBCs are removed by macrophages.
- Haemoglobin components are recycled:
- Globin (protein portion) amino acids are reused.
- Iron is reutilised.
- Haem is excreted in bile.
Aerobic Metabolism
- Cellular metabolism is either aerobic (using oxygen) or anaerobic (not using oxygen).
- Aerobic metabolism is the most efficient.
- Multi-cellular organisms need to transport oxygen to tissues for aerobic metabolism and oxygen storage.
- Specialised proteins for oxygen transport and storage:
- Myoglobin
- Haemoglobin
Haem Group
- The haem group is crucial for oxygen binding by proteins.
- It is not part of the polypeptide chain, but tightly bound to the protein.
- Essential for haemoglobin activity.
- Contains iron in the ferrous (Fe2+) state.
- Iron is held in position by four nitrogen atoms of the protoporphyrin IX ring.
- Iron can form two additional bonds.
Structure of Myoglobin
- Serves as an oxygen reservoir within heart and skeletal muscle cells.
- Contains 153 amino acids, with a molecular weight of 17 kDa.
- Compact protein structure:
- 75% alpha-helix conformation.
- 8 helices labelled A-H.
- Non-helical regions (AB, BC etc.).
- Hydrophilic exterior.
- Hydrophobic interior except for histidines E7 and F8.
Schematic of the O2 binding site
- Haem sits in a crevice near the surface, lined by non-polar residues.
- Distal histidine (E7).
- Proximal histidine (F8).
Conformational Change with O2 Binding
- Deoxy-Mb: Haem iron lies 0.3 Angstroms out of plane.
- Oxy-Mb: Haem iron lies 0.1 Angstroms out of plane.
- Oxygenation moves the haem iron, which in turn moves His F8.
- Helix F moves, triggering movement in other structural elements.
Differences in Hb and Mb
-
Myoglobin: Storage protein.
- Binds tightly to oxygen, dissociation occurs slowly.
- Not cooperative in binding.
- Composed of a single polypeptide.
-
Haemoglobin: Transport protein.
- Transports oxygen to tissues.
- Transports carbon dioxide and protons away from tissues.
- Structure:
- 4 polypeptide chains.
- Each chain has a haem group (can bind 4 oxygen molecules).
- Subunits held together by non-covalent interactions.
Gene Expression of the a & b Chains
- Genes for alpha and beta chains:
- Alpha-like chains: Chromosome 16
- Z a2 a1 Hb Gower 1 HbF HbA2 HbA (z2e2) (a2g2) (a2d2) (a2b2) e Gg Ag d b
- Beta-like chains: Chromosome 11
- Alpha-like chains: Chromosome 16
Hb Variant Forms and Gene Expression
Hb type Expression Chains
HbA Adult a2b2
HbA2 Minor adult form a2d2
HbF Foetal a2g2
Hb Gower 1 embryonic z2e2
Hb Gower 2 embryonic a2e2
Hb Portland embryonic z2g2
Oxygen Dissociation Curve
-
Myoglobin:
- Hyperbolic shaped curve.
- Reversible binding of a single oxygen molecule.
- 100% saturation at a certain partial pressure of oxygen (pO2).
-
Haemoglobin:
- Sigmoidal shaped curve.
- Cooperative binding.
- Dissociates at a higher pO2 than myoglobin, allowing delivery of oxygen from haemoglobin to myoglobin.
O2 Binding to Hb
- Sigmoidal shaped saturation curve indicative of cooperative binding (“cross-talk” between protein subunits).
- Oxygen binding increases the affinity of haemoglobin for additional oxygen molecules.
- Hb dissociates at a higher partial pressure than Mb, facilitating oxygen delivery from Hb to Mb.
Haem Interactions
- The sigmoidal shape of the oxygen binding curve stems from structural changes initiated at one haem group and transmitted to others.
- The affinity of the 4th oxygen bound is 300 times greater than the 1st oxygen bound.
Structural Changes due to Oxygenation
- Tense (T) form: Deoxy-Hb with low affinity for oxygen.
- Relaxed (R) form: Oxy-Hb with high affinity for oxygen.
- T to R transition involves breaking ionic bonds and rearranging hydrophobic interactions.
Allosteric Effects
- Haem-Haem interaction (cooperativity): Oxygen binding at one haem influences binding at other haem groups.
- Bohr effect: Oxygen is released more readily at low pH or increased pCO2.
