Transferrins areglycoproteins found invertebrates which bind and consequently mediate the transport ofiron (Fe) throughblood plasma.[5] They are produced in theliver and contain binding sites for twoFe3+ ions.[6] Human transferrin is encoded by theTFgene and produced as a 76kDa glycoprotein.[7][8]
Transferringlycoproteins 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 80kDa and contains two specific high-affinityFe(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 decreasingpH 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 thehemolymph.[11][13]
When not bound to iron, transferrin is known as "apotransferrin" (see alsoapoprotein).
Transferrins are glycoproteins that are often found in biological fluids of vertebrates. When a transferrin protein loaded with iron encounters atransferrin receptor on the surface of acell, e.g., erythroid precursors in the bone marrow, it binds to it and is transported into the cell in avesicle byreceptor-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 itsligand bound transferrin is then transported through theendocytic 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 theferric form (Fe3+ ).[13]
Theliver 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 thechoroid plexus in theventricular system.[15] The main role of transferrin is to deliver iron from absorption centers in theduodenum and white blood cellmacrophages to all tissues. Transferrin plays a key role in areas where erythropoiesis and active cell division occur.[16] The receptor helps maintain ironhomeostasis in the cells by controlling iron concentrations.[16]
Thegene coding for transferrin in humans is located inchromosome band 3q21.[7]
In humans, transferrin consists of a polypeptide chain containing 679amino acids and two carbohydrate chains. The protein is composed ofalpha helices andbeta sheets that form twodomains.[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-boundreceptor; it is a disulfide-linkedhomodimer.[16] In humans, each monomer consists of 760 amino acids. It enablesligand bonding to the transferrin, as eachmonomer 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 withbovine TF.[8]
Transferrin is also associated with theinnate immune system. It is found in themucosa 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]
An increased plasma transferrin level is often seen in patients with iron deficiencyanemia, 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 intotal 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 asatransferrinemia, a condition characterized by anemia andhemosiderosis in the heart and liver that leads to heart failure and many other complications as well as toH63D 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 serumferritin 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 diminishtumour cells when the receptor is used to attractantibodies.[16] Transferrin levels have been shown to be a promising indicator for diagnosingovarian cancer and cancer-associated functionaliron deficiency.[25][26]
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 theblood-brain barrier via receptor-mediated transport for specific transferrin receptors found in the brain capillary endothelial cells.[27] Due to this functionality, it is theorized thatnanoparticles 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.[28] Advances with transferrin conjugated nanoparticles could lead to non-invasive drug distribution in the brain with potential therapeutic consequences ofcentral nervous system (CNS) targeted diseases (e.g.Alzheimer's orParkinson's disease).[29]
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).[31]
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-resistantmicrocytic anemia.
An examplereference range for transferrin is 204–360 mg/dL.[32] Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test[citation needed].
Reference ranges for blood tests, comparing blood content of transferrin and other iron-related compounds (shown in brown and orange) with other constituents
Members of the family include blood serotransferrin (or siderophilin, usually simply called transferrin);lactotransferrin (lactoferrin); milk transferrin; egg whiteovotransferrin (conalbumin); and membrane-associatedmelanotransferrin.[36]
^Hall DR, Hadden JM, Leonard GA, Bailey S, Neu M, Winn M, et al. (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.Bibcode:2002AcCrD..58...70H.doi:10.1107/s0907444901017309.PMID11752780.
^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.doi:10.1007/s00216-017-0616-z.PMID28971232.S2CID13929228.
^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):7919–7928.doi:10.1021/bi980355j.PMID9609685.
^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):11963–11968.doi:10.1021/bi00096a004.PMID8218271.
^abcBaker EN, Lindley PF (August 1992). "New perspectives on the structure and function of transferrins".Journal of Inorganic Biochemistry.47 (3–4):147–160.doi:10.1016/0162-0134(92)84061-q.PMID1431877.
^abHalbrooks PJ, He QY, Briggs SK, Everse SJ, Smith VC, MacGillivray RT, et al. (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):3701–3707.doi:10.1021/bi027071q.PMID12667060.
^Moos T (November 2002). "Brain iron homeostasis".Danish Medical Bulletin.49 (4):279–301.PMID12553165.
^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.doi:10.2174/187152808784165162.PMID18473900.
^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.doi:10.1002/jbm.a.36145.PMID28639394.
^"Normal Reference Range Table".Interactive Case Study Companion to Pathological Basis of Disease. The University of Texas Southwestern Medical Center at Dallas. Archived fromthe original on 2011-12-25. Retrieved2008-10-25. Kumar V HH (1999).Interactive Case Study Companion to Robbins Pathologic Basis of Disease (6th Edition (CD-ROM for Windows & Macintosh, Individual) ed.). W B Saunders Co.ISBN978-0-7216-8462-8.
![Transferrin bound to its receptor.[19]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aPDB_1suv_EBI.jpg)
![Transferrin receptor complex.[20]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aPDB_2nsu_EBI.jpg)
