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Ferritin
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Ferritin is a ubiquitous protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.[3]
Ferritin is a globular protein complex consisting of 24 protein subunits and is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. Ferritin that is not combined with iron is called apoferritin.
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Description
Ferritin is a 450 kDa protein consisting of 24 subunits that is present in every cell type.[4] In vertebrates, these subunits are both the light (L) and the heavy (H) type with an apparent molecular weight of 19 kDA or 21 kDA respectively; their sequences are about 50% homologous.[4] Amphibians have an additional ("M") type of ferritin;[5] the single ferritin of plants and bacteria most closely resembles the vertebrate H-type.[5] Two types have been recovered in the gastropod Lymnaea, the somatic ferritin being distinct from the yolk ferritin (see below).[5] An additional subunit resembling Lymnaea soma ferritin is associated with shell formation in the pearl oyster.[6] Two types are present in the parasite Schistosoma, one in males, the other in females.[5] All the aforementioned ferritins are most similar, in terms of their primary sequence, with the vertebrate H-type.[5] In E. coli, a 20% similarity to human H-ferritin is recovered.[5] Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide ions. The resulting particle is similar to the mineral ferrihydrite. Each ferritin complex can store about 4500 iron (Fe3+) ions.[4][5]
Some ferritin complexes in vertebrates are hetero-oligomers of two highly-related gene products with slightly different physiological properties. The ratio of the two homologous proteins in the complex depends on the relative expression levels of the two genes.
Mitochondrial ferritin was recently identified as a protein precursor. It is classified as a metal-binding protein which is located within the mitochondria. After the protein is taken up by the mitochondria it can be processed into a mature protein and assemble functional ferritin shells. Its structure was determined at 1.70 angstroms through the use of X-ray diffraction and contains 182 residues. It is 67% helical. The Ramachandran plot [1] shows that the structure of mitochondrial ferritin is mainly alpha helical with a low prevalence of beta sheets.
Genetic structure
In human ferritin, introns are present between the 34/5th,[clarification needed] 82/3rd, and 14/5th amino acid residues; in addition, one to two hundred untranslated bases grace either end of the combined exons.[4] The Tyrosine residue at amino acid position 27 is thought to be associated with biomineralization.[7]
Function
Iron storage
Ferritin serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas that it is required.[8] The function and structure of the expressed ferritin protein varies by a factor of 1000 in different cell types. This is controlled primarily by how much mRNA is translated, and how stable the mRNA is. mRNA concentration is further tweaked by changes to how it is stored and how efficiently it is transcribed.[4] The presence of iron itself is a major trigger for the production of ferritin,[4] with some exceptions (such as the yolk ferritin of the gastropod Lymnaea, which lacks an iron-responsive unit).[5]
Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton Reaction.[9] Hence vertebrates use an elaborate set of protective mechanisms to bind iron in various tissue compartments. Within cells, iron is stored in a protein complex as ferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the reticuloendothelial system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells although hemosiderin is less readily available. Under steady state conditions, the serum ferritin level correlates with total body iron stores; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores.
Because iron is an important mineral in mineralization, ferritin is employed in the shells of organisms such as molluscs to control the concentration and distribution of iron, thus sculpting shell morphology and colouration.[10][11] It also serves in the haemolymph of the polyplacophora where it serves to rapidly transport iron to the mineralizing radula.[12]
Immune response
Ferritin concentrations increase drastically in the presence of an infection or cancer; this is necessary to counter the infective agent's attempt to bind iron from the host's tissue.[13] Infective agents may cause ferritin to migrate from the plasma to within cells, in order to deny iron to the infective agent.[13]
Stress response
The concentration of ferritin has been shown to increase in response to stresses such as anoxia;[14] this implies that it is an acute phase protein.[15]
Mitochondrial ferritin
Mitochondrial ferritin has many roles pertaining to molecular function. It participates in ferroxidase activity, binding, iron ion binding, oxidoreductase activity, ferric iron binding, metal ion binding as well as transition metal binding. Within the realm of biological processes it participates in oxidation-reduction, iron ion transport across membranes and cellular iron ion homeostasis.
Human applications
Ferritin is also used in materials science as a precursor in making iron nanoparticles for carbon nanotube growth by chemical vapor deposition.
Expression
In vertebrates, ferritin is usually found within cells, although it is also present in smaller quantities in the plasma.[13]
Diagnostic uses
Serum ferritin levels are measured in patients as part of the iron studies workup for anemia and for restless legs syndrome. The ferritin levels measured have a direct correlation with the total amount of iron stored in the body including cases of anemia of chronic disease.
