Hemoglobins main function is to carry oxygen to the tissues and cells of the body. Hemoglobin can bind and transport four molecules of oxygen. Hemoglobin is made up of 4 polypeptide globin chains, two alpha and two beta that forms a tetramer heme group with iron located within the tetramer. Globin is the protein part of hemoglobin. The different globin chains are typically 141-146 amino acids in length and each chain is designated by a greek letter. Each chain is subdivided into eight helices designated an alphabetical letter with each helice divided by seven non-helical segments. The globin chains loop to form a cleft pocket for heme which is suspended between the E and the F helices of the polypeptide chain. The ferrous iron in each heme molecule reversibly binds to one oxygen molecule.
Heme is a four ring consisting of carbon, hydrogen and nitrogen atoms called the protoporphyrin IX. The single carbon atoms act as connecting bridges. There are alternating double bonds where the electron resonation absorbs light which is the reason why heme is colored. There are two propionic acid side chains on end rendering it polar, with the rest of the heme molecule being non-polar and hydrophobic.
Globin is a protein so naturally translation and synthesis occurs in the ribosomes while transcription occurs in the nucleus. Transcription of the alpha globin gene which occurs on chromosome 16 produces more mRNA than the beta globin genes which is transcribed on chromosome 11. There are four alpha genes, and only two beta genes. To make up for that discrepancy, translation of the alpha globin is less efficient than that of the beta globin so there are equal amounts of both produced in Hgb A.
Heme is synthesized in the mitochondria and cytoplasm of the bone marrow erythrocyte precursor cells. Biosynthesis begins in the mitochondria with the condensation of glycine and succinyl CoA catalyzed by aminolevulinate synthase (ALA synthase) to form ALA in the cytoplasm. Porphobilinogen synthase converts ALA to porphobilinogen (PBG). Porphobilinogen synthase is the enzyme that is inhibited by lead. PBG is then converted to hydroxymethylbilane which is further converted to uroporphyrinogen III. Uroporphyrinogen III is converted to coproporphyrinogen III. Synthesis then continues back in the mitochondria by the conversion of coproporphyrinogen III to protoporphyrinogen IX. Protoporphyrinogen IX is then converted to protoporphyrin IX by protoporphyrinogen oxidase. From there protoporphyrin IX is converted to heme in the presence of ferrous iron and ferrochelatase. Heme has a negative feedback mechanism on ALA by inhibiting the transcription of the ALA synthase enzyme.
With the synthesis of globin and heme covered the next step is the assembly of the hemoglobin molecule as one. After the globin is released by the ribosomes, each polypeptide chain binds to a single heme molecule. An alpha globin:heme complex and a beta globin:heme polypeptide then combine to form a heterodimer. Now remember that step is repeated as there are four polypeptide chains in a hemoglobin molecule. Two heterodimers then combine to form a tetramer to complete the assembly of the hemoglobin molecule.
When in the deoxygenated state, the iron within the heme molecule is pulled out of plane of the heme ring. When oxygen binds it pulls the iron back into the plane of the heme ring and also causes a shape change in the polypeptide chains which causes a ripple effect among all four polypeptide chains. This phenomenon is allosteric regulation. The allosteric effect is the conformational change in the entire hemoglobin molecule caused by the binding of one oxygen molecule to one ferrous iron molecule within the heme cleft. In the deoxygenated state ionic bridges form creating a stable and rigid configuration. A single molecule of 2,3-DPG binds adjacent polypeptides to further stabilize the hemoglobin molecule. In the oxygenated state there is that allosteric effect which alters the shape of the hemoglobin molecule enough so that ionic bridges are broken which causes the globin molecules to relax and heme cleft enlarges. This allows the remaining three oxygen molecules to bind readily to the ferrous iron.
Oxygen/Hemoglobin Dissociation Curve Effects
The oxyhemoglobin is formed when oxygen binds during physiological respiration within the pulmonary capillaries. Various factors such as pH, CO2 concentration, and 2,3-DPG concentration affect the way that oxygen binds. When talking in terms of the oxygen/hemoglobin dissociation curve it is generally said that curve is sigmoidal; meaning that there is low hemoglobin affinity for oxygen at low oxygen tension and high affinity for oxygen at high oxygen tension. There are values such as the P50 which is defined in terms of the amount of oxygen needed to saturate 50% of the hemoglobin molecule. The PO2 of the lungs are ~ 100 mm/Hg so that means that hemoglobin is 100% saturated when the RBC is in the lungs. Normally a P02 of 27 mm/Hg results in 50% hemoglobin saturation. You can also have shifts to the right or left of the curve. These shifts come from the various factors that were mentioned above. Hemoglobin exists as two forms, a taut (tense) phase and a (R) form or relaxed form. Low pH, high CO2 (such as in the tissues), and high 2,3-DPG initiate a shift to the right, meaning that there is less affinity for oxygen and the oxygen is released into the tissues resulting in the taut form of hemoglobin. Conversely a high pH, low CO2 (such as in the lung capillaries), and low 2,3-DPG results in the relaxed form and a shift to the left creating a higher affinity to oxygen. The partial pressure of the system also affects the affinity to oxygen. At high PO2 levels, such as those present in the lungs, a high affinity relaxed state is favored. In a low PO2 state, such as in the tissues, the low affinity, taut form is favored. Hemoglobin needs to be able to bind oxygen and release it. There is no point in the molecule binding if there is no chance at releasing it. The sigmoidal curve causes it to be efficient at taking up oxygen in the lungs and efficient at releasing it in the tissues
Hemoglobin is an essential aspect of homeostasis for the cells. It needs to functioning and be assembled correctly to efficiently do its job. This is just a brief overview of what it does and the structure of it. More will come on the different hemoglobinopathies (qualitative) and thalassemias (quanitative).