BIOCHEM 2.2 : O2 TRANSPORT AND O2 BINDING PROTEINS
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Consider a scenario where a patient presents with chronic hypoxemia due to a rare genetic mutation affecting 2,3-BPG production in erythrocytes, resulting in increased hemoglobin affinity for oxygen. How would this condition most likely manifest, and what compensatory mechanism might the body employ?

  • Decreased oxygen delivery to tissues; decreased erythropoietin production.
  • Increased oxygen delivery to tissues; increased erythropoietin production.
  • Decreased oxygen delivery to tissues; increased erythropoietin production. (correct)
  • Increased oxygen delivery to tissues; decreased erythropoietin production.

    • A researcher is studying a novel allosteric modulator that selectively stabilizes the T-state of hemoglobin. Which of the following would be the most likely observed effect of this modulator on hemoglobin's oxygen-binding curve and its physiological consequences?

  • A rightward shift in the oxygen-binding curve, enhancing oxygen delivery to tissues. (correct)
  • An upward shift in the oxygen-binding curve, leading to increased oxygen solubility in blood.
  • A leftward shift in the oxygen-binding curve, impairing oxygen delivery to tissues.
  • No change in the oxygen-binding curve, with no effect on oxygen delivery.

    • In a patient with a severe Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, exposure to oxidative stress can lead to hemolytic anemia. What is the underlying mechanism by which G6PD deficiency contributes to erythrocyte damage under oxidative stress conditions?

  • Impaired production of NADPH, leading to increased susceptibility to oxidative damage. (correct)
  • Increased production of NADPH, leading to excessive reactive oxygen species neutralization.
  • Decreased activity of superoxide dismutase, resulting in the accumulation of superoxide radicals.
  • Increased activity of glutathione reductase, causing oxidative damage to the cell membrane.

    • Which of the following scenarios would result in the greatest decrease in hemoglobin's affinity for oxygen?

    <p>A decrease in blood pH from 7.4 to 7.2, alongside an increase in CO2 partial pressure. (B)</p> Signup and view all the answers

    A researcher discovers a new variant of hemoglobin with enhanced oxygen-binding affinity but impaired cooperativity. What would be the most likely consequence of this mutation on oxygen transport and delivery?

    <p>Reduced oxygen delivery at tissues despite higher saturation at the lungs. (D)</p> Signup and view all the answers

    Consider a patient with a rare genetic defect that causes erythrocytes to have a significantly reduced capacity for glycolysis, alongside normal pentose phosphate pathway activity. How would this condition most likely affect oxygen transport and erythrocyte function?

    <p>Decreased oxygen delivery to tissues due to lower 2,3-BPG levels. (A)</p> Signup and view all the answers

    What is the primary consequence of the amino acid substitution in sickle-cell hemoglobin?

    <p>Aggregation of hemoglobin molecules due to hydrophobic interactions, decreasing oxygen-carrying capacity. (D)</p> Signup and view all the answers

    How does the mutation in sickle cell hemoglobin directly impact the structure and function of red blood cells?

    <p>It induces polymerization of hemoglobin, deforming the red blood cells into a sickle shape and reducing their flexibility. (C)</p> Signup and view all the answers

    Which biophysical property is most altered by the amino acid substitution in sickle-cell hemoglobin, leading to its pathological effects?

    <p>Hydrophobic interactions between hemoglobin molecules. (B)</p> Signup and view all the answers

    If a new mutation in hemoglobin were discovered that also caused aggregation, but through ionic interactions rather than hydrophobic interactions, what would be the most likely characteristic of the amino acid substitution?

    <p>Replacement of a positively charged amino acid with a negatively charged amino acid. (C)</p> Signup and view all the answers

    Considering the impact of amino acid sequence on protein function, what fundamental principle is exemplified by the difference between normal and sickle-cell hemoglobin?

    <p>A single amino acid change in a protein can significantly alter its structure, leading to altered function and pathology. (C)</p> Signup and view all the answers

    Given that sickle-cell anemia results from abnormal hemoglobin aggregation, which therapeutic strategy would likely provide the most direct approach to preventing the polymerization of sickle-cell fibers?

