Myoglobin and Hemoglobin: Structure, Function, and Disease
1 Myoglobin
Myoglobin, a well-studied globular protein found in muscle tissue, is simpler in structure than hemoglobin but shares a similar function. It captures oxygen from hemoglobin for storage and utilization within the muscle. This single polypeptide chain protein is comprised of eight alpha-helices (A-H) from the N-terminus. Most of these helices are alpha-helices, with some modifications. In the carboxyl terminus of four helices, shorter 310 helices are present. These helices are thinner and have a larger pitch than alpha-helices, often appearing at the end of an alpha-helix as a distorted turn. The helical segments are named using the flanking segments (e.g., AB). Myoglobin contains a non-protein heme group located within a hydrophobic cavity, interacting through van der Waals forces. The heme group has an iron atom at the center of a tetrapyrrole ring, forming four coordination bonds with nitrogen atoms. The fifth coordination position of the iron is occupied by a proximal histidine (His F8), and the sixth position binds an oxygen molecule. This oxygen binding is myoglobin’s primary function. A distal histidine (His E7) is located opposite the proximal histidine. It prevents the oxidation of Fe2+ to Fe3+ by hindering the alignment of oxygen atoms with the iron. This distal histidine also reduces the binding affinity for CO and CO2, which the isolated heme prefers over oxygen. Additionally, it acts as a proton trap, preventing the catalytic action of protons on Fe2+ autoxidation. Oxygen binding to the heme causes a conformational change, decreasing the Fe2+ atom’s volume. In deoxymyoglobin, Fe2+ is high-spin and paramagnetic, with a large van der Waals radius. Upon oxygenation, it becomes low-spin and diamagnetic, decreasing its radius and moving closer to the heme plane. This shift pulls the proximal histidine and the polypeptide chain, facilitating oxygen access. Myoglobin exhibits a hyperbolic oxygen saturation curve.
2 Hemoglobin
Hemoglobin, a tetramer with two different subunit types (α2β2), contrasts with myoglobin. Its tertiary structure resembles myoglobin, but with only 18% amino acid sequence identity. Subunits interact extensively: 35 amino acids participate in the α1β1 (and α2β2) interaction, while 19 are involved in the α1β2 (and α2β1) interaction. These interactions include hydrophobic interactions, hydrogen bonds, and crucial ion pairs. Oxygenation alters the quaternary structure, affecting the α1β2 and α2β1 interaction but not α1β1 or α2β2. The angle between subunit pairs changes, shifting from a low-affinity T-state (tense) to a high-affinity R-state (relaxed). This shift is driven by the energy of Fe-oxygen bond formation. The T and R states explain hemoglobin’s sigmoidal oxygen saturation kinetics. The Bohr effect describes hemoglobin’s release of H+ upon oxygen binding. This facilitates oxygen delivery to tissues, as CO2 released by tissues is converted to bicarbonate in red blood cells, releasing a proton that is captured by hemoglobin, lowering its oxygen affinity. Hemoglobin also transports CO2 from tissues to the lungs by forming carbamate. Two models explain hemoglobin’s sigmoidal behavior: the concerted model (Monod-Wyman-Changeaux) and the sequential model (Koshland-Nemethy-Filmer). Hemoglobin has allosteric sites, and 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells lowers its oxygen affinity by stabilizing the T-state. Fetal hemoglobin (α2γ2) has a weaker 2,3-BPG binding site, resulting in higher oxygen affinity than maternal hemoglobin. BPG also plays a role in high-altitude adaptation. Sickle cell anemia, caused by a Glu-to-Val mutation in the β-chain, leads to hemoglobin S aggregation and distorted red blood cells. Heterozygotes for this mutation exhibit resistance to malaria. Thalassemia encompasses various hemoglobin gene mutations causing deficient globin synthesis.