Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Oxygen Binding to Hemoglobin Is Regulated by 2,3-Bisphosphoglycerate

The interaction of 2,3-bisphosphoglycerate (BPG) with hemoglobin provides an example of heterotropic allosteric modulation.

BPG is present in relatively high concentrations in erythrocytes. When hemoglobin is isolated, it contains sub stantial amounts of bound BPG, which can be difficult to remove completely. In fact, the O₂-binding curves for hemoglobin that we have examined to this point were obtained in the presence of bound BPG. 2,3-Bisphospho glycerate is known to greatly reduce the affinity of hemoglobin for oxygen—there is an inverse relationship between the binding of O₂ and the binding of BPG. We can therefore describe another binding process for hemoglobin:

HbBPG+O₂⇌HbO₂+BPG

BPG binds at a site distant from the oxygen-binding site and regulates the O₂-binding affinity of hemoglobin in relation to the pO₂ in the lungs. BPG plays an important role in the physiological adaptation to the lower pO₂ available at high altitudes. For a healthy human strolling by the ocean, the binding of O₂ to hemoglobin is regulated such that the amount of O₂ delivered to the tissues is equivalent to nearly 40% of the maximum that could be carried by the blood (Fig. 5–17). Imagine that this person is quickly transported to a mountainside at an altitude of 4,500 meters, where the pO₂ is consider ably lower. The delivery of O₂ to the tissues is now reduced. However, after just a few hours at the higher altitude, the BPG concentration in the blood has begun to rise, leading to a decrease in the affinity of hemoglobin for oxygen. This adjustment in the BPG level has only a small effect on the binding of O₂ in the lungs but a considerable effect on the release of O₂ in the tissues. As a result, the delivery of oxygen to the tissues is re stored to nearly 40% of that which can be transported by the blood. The situation is reversed when the person returns to sea level. The BPG concentration in erythrocytes also increases in people suffering from hypoxia, lowered oxygenation of peripheral tissues due to in adequate functioning of the lungs or circulatory system. The site of BPG binding to hemoglobin is the cavity between the subunits in the T state (Fig. 5–18).

FIGURE 5–17 Effect of BPG on the binding of oxygen to hemoglo bin. The BPG concentration in normal human blood is about 5 mM at sea level and about 8 mM at high altitudes. Note that hemoglobin binds to oxygen quite tightly when BPG is entirely absent, and the binding curve appears to be hyperbolic. In reality, the measured Hill coefficient for O₂-binding cooperativity decreases only slightly (from 3 to about 2.5) when BPG is removed from hemoglobin, but the rising part of the sigmoid curve is confined to a very small region close to the origin. At sea level, hemoglobin is nearly saturated with O₂ in the lungs, but only 60% saturated in the tissues, so the amount of oxy gen released in the tissues is close to 40% of the maximum that can be carried in the blood. At high altitudes, O₂ delivery declines by about one-fourth, to 30% of maximum. An increase in BPG concentration, however, decreases the affinity of hemoglobin for O₂, so nearly 40% of what can be carried is again delivered to the tissues.

FIGURE 5–18 Binding of BPG to deoxyhemoglobin. (a) BPG binding stabilizes the T state of deoxyhemoglobin (PDB ID 1HGA), shown here as a mesh surface image. (b) The negative charges of BPG interact with several positively charged groups (shown in blue in this surface contour image) that surround the pocket between the β subunits in the T state. (c) The binding pocket for BPG disappears on oxygenation, following transition to the R state (PDB ID 1BBB). (Compare (b) and (c) with Fig. 5–10.)

This cavity is lined with positively charged amino acid residues that interact with the negatively charged groups of BPG. Unlike O₂, only one molecule of BPG is bound to each hemoglobin tetramer. BPG lowers hemoglobin’s affinity for oxygen by stabilizing the T state. The transition to the R state narrows the binding pocket for BPG, precluding BPG binding. In the absence of BPG, hemoglobin is converted to the R state more easily. Regulation of oxygen binding to hemoglobin by BPG has an important role in fetal development. Because a fetus must extract oxygen from its mother’s blood, fetal hemoglobin must have greater affinity than the maternal hemoglobin for O₂. The fetus synthesizes γ subunits rather than β subunits, forming α₂γ₂ hemoglobin. This tetramer has a much lower affinity for BPG than normal adult hemoglobin, and a correspondingly higher affinity for O₂.

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مواضيع ذات صلة

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -The Immune Response Features a Specialized Array of Cells and Proteins

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Sickle-Cell Anemia Is a Molecular Disease of Hemoglobin

Protein Denaturation and Folding: - Loss of Protein Structure Results in Loss of Function

Protein Tertiary and Quaternary Structures: -There Are Limits to the Size of Proteins

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Protein-Ligand Interactions Can Be Described Quantitatively

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Myoglobin Has a Single Binding Site for Oxygen

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Oxygen Can Be Bound to a Heme Prosthetic Group

Protein Denaturation and Folding:- Some Proteins Undergo Assisted Folding

Protein Denaturation and Folding:- Polypeptides Fold Rapidly by a Stepwise Process

Protein Denaturation and Folding: - Amino Acid Sequence Determines Tertiary Structure

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes