Myoglobin and Mitochondria: A relationship bound by Oxygen and Nitric Oxide
Myoglobin is a monomeric protein that has amino acids residues. It consists of eight α-helicies connected through the turns with an Oxygen binding site. The heme portion of myoglobin and hemoglobin is extremely important because it aids in oxygen binding. A heme group consists of a central iron atom (Fe II in. Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals.
At the center of protporphyrin, the iron atom is bonded to nitrogen atoms from four pyrrole rings. The iron atom can form two additional bonds, one on each side of the heme plane. These binding sites are called the fifth and sixth coordination sites.
In myoglobin, the fifth coordination site is occupied by the imidazole ring from a histidine residue on the protein. This hisitidine is referred to as the proximal histidine.
The sixth coordination site is available to bind oxygen. The iron atom in deoxymyoglobin lies about four angstroms out of the plane of the protoporphyrin plane because it is too big in that form to fit into the well defined hole. The normal oxidation state of an iron atom has a positive two charge ferrous ion instead of three charge ferric ion and it is too large to fit into the plane of protoporphyrin.
Thus, a ferrous ion is often 0. When oxygen leaves the myoglobin, it leaves as dioxygen rather than superoxide.
This is because superoxide can be damaging to many biological process, and in the leaving of superdioxide, the iron ion will be in the ferric state which stops biding oxygen.
The distal histidine amino acid from the hemoglobin protein molecule further stabilizes the O2 molecule by hydrogen-bonding interactions. Myoglobin is a protein molecule that has a similar structure and function to hemoglobin.
- Myoglobin & Hemoglobin
- Structural Biochemistry/Protein function/Heme group/Myoglobin
- Structural Biochemistry/Protein function/Oxygen-Binding Curve
It is a smaller monomer of polypeptide structure, a globular protein with amino acids and prosthetic heme group binds to proximal histidine group while a distal histidine group interact on the other side of the plane. It binds and stores oxygen without concerning cooperativity. Most importantly, it is the first protein structure to be studied. Myoglobin follows the Michaelis-Menten Kinetic graph as seen from the graph above. One position is used to form a coordinate covalent bond with the side chain of a single histidine amino acid of the protein, called the proximal histidine.
Hemoglobin and Myoglobin
The sixth and last orbital is used for oxygen. It is empty in the nonoxygenated forms of hemoglobin and myoglobin.
The oxidized heme binds oxygen very poorly. Obviously, if this happened to the Fe II groups of hemoglobin and myoglobin, the proteins would be less useful as oxygen carriers.
Oxidation of the heme iron is prevented by the presence of the distal histidine side chain, which prevents the O 2 from forming a linear Fe—O—O bond. We shall consider the transport of O2 from the lungs to the tissues first. In the high O2 environment high pO2 of the lungs there is sufficient O2 to overcome the inhibitory nature of the T state.
During the O2 binding-induced alteration from the T form to the R form several amino acid side groups on the surface of hemoglobin subunits will dissociate protons as depicted in the equation below. This proton dissociation plays an important role in the expiration of the CO2 that arrives from the tissues see below.
Metabolizing cells produce CO2 which diffuses into the blood and enters the circulating red blood cells RBCs. Within RBCs the CO2 is rapidly converted to carbonic acid through the action of carbonic anhydrase as shown in the equation below: This effective CO2 transport process is referred to as isohydric transport. A small percentage of CO2 is transported in the blood as a dissolved gas. As indicated above, within the lungs the high pO2 allows for effective O2 binding by hemoglobin leading to the T to R state transition and the release of protons.
The protons combine with the bicarbonate that arrived from the tissues forming carbonic acid which then enters the RBCs. Through a reversal of the carbonic anhydrase reaction, CO2 and H2O are produced. The CO2 diffuses out of the blood, into the lung alveoli and is released on expiration.
This reaction, depicted below, forms what is called carbamino-hemoglobin. The released protons then promote the dissociation of the carbamino to form CO2 which is then released with expiration.