    <p>Using chaperone molecules or small molecule drugs that bind to hemoglobin and prevent intermolecular hydrophobic interactions. (A)</p> Signup and view all the answers

    How does the absence of mitochondria in mature erythrocytes impact their metabolic processes?

    <p>Erythrocytes depend solely on blood glucose, metabolized anaerobically, as their primary metabolic fuel. (A)</p> Signup and view all the answers

    In erythrocytes, what is the primary purpose of diverting 10-20% of a glycolysis intermediate (1,3-bisphosphoglycerate)?

    <p>To generate an allosteric regulator of hemoglobin's oxygen affinity. (C)</p> Signup and view all the answers

    Why is the metabolism of glucose in erythrocytes primarily anaerobic?

    <p>Erythrocytes lack mitochondria, which are essential for aerobic metabolism. (C)</p> Signup and view all the answers

    How does the pentose phosphate pathway contribute to the function of erythrocytes?

    <p>It protects against oxidative stress and provides NADPH. (D)</p> Signup and view all the answers

    What is the immediate consequence of a point mutation in the beta-hemoglobin gene that results in sickle cell disease?

    <p>Altered primary structure leading to changes in tertiary structure, causing hydrophobic interactions and polymerization. (D)</p> Signup and view all the answers

    What role do the kidneys play in maintaining acid-base balance in conjunction with the lungs and erythrocytes?

    <p>The kidneys reabsorb filtered bicarbonate and generate new bicarbonate to regulate pH. (D)</p> Signup and view all the answers

    How does the structure of hemoglobin facilitate the transport of both oxygen and carbon dioxide?

    <p>Oxygen binds directly to the heme group, while carbon dioxide is primarily processed into bicarbonate for transport. (A)</p> Signup and view all the answers

    What is the significance of erythrocytes losing their subcellular organelles during maturation?

    <p>It maximizes space for hemoglobin, optimizing oxygen-carrying capacity at the expense of other cellular functions. (D)</p> Signup and view all the answers

    During the reversible interconversion stage of the pentose phosphate pathway, what happens to excess pentose phosphates?

    <p>They are recycled into glycolytic intermediates. (B)</p> Signup and view all the answers

    How does a mutation in the primary structure of hemoglobin lead to altered function and disease, as exemplified by sickle cell anemia?

    <p>A change in primary structure can alter secondary, tertiary, and quaternary structures, affecting protein interactions and overall function. (B)</p> Signup and view all the answers

    In what way does the absence of mitochondria in mature erythrocytes directly influence their metabolic strategy, especially when contrasted with other cell types that possess mitochondria?

    <p>Erythrocytes exclusively use glycolysis for ATP production, leading to the generation of lactate, while other cells can utilize oxidative phosphorylation. (C)</p> Signup and view all the answers

    How does the concentration of 2,3-bisphosphoglycerate (2,3-BPG) affect the function of hemoglobin in erythrocytes, and what is the physiological significance of this modulation?

    <p>2,3-BPG decreases hemoglobin's oxygen affinity, facilitating oxygen release in tissues, particularly during periods of high metabolic activity or hypoxia. (B)</p> Signup and view all the answers

    How does the Bohr effect optimize oxygen delivery in metabolically active tissues, and what is the central mechanism driving this process?

    <p>By reducing oxygen binding affinity in response to decreased pH and increased carbon dioxide, facilitating oxygen release in tissues with high metabolic demand. (B)</p> Signup and view all the answers

    What implications does the 'positive cooperativity' of oxygen binding to hemoglobin have on its oxygen saturation curve, and how does this affect oxygen delivery?

    <p>It results in a sigmoidal curve, where the binding of one oxygen molecule increases the affinity for subsequent oxygen molecules, optimizing oxygen loading and unloading. (A)</p> Signup and view all the answers

    How do pulse oximeters utilize the spectral properties of hemoglobin to determine oxygen saturation, and what principle underlies their accuracy?

    <p>By detecting the distinct absorption spectra of oxygenated and deoxygenated hemoglobin at specific wavelengths, allowing calculation of the relative proportions. (B)</p> Signup and view all the answers

    If a patient presents with chronic hypoxemia due to a respiratory disease, how might their erythrocytes adapt over time, and what is the underlying mechanism for this adaptation?

