Transferrins are
glycoproteins found in
vertebrates which bind and consequently mediate the transport of
iron (Fe) through
blood plasma.[5] They are produced in the
liver and contain binding sites for two
Fe3+ ions.[6] Human transferrin is encoded by the TFgene and produced as a 76
kDa glycoprotein.[7][8]
Transferrin
glycoproteins bind iron tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of total body iron, it forms the most vital iron pool with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80
kDa and contains two specific high-affinity
Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (
association constant is 1020 M−1 at pH 7.4)[9] but decreases progressively with decreasing
pH below neutrality. Transferrins are not limited to only binding to iron but also to different metal ions.[10] These glycoproteins are located in various bodily fluids of vertebrates.[11][12] Some invertebrates have proteins that act like transferrin found in the
hemolymph.[11][13]
When not bound to iron, transferrin is known as "apotransferrin" (see also
apoprotein).
Occurrence and function
Transferrins are glycoproteins that are often found in biological fluids of vertebrates. When a transferrin protein loaded with iron encounters a
transferrin receptor on the surface of a
cell, e.g., erythroid precursors in the bone marrow, it binds to it and is transported into the cell in a
vesicle by
receptor-mediated endocytosis.[14] The pH of the vesicle is reduced by hydrogen ion pumps (
H+ ATPases) to about 5.5, causing transferrin to release its iron ions.[11] Iron release rate is dependent on several factors including pH levels, interactions between lobes, temperature, salt, and chelator.[14] The receptor with its
ligand bound transferrin is then transported through the
endocytic cycle back to the cell surface, ready for another round of iron uptake.
Each transferrin molecule has the ability to carry two iron ions in the
ferric form (Fe3+ ).[13]
Humans and other mammals
The
liver is the main site of transferrin synthesis but other tissues and organs, including the brain, also produce transferrin. A major source of transferrin secretion in the brain is the
choroid plexus in the
ventricular system.[15] The main role of transferrin is to deliver iron from absorption centers in the
duodenum and white blood cell
macrophages to all tissues. Transferrin plays a key role in areas where erythropoiesis and active cell division occur.[16] The receptor helps maintain iron
homeostasis in the cells by controlling iron concentrations.[16]
The
gene coding for transferrin in humans is located in
chromosome band 3q21.[7]
In humans, transferrin consists of a polypeptide chain containing 679
amino acids and two carbohydrate chains. The protein is composed of
alpha helices and
beta sheets that form two
domains.[18] The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.[12]
Transferrin also has a transferrin iron-bound
receptor; it is a disulfide-linked
homodimer.[16] In humans, each monomer consists of 760 amino acids. It enables
ligand bonding to the transferrin, as each
monomer can bind to one or two atoms of iron. Each monomer consists of three domains: the protease, the helical, and the apical domains. The shape of a transferrin receptor resembles a butterfly based on the intersection of three clearly shaped domains.[18] Two main transferrin receptors found in humans denoted as transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2). Although both are similar in structure, TfR1 can only bind specifically to human TF where TfR2 also has the capability to interact with
bovine TF.[8]
Transferrin is also associated with the
innate immune system. It is found in the
mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.[21]
Role in disease
An increased plasma transferrin level is often seen in patients with iron deficiency
anemia, during pregnancy, and with the use of oral contraceptives, reflecting an increase in transferrin protein expression. When plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin iron saturation, and a corresponding increase in
total iron binding capacity in iron deficient states[22]
A decreased plasma transferrin level can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as
atransferrinemia, a condition characterized by anemia and
hemosiderosis in the heart and liver that leads to heart failure and many other complications as well as to
H63D syndrome.