- 2,3-Bisphosphoglycerate (2,3-BPG): A molecule present in erythrocytes at equimolar concentrations to haemoglobin.
Bohr effect
- Decreases oxygen affinity of haemoglobin by stabilizing the T (deoxy) form.
- Promotes oxygen unloading in tissues (lower pH, higher pCO2) and loading in the lungs (higher pH).
- Shifts the oxygen dissociation curve to the right, increasing P50.
2,3-BPG
- Present in erythrocytes at nearly equal concentrations with haemoglobin (Hb).
- Binds only to deoxy-Hb, lowering its oxygen affinity.
- Stabilizes the T (tense) conformation of haemoglobin.
- Binding occurs in a central cavity of haemoglobin, which is formed by the beta-chains
- Presence of 2,3-BPG impedes Hb from achieving the R (relaxed) conformation
Importance of 2,3-BPG
- 2,3-BPG promotes oxygen release in tissues.
- Elevations in 2,3-BPG concentration are associated with conditions like anemia and high altitude (lower oxygen availability)
- In situations with significantly lower oxygen availability, the body increases levels of 2,3-BPG to enhance oxygen delivery to the tissues
2,3-BPG and Oxygen Affinity
- Deoxy-Hb + 2,3-BPG: P50 = 26 Torr
- Deoxy-Hb alone: P50 = 1 Torr
- Absence of 2,3-BPG results in high oxygen affinity and reduced oxygen delivery to tissues.
- 2,3-BPG shifts the oxygen dissociation curve to the right, increasing oxygen release in tissues.
- In low oxygen conditions or anaemia, 2,3-BPG levels increase, enhancing oxygen delivery to tissues.
2,3-BPG and Oxygen Delivery
- If 2,3-BPG concentrations are elevated, oxygen delivery to tissues increases.
- This occurs because 2,3-BPG promotes oxygen release from haemoglobin in tissues where oxygen levels are low.
Summary: 2,3-BPG
- 2,3-BPG is a key regulator of oxygen delivery in the body.
- It facilitates efficient oxygen delivery to tissues by decreasing the affinity of haemoglobin for oxygen.
- Elevated 2,3-BPG levels can be beneficial in conditions like anaemia and high altitude.
Blood Composition
- Blood is a complex fluid that circulates throughout the body, making up 7-8% of body weight.
- Blood is slightly alkaline with a pH of 7.35-7.45
- Composed of plasma (55%) and formed elements (45%).
- Plasma is the liquid component that contains dissolved gases, salts, proteins, carbohydrates, and lipids.
- Formed elements include red blood cells (99%), platelets (<1%), and white blood cells (<1%).
- Serum is the fluid remaining after blood clotting, lacking coagulation factors.
Blood Functions
- Carries to body tissues: oxygen, nutrients, hormones, water, solutes, heat
- Carries away from tissues: waste matter, carbon dioxide
Haemopoiesis
- The production and development of new blood cells
- Includes erythropoiesis (red blood cell production), leukopoiesis (white blood cell production), and thrombopoiesis (platelet production).
- Occurs mainly in the bone marrow of the pelvis, cranium, vertebrae, and sternum in adults.
- Extramedullary haemopoiesis can occur in the liver, thymus, and spleen if needed.
- Single stem cell produces over 1 million mature cells, making up less than 0.1% of marrow cells.
- Requires growth factors like erythropoietin, colony stimulating factors, interleukins, and thrombopoietin.
Erythropoiesis
- The process of red blood cell production.
- One proerythroblast typically produces about 16 mature red blood cells.
Erythrocytes (Red Blood Cells)
- Anucleate, discoid shaped cells.
- Have a lifespan of about 120 days.
- 1% are destroyed daily, replaced by new production.
- Anaemia is defined as a decrease in hemoglobin concentration below the reference range for age and sex.
- Inherited haemolytic anaemias include Glucose-6-phosphate dehydrogenase deficiency and sickle cell anaemia.
Life Cycle of Red Blood Cells
- Red blood cells have a lifespan of about 120 days.
- Senescent (old) red blood cells are removed by macrophages.
- Haemoglobin components are recycled:
- Globin is broken down into amino acids for reuse.
- Iron is reutilized in new red blood cell production.
- Haem is excreted in bile.
Aerobic Metabolism
- Most efficient form of metabolism.
- Multi-cellular organisms require oxygen transport to all tissues for aerobic metabolism and oxygen storage.
