transferrin

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.{{cite journal | vauthors = Halbrooks PJ, He QY, Briggs SK, Everse SJ, Smith VC, MacGillivray RT, Mason AB | title = 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 | journal = Biochemistry | volume = 42 | issue = 13 | pages = 3701–7 | date = April 2003 | pmid = 12667060 | doi = 10.1021/bi027071q }} The pH of the vesicle is reduced by hydrogen ion pumps (V-ATPase) to about 5.5, causing transferrin to release its iron ions. Iron release rate is dependent on several factors including pH levels, interactions between lobes, temperature, salt, and chelator. 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 ({{chem|Fe|3+}}).

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.{{cite journal | vauthors = Moos T | title = Brain iron homeostasis | journal = Danish Medical Bulletin | volume = 49 | issue = 4 | pages = 279–301 | date = November 2002 | pmid = 12553165 }} 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. The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.

The gene coding for transferrin in humans is located in chromosome band 3q21.

Medical professionals may check serum transferrin level in iron deficiency and in iron overload disorders such as hemochromatosis.

Drosophila melanogaster has three transferrin genes and is highly divergent from all other model clades, Ciona intestinalis one, Danio rerio has three highly divergent from each other, as do Takifugu rubripes and Xenopus tropicalis and Gallus gallus, while Monodelphis domestica has two divergent orthologs, and Mus musculus has two relatively close and one more distant ortholog. Relatedness and orthology/paralogy data are also available for Dictyostelium discoideum, Arabidopsis thaliana, and Pseudomonas aeruginosa.{{cite journal | vauthors = Gabaldón T, Koonin EV | title = Functional and evolutionary implications of gene orthology | journal = Nature Reviews. Genetics | volume = 14 | issue = 5 | pages = 360–6 | date = May 2013 | pmid = 23552219 | doi = 10.1038/nrg3456 | publisher = Nature Portfolio | author2-link = Eugene Koonin | pmc = 5877793 }}

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.{{cite web | url = http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Projects04/Transferrin/structure.htm | title = Transferrin Structure | date = 2005-07-18 | publisher = St. Edward's University | access-date = 2009-04-24 | url-status = dead | archive-url = https://archive.today/20121211180614/http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Projects04/Transferrin/structure.htm | archive-date = 2012-12-11 }} The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.

The amino acids which bind the iron ion to the transferrin are identical for both lobes; two tyrosines, one histidine, and one aspartic acid. For the iron ion to bind, an anion is required, preferably carbonate ({{chem|CO|3|2−}}).

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.{{cite journal | vauthors = Macedo MF, de Sousa M | title = Transferrin and the transferrin receptor: of magic bullets and other concerns | journal = Inflammation & Allergy - Drug Targets | volume = 7 | issue = 1 | pages = 41–52 | date = March 2008 | pmid = 18473900 | doi = 10.2174/187152808784165162 }} 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. 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.

File:PDB 1suv EBI.jpg|Transferrin bound to its receptor.{{PDB|1suv}}; {{cite journal | vauthors = Cheng Y, Zak O, Aisen P, Harrison SC, Walz T | title = Structure of the human transferrin receptor-transferrin complex | journal = Cell | volume = 116 | issue = 4 | pages = 565–76 | date = Feb 2004 | pmid = 14980223 | doi = 10.1016/S0092-8674(04)00130-8 | s2cid = 2981917 }}

File:PDB 2nsu EBI.jpg|Transferrin receptor complex.{{PDB|2nsu}}; {{cite journal | vauthors = Hafenstein S, Palermo LM, Kostyuchenko VA, Xiao C, Morais MC, Nelson CD, Bowman VD, Battisti AJ, Chipman PR, Parrish CR, Rossmann MG | title = Asymmetric binding of transferrin receptor to parvovirus capsids | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 16 | pages = 6585–9 | date = Apr 2007 | pmid = 17420467 | pmc = 1871829 | doi = 10.1073/pnas.0701574104 | bibcode = 2007PNAS..104.6585H | doi-access = free }}