Studies reveal that a transferrin saturation (serum iron concentration ÷ total iron binding capacity) over 60 percent in men and over 50 percent in women identified the presence of an abnormality in iron metabolism (Hereditary hemochromatosis, heterozygotes and homozygotes) with approximately 95 percent accuracy. This finding helps in the early diagnosis of Hereditary hemochromatosis, especially while serum
ferritin still remains low. The retained iron in Hereditary hemochromatosis is primarily deposited in parenchymal cells, with reticuloendothelial cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the reticuloendothelial cells and then in parenchymal cells. This explains why ferritin levels remain relative low in Hereditary hemochromatosis, while transferrin saturation is high.[23][24]
Transferrin and its receptor have been shown to diminish
tumour cells when the receptor is used to attract
antibodies.[16]
Transferrin and nanomedicine
Many drugs are hindered when providing treatment when crossing the blood-brain barrier yielding poor uptake into areas of the brain. Transferrin glycoproteins are able to bypass the
blood-brain barrier via receptor-mediated transport for specific transferrin receptors found in the brain capillary endothelial cells.[25] Due to this functionality, it is theorized that
nanoparticles acting as drug carriers bound to transferrin glycoproteins can penetrate the blood-brain barrier allowing these substances to reach the diseased cells in the brain.[26] Advances with transferrin conjugated nanoparticles can lead to non-invasive drug distribution in the brain with potential therapeutic consequences of
central nervous system (CNS) targeted diseases (e.g.
Alzheimer's or
Parkinson's disease).[27]
Transferrin is an acute phase protein and is seen to decrease in inflammation, cancers, and certain diseases (in contrast to other acute phase proteins, e.g., C-reactive protein, which increase in case of acute inflammation).[29]
Pathology
Atransferrinemia is associated with a deficiency in transferrin.
In nephrotic syndrome, urinary loss of transferrin, along with other serum proteins such as thyroxine-binding globulin, gammaglobulin, and anti-thrombin III, can manifest as iron-resistant
microcytic anemia.
Reference ranges
An example
reference range for transferrin is 204–360 mg/dL.[30] Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test[citation needed].
Members of the family include blood serotransferrin (or siderophilin, usually simply called transferrin);
lactotransferrin (lactoferrin); milk transferrin; egg white
ovotransferrin (conalbumin); and membrane-associated
melanotransferrin.[34]
^Hall DR, Hadden JM, Leonard GA, Bailey S, Neu M, Winn M, Lindley PF (January 2002). "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. 58 (Pt 1): 70–80.
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^Nicotra S, Sorio D, Filippi G, De Gioia L, Paterlini V, De Palo EF, et al. (November 2017). "Terbium chelation, a specific fluorescent tagging of human transferrin. Optimization of conditions in view of its application to the HPLC analysis of carbohydrate-deficient transferrin (CDT)". Analytical and Bioanalytical Chemistry. 409 (28): 6605–6612.
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abcMacGillivray RT, Moore SA, Chen J, Anderson BF, Baker H, Luo Y, et al. (June 1998). "Two high-resolution crystal structures of the recombinant N-lobe of human transferrin reveal a structural change implicated in iron release". Biochemistry. 37 (22): 7919–28.
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abDewan JC, Mikami B, Hirose M, Sacchettini JC (November 1993). "Structural evidence for a pH-sensitive dilysine trigger in the hen ovotransferrin N-lobe: implications for transferrin iron release". Biochemistry. 32 (45): 11963–8.
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abcBaker EN, Lindley PF (August 1992). "New perspectives on the structure and function of transferrins". Journal of Inorganic Biochemistry. 47 (3–4): 147–60.
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abHalbrooks PJ, He QY, Briggs SK, Everse SJ, Smith VC, MacGillivray RT, Mason AB (April 2003). "Investigation of the mechanism of iron release from the C-lobe of human serum transferrin: mutational analysis of the role of a pH sensitive triad". Biochemistry. 42 (13): 3701–7.
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^Moos T (November 2002). "Brain iron homeostasis". Danish Medical Bulletin. 49 (4): 279–301.
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abcdMacedo MF, de Sousa M (March 2008). "Transferrin and the transferrin receptor: of magic bullets and other concerns". Inflammation & Allergy - Drug Targets. 7 (1): 41–52.
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^Ghadiri M, Vasheghani-Farahani E, Atyabi F, Kobarfard F, Mohamadyar-Toupkanlou F, Hosseinkhani H (October 2017). "Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier". Journal of Biomedical Materials Research Part A. 105 (10): 2851–2864.
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