Both H+ and O2 bind directly to hemoglobin with an inverse affinity that is pH dependent. In the presence of high oxygen, hemoglobin binds oxygen and releases protons. But when oxygen concentration is low, hemoglobin binds H+ and oxygen is released. As will be discussed below, hemoglobin binds O2 specifically to iron Fe2+ in a heme group. The proton, H+, binds randomly to several of hemoglobin’s amino acids, such as histidine.

Hemoglobin binds oxygen cooperatively and generates two conformations designated as the R state (relaxed) and T state (taut). Oxygen has a much higher affinity for hemoglobin in the R state. When the oxygen concentration is reduced or absent, the T state of hemoglobin is dominant. Some of the consequences of changes in pH are illustrated in panel C of Figure1.

Fig1. Hemoglobin as a carrier of oxygen in the circulatory system. (A) X-ray crystallographic structure of hemoglobin. Hemoglobin has a molecular weight of 64,500. It is comprised of three components: (i) two α chains (each 146 amino acids), each folded as a red α helix; (ii) two β chains (each 141 amino acids), each folded as a blue α helix; and (iii) four heme prosthetic groups that are separately associated with one of the four α-helices. Each molecule of hemoglobin can bind four molecules of oxygen (O2) with one O2 per heme group. (B) Structure of hemoglobins heme group with bound oxygen. Each of the four heme groups, known as protoporphyrin IX, has a bound iron atom in its ferrous oxidation state (Fe2+). The four protoporphyrin IXs each has four planar pyrrole rings that are connected together by methylene bridges. Each of the four pyrrole rings is colored peach. (C1) The pH dependency of oxygen binding to hemoglobin. This figure reports the difference in fractional occupancy of the oxygen binding sites on the heme groups of hemoglobin as a function of the pH of the local environment. The comparison was made between a pH 7.6 (less acidic) environment (green line) with that of a lower pH 7.2 (more acidic) environment (red line). At the lower 7.2 pH, the fractional binding of 50% was achieved at a pressure of 4.2 kPa. In contrast, at the higher pH of 7.6, a reduction of the pressure to 2.6 was still adequate to achieve a 50% occupancy of the hemoglobin binding sites. Or to analyze the data differently, at an oxygen pressure of 4.2 kPa, for a pH 7.2, only a 50% occupancy was achieved, while for the pH of 7.6 a higher occupancy of ~75% was achieved. (C2) Physiological effects of oxygen binding to hemoglobin. This panel shows two oxygen-binding curves to hemoglobin, one for a normal healthy individual (dark green line) and one for a person with sickle cell anemia (red line). Sickle cell anemia is a genetic disorder and the anemia can be passed through family generations. The red blood cells which are normally shaped like a disc take on a bold sickling or crescent shape, which makes it difficult for the red blood cells to move through large arteries in the lung and small capillaries in many locations of the body. The specific cause is a mutation in the hemoglobin gene. The classic circular shape of the erythrocytes becomes grossly altered to an abnormal rigid sickle shape (see Figure 15-10, panel C). Thus, as shown here, the hemoglobin from an anemic individual is only able to bind ~50% of the oxygen (red line) as compared with the ~100% for a normal individual (green line).

When the hemoglobin that is present in the circulatory system passes through the lungs (in the presence of high concentrations of oxygen in the blood from inhalation), the pH is ~7.6, and it is relatively easy to saturate the hemoglobin with O2. See Figure 1, panel C. In contrast, when the blood hemoglobin is passing in the peripheral tissues, the pH is on the low side (~ pH 7.2, or more acidic) and the extracellular O2 concentration is intrinsically much lower (due to the metabolic use of O2 in intermediary metabolism of all the tissues). Thus the newly O2 saturated hemoglobin arriving in the peripheral tissues from the lungs is readily able to dissociate O2 from the heme state (Fe2+). This then allows the hemoglobin to convert to the Relaxed state where it is optimized to carry two end products of cellular respiration, namely CO2 and H+, from the tissues back to the lungs and kidneys where they are excreted.

Another useful consequence of hemoglobin’s T state in the peripheral tissues is that ~35% of the total H+ and ~20% of the total CO2 that is released as a waste product of intermediary metabolism can bind to hemoglobin and be transported back to the lungs, where they are exhaled, and kidneys, where they are excreted. The remainder of the CO2 is dissolved in water along with the H+ which generates bicarbonate (HCO3^-) and moves through the circulatory system back to the lungs, where it is converted back to CO2 and is exhaled.

The heart of the hemoglobin structure is shown in Figure 1, panels A/B. The covalent linkage of four pyrrole rings to one another collectively confers upon the hemoglobin protein the ability to transport oxy gen bound to the Fe2+ in the center of the heme group. The four planar pyrrole rings are each connected, in an “oval,” by methylene bridges. Each of the four pyrrole rings in Figure 1B has a peach color. The stoichiometry is one pyrrole ring per one Fe2+ ion which has six coordination bonds. Four of the bonds are in the plane of the overall pyrrole ring, and the other two bonds are perpendicular (one above to an oxygen and one below to a histidine residue of hemoglobin). The Fe2+ ion has a tight bond to O2 and ensures that the O2 will be safely delivered from the lungs through the arteriole system to the peripheral cells.

The four groups of 4 “circular” pyrrole rings are visible (green color) in each of the hemoglobin’s α2β2 subunits (Figure 1A). Thus, one molecule of α2β2 hemoglobin binds four molecules of O2. Also, unfortunately, each pyrrole ring can also bind one carbon monoxide molecule (CO) to the heme group. Since hemoglobin binds CO with a ~250-fold greater affinity than O2, the CO will supplant the normally present O2. This describes why the circumstances of extensive exposure to CO gas can be lethal due to the blocking of transfer of O2 from the lungs to the peripheral tissues.

See Figure 1, panel C; the right panel shows two oxygen-binding curves to hemoglobin, one for a normal healthy individual (dark green line) and one for a person with sickle cell anemia (red line). Sickle cell anemia is a genetic disorder and the anemia can be passed through family generations. The red blood cells which are normally shaped like a disc take on a bold sickling or rigid crescent shape, which makes it difficult for the red blood cells to move through large arteries in the lung and small capillaries in many locations of the body. The specific cause is a mutation in the hemoglobin gene. Thus as shown in Figure 1C on the right side, the hemoglobin from an anemic individual is only able to bind ~50% of the required oxygen (red line) as compared with the ~100% for a normal individual.

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مواضيع ذات صلة

Erythropoietin (the Protein)

Adrenomedullin

Kallikreins and Kinins

Biological Actions of NO

Biological Actions of Endothelins

Red Blood Cell Enzymopathies- Metabolic Pathways

Hemoglobins with Decreased Oxygen Affinity

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Chemistry, Biosynthesis, and Secretion of Endothelins

Chemistry, Biosynthesis, and Secretion of ANP

Hemoglobins with Increased Oxygen Affinity

Specific Enzymes are Associated with Compartments Separated by the Mitochondrial Membranes