Iron is a vital element for several metabolic pathways and physiological processes. The maintenance of iron homeostasis is essential as a change either decrease or excess pose harmful to the human body. Transferrin has a high affinity to ferric iron; therefore, there is little free iron in the body as transferrin binds, in essence, all plasma. Transferrin is a blood-plasma glycoprotein, which plays a central role in iron metabolism and is responsible for ferric-ion delivery. Transferrin functions as the most critical ferric pool in the body. It transports iron through the blood to various tissues such as the liver, spleen and bone marrow. It is an essential biochemical marker of body iron status.
Transferrin divides into subgroups; these are serum transferrin, lactotransferrin, and melanotransferrin. Hepatocytes produce serum transferrin found in the serum, CSF, and semen. Mucosal epithelial cells produce lactotransferrin seen in bodily secretions such as milk. Lactotransferrin has antioxidants, antimicrobial and anti-inflammatory properties. All plasma iron is bound to transferrin. The transferrin-bound iron complex turnover rate is about ten times a day, which is essential to meet the daily demands of erythropoiesis. Therefore, transferrin acts as a balance between reticuloendothelial iron release and bone marrow uptake. Once, iron is bound to transferrin it is transported by transferrin to the bone marrow for production of hemoglobin and portions of erythrocytes. The human body loses iron through perspiration, epithelial cell desquamation, and menstruation. Iron loss is obligatory, and there are no specific means to regulate it. Therefore, iron homeostasis is hugely dependent on the tight regulation of absorption, which occurs mostly in the proximal intestine. The iron-bound transferrin is vital to distribute iron to the different cells of the body.
Transferrin is a free peptide (apotransferin) that undergoes a conformation change after binding with iron. Iron circulates in the plasma until it attaches to a transferrin receptor on a target cell. A carbonate (CO) has to be present to help attract iron to transferrin by creating opposing repulsive charges. Transferrin can bind to two atoms of ferric iron (Fe3+) with high affinity. The carbonate needed also serves as a ligand to stabilize iron in the binding site of transferrin. Clathrin/receptor-mediated endocytosis mediates the uptake of iron by transferrin receptors. An acidic environment of Ph5.6 reduces iron-transferrin affinity, which encourages the release of iron from its binding site and endocytosed into a cell.
Transferrin is a monomeric 80kDA glycoprotein, which consists of two homologous lobes called N- and C- lobes. A short peptide connects the two lobes. The carbohydrate moiety is attached to the C-lobe. Each lobe is further subdivided into two sub-domains- N1 and N2 for the N- lobe; and C1 and C2 for the C-lobe. The sub-domains connect two antiparallel beta sheets that act as flexible joints. The N and C lobes are made up of one aspartic acid, two tyrosine, a histidine, and an arginine. Between each lobe forms a cleft, which allows iron binding. The transferrin molecule shaped to permit iron binding. The sub-domains open to release iron and close when bound.
Functions of transferrin include:
The process of offloading iron-bound transferrin begins with transferrin binding to its cell surface transferrin receptor. It starts with the formation of clathrin-coated pits and internalization of the vesicle into the cytoplasm. The coated vesicle loses its clathrin coat due to a reduction in pH. The reduction of pH by hydrogen ion proton pumps (H+ ATPase) to a pH of 5.5, causes the dissociation of iron-bound transferrin vesicle to release its iron ions. Also, the binding of transferrin to transferrin receptors reduces its affinity for iron. Two pathways can occur once endocytosed–degradation or recycling pathways. The degradation pathway is where the dissociation of ferric ions from transferrin occurs from an early and late endosome. Iron can now be utilized for storage or incorporated into hemoglobin. The recycling pathway involves recycling of transferrin. After the dissociation of iron, transferrin is called apotransferrin. Apotransferrin remains bound to its receptor because it has a high affinity for its receptors at a reduced pH. It recycles back to the plasma membrane still bound to its receptor. At a neutral pH, apotransferrin dissociates from its receptor to enter the circulation, reload iron and repeat the cycle. All transferrin receptors eventually follow the degradation pathway for receptor turnover. An example of a cell is an erythroid precursor in the bone marrow.
In the laboratory, the reference range for transferrin is 204-360 mg/dL. Transferrin can be used to assess the iron level in the body along with other markers in the body. Transferrin level testing is used to determine the cause of anemia, examine iron metabolism and determine the iron-carrying capacity of the blood. Transferrin saturation levels cannot be solely read in isolation but in conjunction with other laboratory tests such as serum ferritin and TIBC. Ferritin is the first marker to become low, therefore more sensitive than transferrin in diagnosing Iron deficiency anemia. Total or Transferrin iron binding capacity (TIBC) is a test which measures the blood capacity to bind iron with transferrin.
Iron deficiency is recognized as the most prevalent nutritional deficit in the world. The amount of transferrin in the blood indicates the amount of iron in the body. High transferrin signifies low iron, which means there is less iron bound to transferrin, allowing for a high circulation of non-bound iron transferrin in the body, revealing a possible iron deficiency anemia. The liver increases production of transferrin as a form of homeostasis to enable transferrin to bind to iron and transport it to the cells. Upregulation of transferrin receptors occurs in iron deficiency anemia. Concerning the percentage of transferrin-iron complex, low iron-bound transferrin indicates low iron levels in the body, which affects hemoglobin and erythropoiesis. The significance of transferrin is that it can detect iron deficiency and can be used to monitor erythropoiesis.
In anemia of chronic disease, there is a decreased transferrin level.
Causes of low transferrin
Low transferrin in plasma indicates iron overload, which means the binding site of transferrin is highly saturated with iron. Iron overload suggests hemochromatosis, which will lead to deposition of iron on tissues.
Other associations with transferrin and its receptors include,