    <p>Increase production of 2,3-BPG, enhancing oxygen unloading in tissues. (B)</p> Signup and view all the answers

    During intense exercise, several factors including increased temperature, decreased pH, and elevated carbon dioxide levels influence hemoglobin's oxygen-binding affinity. Which single factor exerts the most immediate and direct impact on facilitating oxygen release to active muscle tissues?

    <p>The lowered pH, indicative of increased acidity, protonates key amino acid residues in hemoglobin, reducing its oxygen affinity. (C)</p> Signup and view all the answers

    How does carbon monoxide (CO) poisoning affect oxygen transport by hemoglobin, and what is the primary mechanism behind its toxicity at the molecular level?

    <p>CO binds to hemoglobin with a much higher affinity than oxygen, preventing oxygen binding and also increasing hemoglobin's affinity for any remaining oxygen, hindering its release in tissues. (B)</p> Signup and view all the answers

    Flashcards

    Heme Structure

    A complex of iron and porphyrin crucial for oxygen binding in hemoglobin and myoglobin.

    Myoglobin vs Hemoglobin

    Myoglobin stores oxygen in muscle, while hemoglobin transports oxygen in blood.

    Bohr Effect

    The phenomenon where increased CO2 or decreased pH causes hemoglobin to release oxygen.

    Pulse Oximetry

    A non-invasive method to measure blood oxygen saturation.

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    Pentose Phosphate Pathway

    A metabolic pathway that generates NADPH and ribose-5-phosphate for erythrocytes.

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    Erythrocyte Function

    Erythrocytes transport oxygen and carbon dioxide in the bloodstream.

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    Sickle-cell hemoglobin

    A variant of hemoglobin that causes sickle-shaped red blood cells.

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    Hydrophobic interactions

    The tendency of non-polar proteins to clump together in an aqueous environment.

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    Red blood cell deformation

    The change in shape of red blood cells due to sickle-cell hemoglobin.

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    Reduced oxygen capacity

    The decreased ability of sickle-shaped red blood cells to carry oxygen.

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    Aggregation of hemoglobin

    The clumping together of hemoglobin molecules due to hydrophobic interactions.

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    Sickle-cell disease effects

    A condition characterized by recurrent pain and possible complications from distorted red blood cells.

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    Role of Oxygen in Metabolism

    Oxygen is essential for oxidation reactions, ATP generation, and detoxification processes.

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    Erythrocytes (RBCs)

    Mature erythrocytes transport oxygen but do not utilize it, making them crucial for oxygen delivery.

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    Function of Heme

    Heme, primarily in hemoglobin, is crucial for oxygen transport and plays roles in respiration and detoxification.

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    Heme Synthesis Process

    Heme is synthesized from glycine and succinyl-CoA by 5-ALA synthase, involving multiple steps including iron addition.

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    Positive Cooperativity of Hemoglobin

    Hemoglobin shows cooperative binding, meaning binding of one oxygen increases the affinity for others.

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    Acid-Base Balance

    The regulation of pH levels via lungs and kidneys interacting with bicarbonate and carbonic acid.

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    Role of Hemoglobin

    Hemoglobin acts as a buffer for hydrogen ions (H+) from carbonic acid in erythrocytes.

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    Bicarbonate Formation

    Carbon dioxide is processed into bicarbonate in red blood cells (RBCs) for transport.

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    Anaerobic Metabolism in RBCs

    RBCs metabolize glucose exclusively through anaerobic glycolysis, producing lactic acid.

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    Role of 2,3-BPG

    An intermediate in glycolysis that regulates oxygen affinity in hemoglobin.

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    Pentose Phosphate Pathway Functions

    Generates NADPH and pentose phosphates, essential for protecting against oxidative stress.

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    Glucose Utilization Rate

    RBCs have the highest glucose utilization rate, using 10g per kg tissue daily.

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    Sickle Cell Disease

    A hemoglobinopathy caused by a point mutation leading to sickle-shaped RBCs.

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    Mutation Impact on Hemoglobin

    Genetic mutations in hemoglobin can alter its structure and function, causing disorders.

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    Red Blood Cell Maturation

    RBC maturation involves losing organelles: no DNA, ribosomes, or mitochondria are left.