Hemoglobin and Myoglobin
These effects of hydrogen ion concentration are responsible for the well known Bohr effect in which increases in hydrogen ion concentration decrease the amount of oxygen bound by hemoglobin at any oxygen concentration partial pressure. Coupled to the diffusion of bicarbonate out of RBCs in the tissues there must be ion movement into the RBCs to maintain electrical neutrality.
This is the role of Cl- and is referred to as the chloride shift. In this way, Cl— plays an important role in bicarbonate production and diffusion and thus also negatively influences O2 binding to hemoglobin.
Representation of the transport of CO2 from the tissues to the blood with delivery of O2 to the tissues. The CO2 produced through metabolic processes in the tissues diffuses into the blood.
The majority of the CO2 is picked up by the erythrocytes where it is complexed with water via the actions of carbonic anhydrase CA forming carbonic acid.
This process is referred to as the chloride shift. The opposite process occurs when O2 is taken up from the alveoli of the lungs and the CO2 is expelled. The pathway to 2,3BPG synthesis is diagrammed in the figure below. The pathway for 2,3-bisphosphoglycerate 2,3-BPG synthesis within erythrocytes. Synthesis of 2,3-BPG represents a major reaction pathway for the consumption of glucose in erythrocytes. The synthesis of 2,3-BPG in erythrocytes is critical for controlling hemoglobin affinity for oxygen.
Note that when glucose is oxidized by this pathway the erythrocyte loses the ability to gain 2 moles of ATP from glycolytic oxidation of 1,3-BPG to 3-phosphoglycerate via the phosphoglycerate kinase reaction.
In the deoxygenated T conformation, a cavity capable of binding 2,3-BPG forms in the center of the hemoglobin tetramer. A single molecule of 2,3-BPG can occupy this cavity which thereby, stabilizes the T state. Conversely, when 2,3-BPG is not available, or not bound in the central cavity, Hb can bind oxygen forming HbO2 more readily.
Thus, like increased hydrogen ion concentration, increased 2,3-BPG concentration favors conversion of R form Hb to T form Hb and decreases the amount of oxygen bound by Hb at any oxygen concentration. When the oxygen pressure is high enough, such as in the alveoli of the lungs, the binding of a mole of O2 induces the T-to-R transition which causes the 2,3-BPG binding pocket to collapse and the 2,3-BPG is expelled allowing for the rest of the monomers of globin protein to bind O2.
Hemoglobin molecules differing in subunit composition are known to have different 2,3-BPG binding properties with correspondingly different allosteric responses to 2,3-BPG. The consequences are that HbF in fetuses binds oxygen with greater affinity than the mothers HbA, thus giving the fetus preferential access to oxygen carried by the mothers circulatory system.
The orientation of the genes in both clusters is in the same 5' to 3' direction with the earliest expressed genes at the 5' end of both clusters. In addition to functional genes, both clusters contain non-functional pseudogenes. The 5' to 3' orientation of the genes on each chromosome also reflects the developmental timing of their expression with the 5'-most genes expressed earliest. Hemoglobin synthesis begins in the first few weeks of embryonic development within the yolk sac.
By 6—8 weeks of gestation the expression of this version of hemoglobin declines dramatically coinciding with the change in hemoglobin synthesis from the yolk sac to the liver. Developmental patterns of globin gene expression Given the pattern of globin gene activity throughout fetal development and in the adult the composition of the hemoglobin tetramers is of course distinct. Fetal hemoglobin has a slightly higher affinity for oxygen than does adult hemoglobin.
This allows the fetus to extract oxygen more efficiently from the maternal circulation. The overall hemoglobin composition in a normal adult is approximately Developmentally regulated forms of hemoglobin. Due to the developmental pattern of globin gene expression, different tetrameric forms of hemoglobin are present at different times during embryonic, fetal, and adult life spans.