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.{{cite journal | vauthors = Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY | title = Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort | journal = Journal of Clinical Laboratory Analysis | volume = 13 | issue = 6 | pages = 273–9 | year = 1999 | pmid = 10633294 | pmc = 6808097 | doi = 10.1002/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X }}

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{{cite journal | vauthors = Miller JL | title = Iron deficiency anemia: a common and curable disease | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 7 | pages = a011866 | date = July 2013 | pmid = 23613366 | pmc = 3685880 | doi = 10.1101/cshperspect.a011866 }}

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.{{cite journal | vauthors = Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS | title = Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases | journal = Hepatology | location = Baltimore, Md. | volume = 54 | issue = 1 | pages = 328–43 | date = July 2011 | pmid = 21452290 | pmc = 3149125 | doi = 10.1002/hep.24330 }}{{cite web | title = Hemochromatosis | url = http://eguideline.guidelinecentral.com/i/98549-aasld-hemochromatosis/2 | work = guidelinecentral.com }}

Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.

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.{{cite journal | vauthors = Ghadiri M, Vasheghani-Farahani E, Atyabi F, Kobarfard F, Mohamadyar-Toupkanlou F, Hosseinkhani H | title = Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier | journal = Journal of Biomedical Materials Research Part A | volume = 105 | issue = 10 | pages = 2851–2864 | date = October 2017 | pmid = 28639394 | doi = 10.1002/jbm.a.36145 }} 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.{{cite journal | vauthors = Gaspar R | title = Nanoparticles: Pushed off target with proteins | journal = Nature Nanotechnology | volume = 8 | issue = 2 | pages = 79–80 | date = February 2013 | pmid = 23380930 | doi = 10.1038/nnano.2013.11 | bibcode = 2013NatNa...8...79G }} 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).{{cite journal | vauthors = Li S, Peng Z, Dallman J, Baker J, Othman AM, Blackwelder PL, Leblanc RM | title = Crossing the blood-brain-barrier with transferrin conjugated carbon dots: A zebrafish model study | journal = Colloids and Surfaces B: Biointerfaces | volume = 145 | pages = 251–256 | date = September 2016 | pmid = 27187189 | doi = 10.1016/j.colsurfb.2016.05.007 | doi-access = free }}

Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored through laboratory testing.{{cite journal | vauthors = Sharpe PC | title = Biochemical detection and monitoring of alcohol abuse and abstinence | journal = Annals of Clinical Biochemistry | volume = 38 | issue = Pt 6 | pages = 652–64 | date = November 2001 | pmid = 11732647 | doi = 10.1258/0004563011901064 | s2cid = 12203099 | doi-access = }}

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).{{cite journal | vauthors = Jain S, Gautam V, Naseem S | title = Acute-phase proteins: As diagnostic tool | journal = Journal of Pharmacy & Bioallied Sciences | volume = 3 | issue = 1 | pages = 118–27 | date = January 2011 | pmid = 21430962 | pmc = 3053509 | doi = 10.4103/0975-7406.76489 | doi-access = free }}

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.

An example reference range for transferrin is 204–360 mg/dL.{{cite web|url=http://pathcuric1.swmed.edu/PathDemo/nrrt.htm |title=Normal Reference Range Table |work=Interactive Case Study Companion to Pathological Basis of Disease |publisher=The University of Texas Southwestern Medical Center at Dallas |access-date=2008-10-25 |url-status=dead |archive-url=https://web.archive.org/web/20111225185659/http://pathcuric1.swmed.edu/PathDemo/nrrt.htm |archive-date=2011-12-25 }}
{{cite book | author = Kumar V, Hagler HK | title = Interactive Case Study Companion to Robbins Pathologic Basis of Disease | edition = 6th Edition (CD-ROM for Windows & Macintosh, Individual) | publisher = W B Saunders Co | year = 1999 | isbn = 0-7216-8462-9 }} Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test{{citation needed|date=November 2023}}.