- Specialized proteins for this include myoglobin and haemoglobin.
Haem Group
- The oxygen binding of proteins relies on the haem group.
- A non-protein component tightly bound to the protein.
- Essential for haemoglobin activity.
- Contains iron (Fe2+), held in position by 4 nitrogen atoms.
- Iron can make 2 more bonds, allowing oxygen binding.
Structure of Myoglobin
- Oxygen reservoir within heart and skeletal muscle cells.
- Composed of 153 amino acids and has a molecular weight of 17kDa.
- Structure includes:
- 75% alpha-helix.
- 8 helices (labelled A-H).
- Non-helical regions.
- Hydrophilic exterior and hydrophobic interior, except for histidines E7 and F8.
Oxygen Binding Site
- Haem sits in a crevice near the surface lined with non-polar residues.
- Distal His (E7) and proximal His (F8) are crucial for oxygen binding.
Conformational Change with Oxygen Binding
- Deoxy-Mb: Haem iron lies 0.3 Å out of plane.
- Oxy-Mb: Haem iron lies 0.1 Å out of plane.
- Oxygenation moves the haem iron, which moves His F8.
- Helix F moves, causing other structural elements to shift.
Differences in Hb and Mb
- Mb is a storage protein, binding oxygen avidly and dissociating slowly.
- Mb is not cooperative, only has one polypeptide chain.
- Hb is a transport protein, 4 polypeptide chains, and is cooperative.
Haemoglobin
- Has two major functions:
- Transports oxygen to tissues.
- Transports carbon dioxide and protons away from tissues.
- Has four polypeptide chains, each with a haem group.
- Binds four oxygen molecules.
- Subunits are held together by non-covalent interactions.
Gene Expression of the Alpha and Beta Chains
- Genes for alpha and beta chains are located on different chromosomes:
- Alpha-like chains on chromosome 16.
- Beta-like chains on chromosome 11.
- Various haemoglobin forms are expressed throughout development.
- The most common adult haemoglobin form is HbA (alpha2beta2).
Haemoglobin Variant Forms and Gene Expression
- Hb type | Expression | Chains
- HbA | Adult | alpha2beta2
- HbA2 | Minor adult form | alpha2delta2
- HbF | Foetal | alpha2gamma2
- Hb Gower 1 | Embryonic | zeta2epsilon2
- Hb Gower 2 | Embryonic | alpha2epsilon2
- Hb Portland | Embryonic | zeta2gamma2
Oxygen Dissociation Curve
- Myoglobin has a hyperbolic curve, indicating reversible binding of a single oxygen molecule.
- Haemoglobin has a sigmoid curve, indicating cooperative binding of oxygen molecules.
- Haemoglobin dissociates at a higher partial pressure than myoglobin, allowing oxygen delivery from haemoglobin to myoglobin.
- Haemoglobin can interact with 4 oxygen molecules, with the affinity increasing for each subsequent oxygen molecule.
Structural Changes due to Oxygenation
- Tense (T) form: Deoxy-Hb, low affinity for oxygen.
- Relaxed (R) form: Oxy-Hb, high affinity for oxygen.
- The transition between these forms involves breaking of ionic bonds and changes in hydrophobic interactions.
Allosteric Effects
- Haem-Haem interaction: Cooperativity, the binding of one oxygen molecule to a subunit increases the affinity of the other subunits for oxygen.
- Bohr effect: The release of oxygen is favored under conditions of low pH or high pCO2.
- 2,3 Bisphosphoglycerate (2,3-BPG): A molecule that binds to deoxy-Hb and decreases its affinity for oxygen.
The Bohr Effect
- The Bohr effect is a phenomenon that results in lower oxygen affinity of haemoglobin at low pH or higher pCO2.
- This facilitates the unloading of oxygen in tissues and loading of oxygen in the lungs.
- This is primarily due to the stabilization of the tense (deoxy) form of haemoglobin by protons (H+) or carbon dioxide (pCO2).
- The shift in the oxygen dissociation curve towards the right indicates an increase in P50 (the partial pressure of oxygen at which haemoglobin is 50% saturated).
- The Bohr effect ensures efficient handling of oxygen by haemoglobin.
2,3-BPG
- 2,3-BPG is present in erythrocytes at similar concentrations to haemoglobin.
- It binds to deoxy-Hb only, reducing its affinity for oxygen.
- This binding stabilizes the taut (T) conformation of haemoglobin.
