How Oxygen Binding To Hemoglobin

*A reported dissociation constant is valid only for the particular solution conditions under which it was measured. Kd values for a protein-ligand interaction can be altered, sometimes by several orders of magnitude, by changes in the solution's salt concentration, pH, or other variables.

interaction of avidin with biotin, an enzyme cofactor, is among the strongest noncovalent biochemical interactions known.

*A reported dissociation constant is valid only for the particular solution conditions under which it was measured. Kd values for a protein-ligand interaction can be altered, sometimes by several orders of magnitude, by changes in the solution's salt concentration, pH, or other variables.

interaction of avidin with biotin, an enzyme cofactor, is among the strongest noncovalent biochemical interactions known.

^This immunoglobulin was isolated as part of an effort to develop a vaccine against HIV. Immunoglobulins (described later in the chapter) are highly variable, and the Kd reported here should not be considered characteristic of all immunoglobulins.

Calmodulin has four binding sites for calcium. The values shown reflect the highest- and lowest-affinity binding sites observed in one set of measurements.

162 Part I Structure and Catalysis

Protein Structure Affects How Ligands Bind

The binding of a ligand to a protein is rarely as simple as the above equations would suggest. The interaction is greatly affected by protein structure and is often accompanied by conformational changes. For example, the specificity with which heme binds its various ligands is altered when the heme is a component of myoglobin. Carbon monoxide binds to free heme molecules more than 20,000 times better than does O2 (that is, the Kd or P50 for CO binding to free heme is more than 20,000 times lower than that for O2), but it binds only about 200 times better when the heme is bound in myoglobin. The difference may be partly explained by steric hindrance. When O2 binds to free heme, the axis of the oxygen molecule is positioned at an angle to the Fe—O bond (Fig. 5-5a). In contrast, when CO binds to free heme, the Fe, C, and O atoms lie in a straight line (Fig. 5-5b). In both cases, the binding reflects the geometry of hybrid orbitals in each ligand. In myoglobin, His64 (His E7), on the O2-binding side of the heme, is too far away to coordinate with the heme iron, but it does interact with a ligand bound to heme. This residue, called the distal His, does not affect the binding of O2 (Fig. 5-5c) but may preclude the linear binding of CO, providing one explanation for the diminished binding of CO to heme in myoglobin (and hemoglobin). A reduction in CO binding is physiologically important, because CO is a low-level byproduct of cellular metabolism. Other factors, not yet well-defined, also seem to modulate the interaction of heme with CO in these proteins.

The binding of O2 to the heme in myoglobin also depends on molecular motions, or "breathing," in the protein structure. The heme molecule is deeply buried in the folded polypeptide, with no direct path for oxygen to move from the surrounding solution to the ligand-binding site. If the protein were rigid, O2 could not enter or leave the heme pocket at a measurable rate. However, rapid molecular flexing of the amino acid side chains produces transient cavities in the protein structure, and O2 evidently makes its way in and out by moving through these cavities. Computer simulations of rapid structural fluctuations in myoglobin suggest that there are many such pathways. One major route is provided by rotation of the side chain of the distal His (His64), which occurs on a nanosecond (10~9 s) time scale. Even subtle conformational changes can be critical for protein activity.

Oxygen Is Transported in Blood by Hemoglobin

Q Oxygen-Binding Proteins—Hemoglobin: Oxygen Transport

Nearly all the oxygen carried by whole blood in animals is bound and transported by hemoglobin in erythrocytes (red blood cells). Normal human erythrocytes are small (6 to 9 ^m in diameter), biconcave disks. They are formed from precursor stem cells called hemocytoblasts. In

Heme Binding Site Myoglobin

FIGURE 5-5 Steric effects on the binding of ligands to the heme of myoglobin. (a) Oxygen binds to heme with the O2 axis at an angle, a binding conformation readily accommodated by myoglobin. (b) Carbon monoxide binds to free heme with the CO axis perpendicular to the plane of the porphyrin ring. When binding to the heme in myoglobin, CO is forced to adopt a slight angle because the perpendicular arrangement is sterically blocked by His E7, the distal His. This effect weakens the binding of CO to myoglobin. (c) Another view (derived from PDB ID 1MBO), showing the arrangement of key amino acid residues around the heme of myoglobin. The bound O2 is hydrogen-bonded to the distal His, His E7 (His64), further facilitating the binding of O2.

FIGURE 5-5 Steric effects on the binding of ligands to the heme of myoglobin. (a) Oxygen binds to heme with the O2 axis at an angle, a binding conformation readily accommodated by myoglobin. (b) Carbon monoxide binds to free heme with the CO axis perpendicular to the plane of the porphyrin ring. When binding to the heme in myoglobin, CO is forced to adopt a slight angle because the perpendicular arrangement is sterically blocked by His E7, the distal His. This effect weakens the binding of CO to myoglobin. (c) Another view (derived from PDB ID 1MBO), showing the arrangement of key amino acid residues around the heme of myoglobin. The bound O2 is hydrogen-bonded to the distal His, His E7 (His64), further facilitating the binding of O2.

the maturation process, the stem cell produces daughter cells that form large amounts of hemoglobin and then lose their intracellular organelles—nucleus, mitochondria, and endoplasmic reticulum. Erythrocytes are thus incomplete, vestigial cells, unable to reproduce and, in humans, destined to survive for only about 120 days. Their main function is to carry hemoglobin, which is dissolved in the cytosol at a very high concentration (~34% by weight).

In arterial blood passing from the lungs through the heart to the peripheral tissues, hemoglobin is about 96% saturated with oxygen. In the venous blood returning to the heart, hemoglobin is only about 64% saturated. Thus, each 100 mL of blood passing through a tissue releases

Was this article helpful?

0 0
Dr. Atkins New Diet Revolution

Dr. Atkins New Diet Revolution

Wanting to lose weight and dont know where to start? Dr Atkins will help you out and lose weight fast. Learn more...

Get My Free Ebook


Responses

  • paladin
    How oxygen binding to hemoglobin?
    7 years ago
  • LEA
    How does hemoglobin bind with oxygen steps?
    4 years ago
  • henriikka lenkkeri
    How does his64 bind to oxygen in myoglobin?
    3 years ago

Post a comment