Normal hemoglobin structure and function

The adult major hemoglobin molecule, Hb A, is a tetramer formed by four polypeptide chains: two a chains and two P chains. Each of these chains is attached to a prosthetic group (heme) formed by protoporphyrin IX in a complex with a single iron molecule (Figure 14.1).

Hemoglobin tetramer

(a) Front view

(a) Front view

Fig. 14.1 Hemoglobin molecule

The front view depicts the hemoglobin tetramer and the three axes of symmetry. The vertical line (marked by a solid ellipse) tracks the true twofold axis of symmetry (if you look down this axis you will see first the central cavity constituted by the P chains). The dashed ellipses and dashed lines mark the two pseudoaxes of symmetry, since the symmetry is only approximate. Only the 21 carbons are shown, with none of the side chains. Numbers in bold type depict the residues in direct contact between the a1 and P2 chains. In deep red is shown the a1P2 dimer, which never dissociates and interacts with the a2P1 dimer (light color) to change the conformation from T to R. Alterations in this area can produce high- or low-affinity hemoglobins. The side view of the tetramer depicts the stable dimer—the one that does not move or dissociate.

The heme is semi-buried in the globin, surrounded by a hydrophobic niche that favors the maintenance of the ferrous state of the iron. The heme pocket is large enough for oxygen to penetrate, but large ligands (molecules capable of binding to the iron), such as carbon monoxide and the family of iso-cyanates, have progressive difficulty in finding the iron.

Oxygen transport to tissues, the ultimate purpose of hemoglobin, is dependent on blood flow, which in turn is affected by cardiac output and by microcirculatory size and distribution, the hemoglobin concentration and O2 extraction by the tissues, which in turn is dependent on the shape of the oxygen binding curve of the red cells and on tissue pO2. The shape of the oxygen equilibrium curve for hemoglobin is sigmoid. This shape is determined by the extent of cooperativity. The initial portion of the curve has a very low slope, reflecting a low affinity for oxygen by hemoglobin at the beginning of the loading process. In other words, when hemoglobin is totally deoxygenated it has a rather poor avidity for oxygen (Figure 14.2). As the loading proceeds, and as the molecule binds more oxygen molecules, the slope of the reaction begins to change rapidly and becomes steep, indicating that the affinity for oxygen has markedly increased. After two molecules of oxygen have bound to two hemes of deoxyhemoglobin tet-ramers, the protein changes its avidity for oxygen. This property helps hemoglobin tetramers to promptly become fully oxygenated. Hence, in red cells that are exposed to sufficient oxygen to oxygenate only half of the hemes available, most molecules will either not be oxygenated at all or will be entirely oxygenated, with a very small compartment of partially oxygenated molecules.

At the molecular level, cooperativity is accounted for by the fact that hemoglobin can exist stably in only two different conformations, one for the oxygenated molecule (R state) and another for the deoxygenated molecule (T state), without intermediate conformations. The molecule of hemoglobin will bind two or three molecules of oxygen at low affinity (T state). While this concept has been challenged recently, postulated intermediate stable states have not been generally recognized.

The heme triggering mechanism for conformational change has been resolved. The iron in deoxyhemoglobin is slightly out of the plane of the heme (domed configuration) because the pyrrole rings are also slightly pyramidal. When the ligand binds the sixth coordinating position of the iron, significant steric stresses are introduced, and to relieve this strain the distal histidine moves 8° to become perpendicular to the heme, significantly decreasing the doming of the iron (the angle between iron and the heme decreases to 4°). There is also the displacement of FG5 in the same direction of the histidine F8. The configuration around the heme has now changed to the oxygenated (R state), and a chain of events

Horse methemoglobin

Horse deoxyhemoglobin

Horse methemoglobin

Horse deoxyhemoglobin

Fig. 14.2 The allosteric transition of hemoglobin: R^T

Right: Deoxygenated (T, tense) conformation of hemoglobin. Notice that the centre cavity (space between the two p chains, in blue) is las rger than in the oxygenated tetramer (left). This space in the molecule is occupied by 2,3-diphosphoglycerate (2,3-DPG) when the tetramer is in the blue cell. The allosteric effector, 2,3-DPG, is in a little over equimolar concentration with the tetramer. The T form has low affinity for oxygen, ¿eft: Oxygenated (R, relaxed) conformational state of hemoglobin: the central cavity has been reduced in size by the movement of the p chains (blue) towards each other. This tetramer cannot bind 2,3-DPG. The R form has high affinity for oxygen. The change in conformation forms and breaks bonds between the p and a chains (p dimers (blue) and a chains (white)) on each side of the central cavity. The title says 'methemoglobin' but this hemoglobin form is identical to oxyhemoglobin. Perutz did his crystallography for reasons of convenience.

takes place involving the critical interactions that change the conformation of the hemoglobin tetramer.

Hemoglobin binds CO2 while it is delivering O2 and releases CO2 when it is binding O2, helping to dissipate the increase in concentration of CO2 in the tissues and conveniently delivering this metabolic end product to the alveoli of the lungs. It accomplishes this particular task with ease because carbon dioxide is an inhibitor of hemoglobin oxygen-carrying capacity by decreasing the oxygen affinity of the molecule.

Hemoglobin binds hydrogen ions efficiently in a low-pH environment and releases them when it encounters high pH (the Bohr effect). The Bohr effect describes the changes in oxygen affinity secondary to pH changes within a certain range: the lower the pH the lower the affinity or the higher the p50. This means that an increased concentration of protons favors a low-affinity state in hemoglobin. In other words, deoxyhe-moglobin binds more protons than the oxy conformer does.

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