- 2,3-BPG forms salt bridges with positively charged residues on the beta subunits in a central cavity.
- This narrowing of the central cavity squeezes out 2,3-BPG upon oxygenation.
- Haemoglobin with 2,3-BPG removed has a higher oxygen affinity.
Effect of 2,3-BPG
- Increased 2,3-BPG concentration shifts the oxygen dissociation curve to the right.
- This facilitates more efficient oxygen delivery to tissues by increasing the release of oxygen at lower oxygen partial pressures.
- At low oxygen levels or in cases of anaemia, 2,3-BPG levels increase to enhance oxygen delivery.
Blood Composition
- Blood is a vital organ, circulating throughout the body, responsible for transporting materials and regulating bodily functions.
- A 70 kg man has approximately 5.6 L of blood, representing 7-8% of body weight.
- Blood is slightly alkaline, with a pH range of 7.35-7.45.
Blood Components
- Blood is composed of plasma (55%) and formed elements (45%).
- Plasma is the liquid component containing dissolved substances like gases, salts, proteins, carbohydrates, and lipids.
- Formed elements include red blood cells (erythrocytes) (99%), platelets (<1%), and white blood cells (leukocytes) (<1%).
- Serum is the fluid remaining after blood clots and does not contain coagulation factors.
Blood Functions
- Carries to Body Tissues: oxygen, nutrients, hormones, water, solutes, heat
- Carries Away From Tissues: waste products, carbon dioxide
Haemopoiesis: Blood Cell Production
- Haemopoiesis is responsible for producing and developing new blood cells, including:
- Erythropoiesis: Red blood cell (RBC) production
- Leucopoiesis: White blood cell (WBC) production
- Thrombopoiesis: Platelet production
- There are significantly more RBCs (~500x) in circulation than WBCs.
Haematopoiesis: Sites & Key Features
- In children, haematopoiesis primarily occurs in the marrow of long bones like the femur and tibia.
- In adults, it occurs in the pelvis, cranium, vertebrae, and sternum.
- Extramedullary haematopoiesis (e.g., in liver, thymus, or spleen) can occur if necessary.
- Maturation, activation, and proliferation of lymphoid cells happen in the spleen and lymph nodes.
- A single stem cell produces over a million mature cells, representing less than 0.1% of all cells in bone marrow.
- Stem cells grow and divide in the bone marrow.
- Loss of Cell Adhesion Molecules (CAMs) allows cells to leave the marrow and enter circulation.
- Growth factors are crucial for haematopoiesis, including:
- Erythropoietin
- Colony stimulating factors
- Interleukins
- Thrombopoietin
Erythropoiesis: Red Blood Cell Production
- One proerythroblast typically gives rise to 16 mature RBCs.
Erythrocytes: Characteristics & Life Cycle
- Erythrocytes are anucleate (lacking a nucleus) and have a discoid shape.
- They have a lifespan of approximately 120 days, with 1% destroyed daily.
- Anaemia: a decrease in Hb concentration below the reference range for age and sex (female: 11.5 – 16.0 g/dL, male: 13.5 – 17.5 g/dL).
-
Inherited haemolytic anaemias:
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Sickle cell anaemia
- Senescent (aging) RBCs are removed by macrophages.
- Haemoglobin components are recycled, with globin used to make amino acids and iron reutilized.
- Haem is excreted in bile.
Aerobic Metabolism: Oxygen Transport
- Multicellular organisms require oxygen for aerobic metabolism and utilize specialized proteins for oxygen transport and storage:
- Myoglobin
- Haemoglobin
Haem Group: Oxygen Binding
- The haem group is essential for oxygen binding by proteins.
- It is not part of the polypeptide chain but is tightly bound to the protein.
- Haem contains iron (Fe2+/ferrous) held in position by four nitrogen atoms.
- Fe2+ can form two additional bonds, one with oxygen.
- Protoporphyrin IX + Fe2+ = Haem
Myoglobin: Oxygen Reservoir
- Myoglobin is a storage protein found in heart and skeletal muscle cells.
- It is a compact protein with 153 amino acids and a molecular weight of 17 kDa.
- Structure:
- 75% alpha-helix
- 8 helices (A-H)
- Non-helical regions (AB, BC, etc.)
- Hydrophilic exterior
- Hydrophobic interior except for histidines E7 and F8
Myoglobin: Oxygen Binding
- Haem sits in a crevice near the surface lined with non-polar residues.