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    Study Notes

    Oxygen Transport and Oxygen Binding Proteins

    • Oxygen is crucial for various metabolic processes, detoxification, and ATP generation.
    • Oxygen acts as an electron acceptor, and can accept single electrons.
    • Reactive oxygen species are formed when oxygen accepts single electrons.
    • Oxidases, peroxidases, and oxygenases bind O2 and transfer single electrons to it via a metal.
    • Oxygen transport is carried out by mature erythrocytes (RBCs) which make up 40-45% of blood volume and the majority of formed elements in blood.

    Objectives

    • Describe heme synthesis, structure, and importance for myoglobin and hemoglobin.

    • Compare and contrast myoglobin and hemoglobin, their structure, behavior, localization, and use.

    • Explain pulse oximetry and its use in evaluating normal and abnormal oxygen transport.

    • Explain allosteric regulation of oxygen binding to hemoglobin and consequences of changes in pH, CO2 levels, and 2,3-BPG.

    • Evaluate erythrocyte structure, function, and metabolism.

      • List key differences between erythrocytes and other human cells in terms of structure and contents.
      • Summarize differences in glucose metabolism between erythrocytes compared to other cell types.

    • Compare and contrast oxygen and carbon dioxide transport within erythrocytes.

      • Explain the role of bicarbonate in carbon dioxide regulation.
      • Summarize roles of lungs, kidneys, tissues, and erythrocytes in CO2 regulation and acid-base balance.

    • Explain the importance of the pentose phosphate pathway for erythrocyte function and oxidative phosphorylation.

    • Describe the role of oxidation-reduction reactions in the pentose phosphate pathway, comparing reversible and irreversible steps.

    • Determine the consequences of loss or gain of function changes in the pentose phosphate pathway.

    • Compare and contrast sickle cell disease and hemoglobinopathies, including classification, biochemical changes, and clinical consequences.

    Oxygen Basics

    • Oxygen is required for numerous metabolic processes, detoxification reactions, and ATP generation.
    • Oxygen's primary role is to act as an electron acceptor.
    • Oxygen radicals/reactive oxygen species (ROS) are formed when oxygen accepts single electrons. (Further details on these are in a subsequent lecture.)
    • Metal-containing enzymes bind O2 and transfer single electrons to it.

    Oxygen Transport

    • Oxygen transport occurs via mature erythrocytes (RBCs).
    • RBCs are structurally and metabolically the simplest cells in the body.
    • RBCs represent a significant portion (40-45%) of blood volume and the majority (90%) of formed elements in blood.

    Oxygen Binding (Heme)

    • Heme is an iron-containing prosthetic group within porphyrin rings.
    • Iron ions in heme are held in place by nitrogen molecules, playing a role in a wide range of processes including oxygen transport, respiration, diatomic gas sensing, signal transduction, detoxification, molecular genetics processes (including transcription, translation and microRNA processing), protein stability, and mitochondrial import.
    • Heme production in humans is primarily carried out by red blood cells (85%).
      • Liver is the second major source of heme production.

    Heme Synthesis

    • Heme synthesis occurs from glycine and succinyl CoA.
    • 5-aminolevulinate (5-ALA) is a key intermediate in the process.
    • Porphobilinogen (PBG) molecules combine, followed by cyclization.
    • Decarboxylation and oxidation of PBG within the mitochondria
    • Iron addition is the final step in heme production.

    Oxygen Binding Proteins: Myoglobin and Hemoglobin

    • Myoglobin: Compact globular protein binding one oxygen molecule; tissue storage protein; high affinity for O2, important for rapid activity during high energy demand.
    • Hemoglobin: Tetramer of four globin subunits, binding four oxygen molecules. Oxygen transport protein for blood, most common form is composed of two α and two β-globin subunits. There are also less common forms like fetal hemoglobin.

    Oxygen Transport and Positive Cooperativity

    • Oxygen binding to hemoglobin follows classic cooperativity.
    • The tetramer structure of hemoglobin does not maintain symmetry when binding and releasing oxygen.
    • Oxygen binding parameters, such as fractional saturation, are represented by a sigmoidal curve with respect to partial oxygen pressure (pO2).

