Oxygen Binding by Heme Proteins

Myoglobin/Hemoglobin Structure - The myoglobin-hemoglobin family of proteins employs Fe(II) for O 2 binding. Throughout the myoglobin-hemoglobin family, the iron is chelated by a tetrapyrrole ring system called protoporphyrin IX, one of a large class of porphyrin compounds. The basic ring structure of a porphyrin is shown in Figure 7.4a, and protoporphyrin IX is shown in Figure 7.4b. Other porphyrins include chlorophyll, the cytochrome proteins, and some natural pigments. The iron-porphyrin in hemoglobin accounts for the red color of blood, and the magnesium-porphyrin in chlorophyll is responsible for the green of plants.

The complex of protoporphyrin IX with Fe(II) is called heme (Figure 7.4c). This prosthetic group is noncovalently bonded in a hydrophobic crevice in the myoglobin or hemoglobin molecule (see Figure 7.3). The binding of oxygen to heme is illustrated in Figure 7.5, which shows the oxygenated form of myoglobin.

Geometry of fe Linkage - Fe(II) is normally octahedrally coordinated, which means it usually has six ligands, or binding groups, attached to it. As shown in Figure 7.5a, the nitrogen atoms of the porphyrin ring account for four ligands. Two remaining coordination sites lie along an axis perpendicular to the plane of the porphyrin ring. In both the deoxygenated and the oxygenated forms of myoglobin, one site is occupied by the nitrogen of histidine residue number 93. The eight helical segments in myoglobin and each of the four subunits of hemoglobin are called A through H (as shown in Figure 6.1), and residue 93 is located in the F helix (Figure 7.5b). In the nomenclature often employed, this residue is called histidine F8. Because it is in direct contact with the Fe atom, it is also called the proximal histidine. In deoxymyoglobin, the remaining coordination site, on the other side of the iron, is occupied by a water molecule. When oxygen is bound, making oxymyoglobin, O 2 displaces the water molecule. On the other side of the bound O 2 lies histidine reside 64, or E7, also called the distal histidine. An almost identical mode of oxygen binding is found in each subunit of hemoglobin.

Oxygen/Oxidation - If myoglobin or hemoglobin is stored in air, outside the cellular environment, their Fe(II) slowly oxidizes to Fe(III), forming metmyoglobin or methemoglobin. Neither metmyoglobin nor methemoglobin can bind oxygen. This oxidation is not unexpected. In fact, an oxygen molecule in such close contact with a ferrous [Fe(II)] ion would be expected to convert the latter to the ferric [Fe(III)] state. In the cell, in the hydrophobic, protected environment in the interior of myoglobin or hemoglobin, however, a temporary electron rearrangement occurs upon binding of oxygen, preventing the oxidation of iron. When the oxygen is released, the iron remains in the Fe(II) state, able to bind another O 2. Protection of the oxygen-binding Fe(II) from irreversible oxidation is the functional reason for the existence of myoglobin and hemoglobin. That is, the secondary and tertiary structures of these two molecules provide environments in which the first step of an oxidation reaction (the binding of oxygen) is permitted, but the final step (oxidation) is blocked.

Toxicity of Carbon Monoxide - The heme pocket can bind some other small molecules besides O 2. The most physiologically important one is carbon monoxide (CO), which is approximately the same size and shape as O 2. However, CO is bound with much greater affinity to myoglobin and hemoglobin than is O 2, and the binding is not readily reversible. This is why CO is such a toxic gas - it ties up oxygen binding sites and thereby blocks respiration.

See also: Oxygen Binding by Myoglobin, Oxygen Binding by Hemoglobin, Models of Allosteric Activity, Histidine