Formation of Hemoglobin
Synthesis of hemoglobin begins in the proerythroblasts and continues slightly even into the reticulocyte stage, for when the reticulocytes leave the bone marrow and pass into the blood stream they continue to form minute quantities of hemoglobin for another day or so.
Quantity of Hemoglobin in the Cells.
Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to approximately 34 gm/dl of cells. The concentration never rises above this value. Furthermore, in normal persons the percentage of hemoglobin is almost always near the maximum in each cell. However, when hemoglobin formation is deficient in the bone marrow, the percentage of hemoglobin in the cells may fall considerably below this value, and the volume of the red cell may decrease as well because of diminished hemoglobin to fill the cell.
When the hematocrit (the percentage of the blood that is cells — normally 40 to 45 per cent) and the quantity of hemoglobin in each respective cell are normal, the whole blood of men contains an average of 16 g/dl and of women an average of 14 gm/dl.
There are slight variations in the subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains.
Types of Hb:
· ·Hemoglobin A, is a combination of two alpha chains and two beta chains, it is the most common form of hemoglobin (95-98%)in the adult human being.
· Hemoglobin A2, is a combination of two alpha chains and two delta chains, it represents 2-3% of hemoglobin in the adult human being.
· Hemoglobin F (fetus Hb), is a combination of two alpha chains and two gamma chains, also it is found in newborns blood of about 1% of their hemoglobin.
Because each chain has a heme prosthetic group, there are four separate iron atoms in each hemoglobin molecule; each of these can bind with 1 molecule of oxygen, making a total of 4 molecules of oxygen (or 8 atoms) that can be transported by each hemoglobin molecule. Hemoglobin has a molecular weight of 64,458.
The nature of the hemoglobin chains determines the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia the amino acid valine is substituted for glutamic acid at one point in each of the two beta chains. When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the red blood cells that are sometimes 15 micrometers in length. These make it almost impossible for the cells to pass through the small capillaries, and the spiked ends of the crystals are very likely to rupture the cell membranes, thus leading to sickle cell anemia.
Combination of Hemoglobin with Oxygen:
The most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. For the primary function of hemoglobin in the body depends upon its ability to combine with oxygen in the lungs and then to release this oxygen readily in the tissue capillaries where the gaseous tension of oxygen is much lower than in the lungs.
Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the six "coordination" bonds of the iron atom. This is an extremely loose bond so that the combination is easily reversible. Furthermore, the oxygen does not become ionic oxygen but is carried as molecular oxygen to the tissues, where, because of the loose, readily reversible combination, it is released into the tissue fluids in the form of dissolved molecular oxygen, rather than ionic oxygen.
IRON
Because iron is important for formation of hemoglobin, myoglobin, and other substances such as the cytochromes, cytochrome oxidase, peroxidase, and catalase, it is essential to understand the means by which iron is utilized in the body.
The total quantity of iron in the body averages about 4 g, approximately 65 per cent of which is present in the form of hemoglobin. About 4 per cent is present in the form of myoglobin, 1 per cent in the form of the various heme compounds that promote intracellular oxidation, 0.1 per cent combined with the protein transferrin in the blood plasma, and 15 to 30 per cent stored mainly in the reticuloendothelial system and liver parenchymal cells in the form of ferritin.
Transport and Storage of Iron:
Transport, storage, and metabolism of iron in the body are illustrated in Figure (8), and may be explained as follows: When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. The iron is loosely combined with the globulin molecule and, consequently, can be released to any of the tissue cells at any point in the body. Excess iron in the blood is deposited in all cells of the body but especially in the reticuloendothelial cells and liver hepatocytes. In the cell cytoplasm, it combines mainly with a protein, apoferritin, to form ferritin.This iron stored in ferritin is called storage iron.
Smaller quantities of the iron in the storage pool are stored in an extremely insoluble form called hemosiderin. This is especially true when the total quantity of iron in the body is more than the apoferritin storage pool can accommodate.
When the quantity of iron in the plasma falls very low, iron is removed from ferritin quite easily, but less easily from hemosiderin. The iron is then transported by the transferrin in the plasma to the portions of the body where it is needed.