    Allosteric Regulation of Hemoglobin

    • Hemoglobin's oxygen binding affinity is regulated by small molecules (allosteric effectors).
    • Key allosteric effectors include H+, CO2, and 2,3-bisphosphoglycerate (2,3-BPG).
    • Increases in H+, CO2, and 2,3-BPG result in decreased oxygen affinity, facilitating oxygen release in tissues.
    • Effects of these allosteric effectors are additive.

    Bohr Effect

    • Changes in pH affect hemoglobin's oxygen affinity.
    • Enables oxygen unloading in tissues where pH is lower (due to increased CO2 and H+).

    Pulse Oximetry

    • Pulse oximeters measure oxygen saturation (SpO2) from hemoglobin in the blood via visible and infrared light transmission.
    • These measurements give information on oxygen saturation (SpO2), pulse rate, and body temperature.
    • SpO2 helps assess cardiopulmonary status.
    • Pulse oximetry assessment provides clinical value and practical applications like at-home monitoring (e.g., during COVID-19).

    CO2 and Hydrogen Ions

    • Interconnection between lungs, kidneys, and erythrocytes determines acid-base balance.
    • Lungs facilitate gas exchange (O2-in, CO2-out) with CO2 converted to bicarbonate for transport.
    • Plasma transports CO2 as bicarbonate.
    • Hemoglobin acts as a buffer for H+ from carbonic acid.
    • Erythrocytes transport both O2 and CO2.
    • Kidneys reabsorb filtered bicarbonate and generate new bicarbonate. The process is important for maintaining acid-base balance in the body.

    Carbon Dioxide in RBCs

    • RBCs carry both oxygen and carbon dioxide.
    • Carbon dioxide primarily travels as bicarbonate within the erythrocyte.
    • Removal of CO2 from RBCs involves reversing the steps to exhale from the lungs.

    More on Erythrocytes

    • RBCs lose organelles (e.g., nucleus, ribosomes).
    • They have the highest specific rate of glucose use, metabolizing it to lactate via anaerobic glycolysis.
    • 90% of glucose metabolism in RBCs results in lactate.

    Anaerobic Metabolism in RBCs

    • Glucose is broken down to generate two molecules of pyruvate.
    • RBCs carry out anaerobic glycolysis, converting pyruvate to lactate, which is a source of ATP.
    • 1,3-bisphosphoglycerate(1,3-BPG) is an important intermediate in glycolysis.
    • 2,3-bisphosphoglycerate (2,3-BPG) is an allosteric regulator of hemoglobin's oxygen affinity, crucial for oxygen unloading in tissues.
    • Approximately 10-20% of 1,3-BPG is converted to 2,3-BPG.
    • Pentose phosphate pathway protects from oxidative stress and generates NADPH.

    Pentose Phosphate Pathway

    • The pentose phosphate pathway generates NADPH and pentose phosphates.
    • The pathway has reversible interconversion stages where excess pentose phosphates are recycled into glycolytic intermediates.

    Oxygen Deficiency and Hemoglobinopathies

    • Oxygen deficiency can be linked to mutations in genes encoding hemoglobin.
    • Hemoglobinopathies are classified by prominent changes in protein structure, function, or regulation.
    • Sickle cell disease is an example, a point mutation in the beta-hemoglobin gene causing valine to replace glutamic acid in the protein structure. This leads to hydrophobic interactions and polymerization when deoxygenated, distorting the red blood cells into a sickle shape.

    Importance of Primary Structure to Function

    • Primary structure influences secondary, tertiary, and quaternary structures ultimately impacting protein function.
    • Normal vs. sickle-cell hemoglobin differs in a single amino acid (valine versus glutamate), which significantly alters the protein's structure and solubility.

    Hemoglobinopathies

    • This section details various hemoglobinopathies based on classification, common mutations, frequency, biochemical changes, and clinical consequences.
    • The listed hemoglobinopathies include differences in solubility, oxygen affinity, and stable states (reduced versus oxidized).

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    BMS 531.09 Oxygen Transport and Hemoglobin PDF

    Description

    Test your knowledge on hemoglobin physiology and related pathologies in this quiz. Explore conditions like hypoxemia, G6PD deficiency, and the effects of allosteric modulators on hemoglobin. Understand how various factors can affect oxygen affinity and the body's compensatory mechanisms.

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