Globular Proteins: Hemoglobin and Myoglobin

Written by: Adnan Mousa, M.D.

Keywords: Hemoglobin, Myoglobin, Oxygen binding, Cooperative binding, Hyperbolic curve, Sigmoidal curve, Oxygen transport

Overview

Hemoglobin and myoglobin are crucial globular proteins responsible for oxygen transport and storage. Myoglobin, a monomeric protein with a single heme group, exhibits a hyperbolic oxygen-binding curve, making it efficient for oxygen storage in muscle tissues. In contrast, hemoglobin is a tetramer composed of four subunits, displaying cooperative binding that results in a sigmoidal curve, enhancing oxygen delivery to tissues. The heme group, essential for oxygen binding, is stabilized by covalent linkages with globin chains. The distal histidine near the heme group facilitates effective oxygen binding while reducing carbon monoxide affinity. Additionally, 2,3-bisphosphoglycerate (BPG) promotes oxygen release, with the Bohr effect enhancing oxygen delivery under increased CO2 levels and lower pH. Understanding these proteins is vital for managing disorders like sickle cell disease and thalassemia, as well as their roles in exercise physiology and altitude adaptation.

Hemoglobin vs. Myoglobin

Table 1: Myolglobin vs Hemoglobin

Figure 1. Hemoglobin tetramer (a) and heme group (b).

OpenStax College. (2013, June 19). Illustration from Anatomy & Physiology. Connexions Web site. http://cnx.org/content/col11496/1.6/

Oxygen Dissociation Curves

Illustrates the relationship between arterial partial pressure of oxygen (PaO₂) and the saturation percentage of hemoglobin (Hb) or myoglobin with oxygen (SaO2), demonstrating the binding affinity for O₂.

Binding Curves:

●       Myoglobin:

−        Displays a hyperbolic curve due to its single polypeptide chain and monomeric heme.

−        Binds O₂ efficiently, suitable for its role in oxygen storage in muscle tissues.

●       Hemoglobin:

−        Exhibits a sigmoidal (S-shaped) curve due to positive cooperativity.

−        Cooperative binding is when binding of one O₂ molecule increases the affinity of adjacent heme sites for additional O₂.

−        Curve starts flat at low O₂, steepens as O₂ binds, and plateaus at high O₂ concentrations.

Physiological Shifts in Hemoglobin's O₂ Dissociation Curve:

●       Rightward Shift: Decreased affinity for O₂.

−        Impacts:

●       Enhances O₂ release to tissues.

●       Beneficial during increased metabolic demand (e.g., exercise, high altitude).

−        Causes:

●       Elevated carbon dioxide (PCO₂).

●       Increased body temperature.

●       Acidosis (lower pH).

●       Increased 2,3-bisphosphoglycerate (2,3-BPG).

●       Leftward Shift: Increased affinity for O₂.

−        Impacts:

●       Reduces O₂ delivery to tissues.

●       May trigger erythropoietin synthesis due to renal hypoxia.

−        Causes:

●       Decreased carbon dioxide (PCO₂).

●       Lower body temperature.

●       Alkalosis (higher pH).

●       Decreased 2,3-BPG levels.

●       Presence of fetal hemoglobin (HbF) or carbon monoxide (CO).

Figure 2. Oxygen-Hemoglobin dissociation curve

Webb, K. L. (2022). Influence of high hemoglobin-oxygen affinity on humans during hypoxia [Figure]. Frontiers in Physiology. https://doi.org/10.3389/fphys.2021.763933 

Figure 3. Myoglobin vs Hemoglobin dissociation curves

蛇守护的苹果堆. (2020, January 18). Hb和Mb的氧解离曲线 [Oxygen dissociation curves of Hb and Mb] [Image]. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Hb%E5%92%8CMb%E7%9A%84%E6%B0%A7%E8%A7%A3%E7%A6%BB%E6%9B%B2%E7%BA%BF.png

Heme Structure

●       Heme is a planar structure composed of a porphyrin ring.

●       The porphyrin ring contains ferrous iron (Fe²⁺) coordinated at its center.

●       The iron is held in place by bonds to four nitrogen atoms from the porphyrin ring.

●       Fe²⁺ can form two additional bonds, one on each side of the planar ring.

●       Binding Sites:

−        In hemoglobin, one of these additional positions is coordinated to the side chain of a histidine residue from the globin molecule.

−        The other position is available for binding oxygen (O₂).

Figure 4. Porphyrin ring in heme A.

Yikrazuul. (2010, August 3). Heme a [Own work]. https://commons.wikimedia.org/wiki/File:Heme_a.svg

Figure 5. Binding of oxygen to heme group.

Smokefoot. (2017, November 1). Oxygenation of heme protein [Own work]. https://commons.wikimedia.org/wiki/File:Mboxygenation.png

Figure 6. Binding of distal histidine to heme group.

Mrbean427. (2008, December 4). Showing the oxygen stabilization with distal histidine's hydrogen bonding with the O₂ molecule [Own work]. https://commons.wikimedia.org/wiki/File:HEME_%2B_DISTAL_HISTIDINE.jpg

Distal Histidine and 2,3-Bisphosphoglycerate (BPG)

Table 2: Distal histidine and 2,3-Bisphosphoglycerate

Bohr Effect

●       Affinity relationship: Increase in CO₂ and H⁺ levels → decrease in hemoglobin’s (Hb) affinity for oxygen (O₂).

●       In high metabolism: High levels of CO₂ and H⁺ ions, produced by active tissues, cause hemoglobin to release more oxygen where it's needed.

●       Importance: It ensures that oxygen is delivered efficiently to tissues that are using more oxygen, like muscles during exercise.

Haldane Effect

●       Affinity Relationship: The affinity of hemoglobin (Hb) for carbon dioxide (CO₂) decreases when it is oxygenated.

●       Oxygenation in the Lungs: In areas with high oxygen levels, such as the lungs, oxygenated hemoglobin releases CO₂ for exhalation.

●       CO₂ Uptake in Tissues: In peripheral tissues with low oxygen, deoxygenated hemoglobin facilitates the uptake of CO₂.

●       Gas Exchange Efficiency: This effect ensures oxygen is absorbed while carbon dioxide is expelled from the body.

Hemoglobin S (HbS)

●       Hemoglobin S (HbS) is a form of hemoglobin that differs from normal hemoglobin (HbA) due to a single change in the amino acid sequence of the β-globin chain.

●       HbS can clump together (polymerize) when oxygen levels are low

●       The polymerization leads to the formation of sickle-shaped red blood cells, which can block blood vessels and reduce oxygen delivery to tissues.

●       Individuals with sickle cell disease often experience chronic anemia and other health complications due to the decreased oxygen supply to their tissues.

Associated Conditions

Table 3: Clinical examples