File:Blood values sorted by mass and molar concentration.png, comparing blood content of transferrin and other iron-related compounds (shown in brown and orange) with other constituents]]

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A high transferrin level may indicate an iron deficiency anemia. Levels of serum iron and total iron binding capacity (TIBC) are used in conjunction with transferrin to specify any abnormality. See interpretation of TIBC. Low transferrin likely indicates malnutrition.

Transferrin has been shown to interact with insulin-like growth factor 2{{cite journal | vauthors = Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T | title = Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3 | journal = FEBS Letters | volume = 509 | issue = 3 | pages = 395–8 | date = December 2001 | pmid = 11749962 | doi = 10.1016/S0014-5793(01)03204-5 | s2cid = 22895295 | doi-access = free }} and IGFBP3.{{cite journal | vauthors = Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P | title = Transferrin is an insulin-like growth factor-binding protein-3 binding protein | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 4 | pages = 1806–13 | date = April 2001 | pmid = 11297622 | doi = 10.1210/jcem.86.4.7380 | doi-access = free }} Transcriptional regulation of transferrin is upregulated by retinoic acid.{{cite journal | vauthors = Hsu SL, Lin YF, Chou CK | title = Transcriptional regulation of transferrin and albumin genes by retinoic acid in human hepatoma cell line Hep3B | journal = The Biochemical Journal | volume = 283 ( Pt 2) | issue = 2 | pages = 611–5 | date = April 1992 | pmid = 1315521 | pmc = 1131079 | doi = 10.1042/bj2830611 }}

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.{{cite journal | vauthors = Chung MC | title = Structure and function of transferrin | journal = Biochemical Education | volume = 12 | issue = 4 | pages = 146–154 |date=October 1984 | doi = 10.1016/0307-4412(84)90118-3 }}

• Beta-2 transferrin
• Transferrin receptor
• Total iron-binding capacity
• Transferrin saturation
• Ferritin
• [https://invitria.com/products/optiferrin-recombinant-human-transferrin/ Optiferrin recombinant human transferrin]
• Atransferrinemia
• Hypotransferrinemia
• HFE H63D gene mutation

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• {{cite journal | vauthors = Hershberger CL, Larson JL, Arnold B, Rosteck PR, Williams P, DeHoff B, Dunn P, O'Neal KL, Riemen MW, Tice PA | display-authors = 6 | title = A cloned gene for human transferrin | journal = Annals of the New York Academy of Sciences | volume = 646 | issue = 1 | pages = 140–54 | date = December 1991 | pmid = 1809186 | doi = 10.1111/j.1749-6632.1991.tb18573.x | bibcode = 1991NYASA.646..140H | s2cid = 19519911 }}
• {{cite book | vauthors = Bowman BH, Yang FM, Adrian GS | title = Transferrin: evolution and genetic regulation of expression | volume = 25 | pages = 1–38 | year = 1989 | pmid = 3057819 | doi = 10.1016/S0065-2660(08)60457-5 | isbn = 9780120176250 | series = Advances in Genetics }}
• {{cite journal | vauthors = Parkkinen J, von Bonsdorff L, Ebeling F, Sahlstedt L | title = Function and therapeutic development of apotransferrin | journal = Vox Sanguinis | volume = 83 | issue = Suppl 1 | pages = 321–6 | date = August 2002 | pmid = 12617162 | doi = 10.1111/j.1423-0410.2002.tb05327.x | s2cid = 5876134 }}

{{Refend}}

• {{MeshName|Transferrin}}
• {{PDBe-KB2|P02787|Serotransferrin}}

{{PDB Gallery|geneid=7018}}

{{Iron-binding proteins}}

{{Beta globulins}}

{{Acute phase proteins}}

{{Iron metabolism}}

{{Authority control}}

Category:Chemical pathology

Category:Iron metabolism

Category:Transferrins