A unique characteristic of the transferrin molecule is that it binds especially strongly with receptors in the cell membranes of erythroblasts in the bone marrow. Then, along with its bound iron, it is ingested into the erythroblasts by endocytosis. There the transferrin delivers the iron directly to the mitochondria, where heme is synthesized. In persons who do not have adequate quantities of transferrin in their blood, failure to transport iron to the erythroblasts in this manner can cause severe hypochromic anemia;that is, decreased numbers of red cells containing very little hemoglobin.
When red blood cells have lived their life span and are destroyed, the hemoglobin released from the cells is ingested by the cells of the monocyte-macrophage system. There free iron is liberated, and it can then be either stored in the ferritin pool or reused for formation of hemoglobin.
Daily Loss of Iron:
About 1 milligram of iron is excreted each day by men, mainly into the feces. Additional quantities of iron are lost whenever bleeding occurs. In women, the menstrual loss of blood brings the average iron loss to a value of approximately 2 mg/day.
Obviously, the average quantity of iron derived from the diet each day must at least equal that lost from the body.
Iron is absorbed from all parts of the small intestine, mostly by the following mechanism. The liver secretes moderate amounts of apotransferrin into the bile that flows through the bile duct into the duodenum. In the small intestine, the apotransferrin binds with free iron and also with some iron compounds such as hemoglobin and myoglobin from meat, two of the most important sources of iron in the diet. This combination is called transferrin. It in turn is attracted to and binds with receptors in the membranes of the intestinal epithelial cells. Then, by the process ofpino-cytosis, the transferrin molecule, carrying with it its iron store, is absorbed into the epithelial cells and later is released on the blood side of these cells in the form of plasma transferrin.
The rate of iron absorption is extremely slow, with a maximum rate of only a few milligrams per day. This means that when tremendous quantities of iron are present in the food, only small proportions of this can be absorbed.
Iron Balance:
When the body has become saturated with iron so that essentially all of the apoferritin in the iron storage areas is already combined with iron, the rate of absorption of iron from the intestinal tract becomes greatly decreased. On the other hand, when the iron stores have been depleted of iron, the rate of absorption becomes greatly accelerated, to as much as five or more times as great as when the iron stores are saturated. Thus, the total body iron is regulated to a great extent by altering the rate of absorption.
Feedback Mechanisms for Regulating Iron Absorption:
Two mechanisms that play at least some role in regulating iron absorption are the following: (1) When essentially all the apoferritin in the body has become saturated with iron, it becomes difficult for transferrin to release iron to the tissues. As a consequence, the transferrin, which is normally only one-third saturated with iron, now becomes almost fully bound with iron, so that the transferrin accepts almost no new iron from the mucosal cells. Then, as a final stage of this process, the excess iron in the mucosal cells themselves depresses active absorption of iron from the intestinal lumen.
(2) When the body already has excess stores of iron, the liver decreases its rate of formation of apotransferrin, thus reducing the concentration of this iron-transporting molecule in the plasma and also in the bile. Therefore, less iron is then absorbed by the intestinal apotransferrin mechanism, and less iron can also be transported away from the intestinal epithelial cells in the plasma by plasma transferrin.
Yet, despite these feedback control mechanisms for regulating iron absorption, when a person eats extremely large amounts of iron compounds, excess iron does enter the blood and can lead to massive deposition of hemosiderin in the reticuloendothelial cells throughout the body, which at times can be very damaging.
Destruction of Red Blood Cells
When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Even though mature red cells do not have a nucleus, mitochondria, or endoplasmic reticulum, they nevertheless have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of adenosine triphosphate (ATP). ATP in turn serves the red cell in several important ways:
(1) Maintaining the pliability of the cell membrane.
(2) Maintaining membrane transport of ions.
(3) Keeping iron of the cell s hemoglobin in the ferrous form, rather than the ferric form (which causes the formation of methemoglobin that will not carry oxygen).
(4) preventing oxidation of the proteins in the red cell.
Destruction of Hemoglobin:
The hemoglobin released from the cells when they burst is phagocytized almost immediately by macrophages in many parts of the body, but especially in the liver, spleen, and bone marrow. During the next few hours to days, the macrophages release the iron from the hemoglobin back into the blood to be carried by transferrin either to the bone marrow for production of new red blood cells or to the liver and other tissues for storage in the form of ferritin. The porphyrin portion of the hemoglobin molecule is converted by the macrophages, through a series of stages, into the bile pigment bilirubin, which is released into the blood and later secreted by the liver into the bile.