- E7 (distal His) and F8 (proximal His) are important for oxygen binding.
Myoglobin: Conformational Changes
- Deoxy-Mb: Haem iron lies out of plane by 0.3 Å.
- Oxy-Mb: Haem iron lies out of plane by 0.1 Å.
- Oxygenation moves the haem iron, which also moves His F8.
- Helix F movement causes other structural changes.
Haemoglobin: Structure & Function
- Two primary functions:
- Transports oxygen to tissues
- Transports carbon dioxide and protons away from tissues
- Structure:
- 4 polypeptide chains
- Each chain has a haem group, capable of binding one oxygen atom.
- Subunits are held together by non-covalent interactions.
Haemoglobin: Gene Expression Of The Alpha & Beta Chains
- Genes for alpha and beta chains:
- Alpha-like chains: chromosome 16
- z -> a2 -> a1
- Hb Gower 1 (z2e2) -> Hb F (a2g2) -> Hb A2 (a2d2) -> Hb A (a2b2)
- Beta-like chains: chromosome 11 - e -> Gg -> Ag -> d -> b
- Alpha-like chains: chromosome 16
Haemoglobin: Variant Forms & Gene Expression
- Hb type Expression Chains
- HbA Adult a2b2
- HbA2 Minor adult form a2d2
- HbF Foetal a2g2
- Hb Gower 1 embryonic z2e2
- Hb Gower 2 embryonic a2e2
- Hb Portland embryonic z2g2
Oxygen Dissociation Curve: Haemoglobin v. Myoglobin
- Myoglobin has a hyperbolic-shaped oxygen dissociation curve, indicating reversible binding of a single oxygen molecule at all sites.
- Haemoglobin has a sigmoid-shaped curve, indicating cooperative binding, where oxygen binding to one site affects the affinity of other sites.
- Myoglobin has a higher affinity for oxygen than haemoglobin, facilitating oxygen delivery from Hb to Mb.
Haemoglobin: Oxygen Binding and Cooperative Interactions
- Haemoglobin's sigmoid saturation curve reflects the cooperative binding of oxygen, meaning interactions between the protein subunits.
- The 4th oxygen bound has 300 times higher affinity than the 1st.
- Oxygen binding increases the affinity for subsequent oxygen molecules.
Haemoglobin: Structural Changes Due to Oxygenation
- Tense (T) form: Deoxy-Hb, low affinity for oxygen.
- Relaxed (R) form: Oxy-Hb, high affinity for oxygen.
- Changes in ionic and hydrophobic interactions between subunits contribute to the T and R forms.
Haemoglobin: Allosteric Effects
- Haem-Haem interaction (cooperativity): Oxygen binding at one site affects the affinity of others.
- Bohr effect: Oxygen is released more easily at low pH or high pCO2, favouring oxygen unloading in tissues and loading in the lungs.
- 2,3 Bisphosphoglycerate (BPG): Binds to deoxy-Hb in erythrocytes, decreasing its affinity for oxygen and stabilizing the tense (T) conformation.
- It shifts the oxygen dissociation curve to the right (higher P50), indicating a decreased oxygen affinity.
2,3-BPG: Effects on Oxygen Affinity
- 2,3-BPG binds to a central cavity in deoxy-Hb, forming salt bridges with positively charged residues on the beta subunits.
- These interactions stabilize the T conformation and must be broken during oxygenation.
- Oxygenation causes the cavity to narrow and squeeze out 2,3-BPG.
- Hb without 2,3-BPG has a higher oxygen affinity.
2,3-BPG: Physiological Significance
- Deoxy-Hb + 2,3-BPG: P50 = 26 Torr (lower oxygen affinity)
- Deoxy-Hb alone: P50 = 1 Torr (higher oxygen affinity)
- 2,3-BPG promotes oxygen release in tissues by decreasing oxygen affinity and shifting the saturation curve to the right.
- When oxygen levels are low (low oxygen tensions) or in anaemia, 2,3-BPG levels increase to facilitate oxygen delivery to tissues.
- Elevated 2,3-BPG increases oxygen delivery to tissues.
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Test your knowledge on the components and functions of human blood, focusing on hemoglobin, myoglobin, and the processes involved in erythropoiesis. Learn about the structure of red blood cells and the significance of iron in oxygen transport. This quiz covers key concepts related to blood physiology and hematology.
