Biochemistry, Transferrin


Article Author:
Aminat Ogun


Article Editor:
Adebayo Adeyinka


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Updated:
1/16/2019 8:00:09 AM

Introduction

Iron is a vital element for several metabolic pathways and physiological processes[1]. 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.

Fundamentals

Transferrin divides into subgroups; these are serum transferrin, lactotransferrin, and melanotransferrin[2]. 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[3]. The transferrin-bound iron complex turnover rate is about ten times a day, which is essential to meet the daily demands of erythropoiesis[4]. 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[5]. The iron-bound transferrin is vital to distribute iron to the different cells of the body.    

Cellular

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[6].  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[1].    

Molecular

Transferrin is a monomeric 80kDA glycoprotein, which consists of two homologous lobes called N- and C- lobes[7]. 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[8]. 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.

Function

Functions of transferrin include:

  • Free Fe3+ is insoluble at a neutral pH, when iron binds to transferrin it becomes soluble. 
  • Deliver and transfer iron to all the various biological tissues between sites of absorption, utilization, and storage[9].
  • Prevent the formation of reactive oxygen species.
  • Chelate free toxic iron and act as a protective scavenger.
  • Deliver WBC macrophages to all tissues[10]
  • Transferrin is a part of the innate immune system, the binding of transferrin to iron impedes bacterial survival.
  • Transferrin acts as a marker for inflammation; the level of transferrin decreases during inflammation.

Mechanism

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[11]. 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[11]. 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. 

Testing

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[12].  Total or Transferrin iron binding capacity (TIBC) is a test which measures the blood capacity to bind iron with transferrin.

Clinical Significance

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[13].  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

  • Liver damage leading to reduced production of transferrin
  • Kidney insult or injury leads to loss of transferrin in urine.
  • Infection
  • Malignancy
  • Atransferrinemia: A genetic mutation, resulting in the absence of transferrin, which leads to hemosiderosis in the heart and liver, which can lead to heart and liver failure. This condition is treated by plasma infusion.

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,

  • Diminishing tumor cells when the receptor is used to attract antibodies
  • High transferrin saturation increased the risk of cardiovascular mortality if patients have high transferrin saturation (>55%) and LDL levels[14]

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Biochemistry, Transferrin - Questions

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The protein responsible for the transport of iron in the body is which one of the following?



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Where does utilization of iron in the body primarily occur?



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In iron deficiency anemia, the level of which marker will first become low?



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Low level of transferrin in the body might lead to a clinical condition called which of the following?



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Biochemistry, Transferrin - References

References

Steere AN,Byrne SL,Chasteen ND,Mason AB, Kinetics of iron release from transferrin bound to the transferrin receptor at endosomal pH. Biochimica et biophysica acta. 2012 Mar     [PubMed]
Wally J,Buchanan SK, A structural comparison of human serum transferrin and human lactoferrin. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 2007 Jun     [PubMed]
Giansanti F,Panella G,Leboffe L,Antonini G, Lactoferrin from Milk: Nutraceutical and Pharmacological Properties. Pharmaceuticals (Basel, Switzerland). 2016 Sep 27     [PubMed]
Anderson ER,Shah YM, Iron homeostasis in the liver. Comprehensive Physiology. 2013 Jan     [PubMed]
Luck AN,Mason AB, Transferrin-mediated cellular iron delivery. Current topics in membranes. 2012     [PubMed]
Wally J,Halbrooks PJ,Vonrhein C,Rould MA,Everse SJ,Mason AB,Buchanan SK, The crystal structure of iron-free human serum transferrin provides insight into inter-lobe communication and receptor binding. The Journal of biological chemistry. 2006 Aug 25     [PubMed]
Hall DR,Hadden JM,Leonard GA,Bailey S,Neu M,Winn M,Lindley PF, The crystal and molecular structures of diferric porcine and rabbit serum transferrins at resolutions of 2.15 and 2.60 A, respectively. Acta crystallographica. Section D, Biological crystallography. 2002 Jan     [PubMed]
Gordon S,Plüddemann A, Tissue macrophages: heterogeneity and functions. BMC biology. 2017 Jun 29     [PubMed]
Tandara L,Salamunic I, Iron metabolism: current facts and future directions. Biochemia medica. 2012     [PubMed]
Grant BD,Donaldson JG, Pathways and mechanisms of endocytic recycling. Nature reviews. Molecular cell biology. 2009 Sep     [PubMed]
Waldvogel-Abramowski S,Waeber G,Gassner C,Buser A,Frey BM,Favrat B,Tissot JD, Physiology of iron metabolism. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2014 Jun     [PubMed]
Bermejo F,García-López S, A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World journal of gastroenterology. 2009 Oct 7     [PubMed]
Wells BJ,Mainous AG 3rd,King DE,Gill JM,Carek PJ,Geesey ME, The combined effect of transferrin saturation and low density lipoprotein on mortality. Family medicine. 2004 May     [PubMed]
Dautry-Varsat A, Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor. Biochimie. 1986 Mar     [PubMed]

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