A normal ferritin blood level, referred to as the "reference interval," is now determined by many testing laboratories, such as LabCorp, using the Roche enhanced chemiluminescence immunoassay (ECLIA) methodology. The Roche ECLIA reference ranges for ferritin are 30-400 ng/mL for males, and 13-150 ng/mL for females. Other tests are in usage that rely on different methods and may have different reference ranges.
Low
If the ferritin level is low, there is a risk for lack of iron, which could lead to anemia. Low ferritin levels (<50 ng/mL) have however been associated with the symptoms of restless legs syndrome, even in the absence of anemia and sickness.[16]
In the setting of anemia, serum ferritin is the most sensitive lab test for iron deficiency anemia.[17]
Low ferritin may also indicate hypothyroidism or vitamin C deficiency.
In a certain study in Paris, France, the level of iron in the blood (measured by ordering a ferritin serum test) has been connected to ADHD in children. Specifically, the lower the iron level, the more severe the ADHD symptoms.[18]
Elevated
If ferritin is high there is iron in excess.
Ferritin is also used as a marker for iron overload disorders, such as hemochromatosis, hemosiderosis and porphyria in which the ferritin level may be abnormally raised.
As ferritin is also an acute-phase reactant, it is often elevated in the course of disease. A normal C-reactive protein can be used to exclude elevated ferritin caused by acute phase reactions.
Ferritin can be elevated during periods of acute malnourishment.[19]
Application
Cavities formed by ferritin and mini-ferritins (Dps) proteins have been successfully used as the reaction chamber for the fabrication of metal nanoparticles (NPs).[20][21][22][23] Protein shells served as a template to restrain particle growth and as a coating to prevent coagulation/aggregation between NPs. Using various sizes of protein shells, various sizes of NPs can be easily synthesized for chemical, physical and bio-medical applications
See also
References
- ^ PDB 1lb3; Granier T, Langlois d'Estaintot B, Gallois B, Chevalier JM, Précigoux G, Santambrogio P, Arosio P (January 2003). "Structural description of the active sites of mouse L-chain ferritin at 1.2 A resolution". J. Biol. Inorg. Chem. 8 (1-2): 105–11. doi:10.1007/s00775-002-0389-4. PMID 12459904.
- ^ PDB 1r03; Langlois d'Estaintot B, Santambrogio P, Granier T, Gallois B, Chevalier JM, Précigoux G, Levi S, Arosio P (July 2004). "Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala". J. Mol. Biol. 340 (2): 277–93. doi:10.1016/j.jmb.2004.04.036. PMID 15201052.
- ^ Iron Use and Storage in the Body: Ferritin and Molecular Representations, Rachel Casiday and Regina Frey, Department of Chemistry, Washington University, St. Louis.
- ^ a b c d e f Theil, E. (1987). "Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms.". Annual review of biochemistry 56: 289–315. doi:10.1146/annurev.bi.56.070187.001445. PMID 3304136.
- ^ a b c d e f g h Andrews, S. C.; Harrison, P. M.; Yewdall, S. J.; Arosio, P.; Levi, S.; Bottke, W.; Von Darl, M.; Briat, J. F. �O. et al. (1992). "Structure, function, and evolution of ferritins". Journal of Inorganic Biochemistry 47: 161. doi:10.1016/0162-0134(92)84062-R.
- ^ Zhang, Y. (2003). "A novel ferritin subunit involved in shell formation from the pearl oyster (Pinctada fucata)". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. doi:10.1016/S1096-4959(03)00050-2.
- ^ De Zoysa, M.; Lee, J. (2007). "Two ferritin subunits from disk abalone (Haliotis discus discus): cloning, characterization and expression analysis.". Fish & shellfish immunology 23 (3): 624–635. doi:10.1016/j.fsi.2007.01.013. PMID 17442591.
- ^ Seckback, J. (1982). "Ferreting out the secrets of plant ferritin - A review". Journal of Plant Nutrition 5: 369–394. doi:10.1080/01904168209362966.
- ^ Orino, K.; Lehman, L.; Tsuji, Y.; Ayaki, H.; Torti, S. V.; Torti, F. M. (2001). "Ferritin and the response to oxidative stress". Biochemical Journal 357 (Pt 1): 241. doi:10.1042/0264-6021:3570241. PMID 11415455.
- ^ Jackson, D. J.; Wörheide, G.; Degnan, B. M. (2007). "Dynamic expression of ancient and novel molluscan shell genes during ecological transitions". BMC Evolutionary Biology 7: 160. doi:10.1186/1471-2148-7-160. PMID 17845714.
- ^ Yano, M.; Nagai, K.; Morimoto, K.; Miyamoto, H. (2006). "Shematrin: a family of glycine-rich structural proteins in the shell of the pearl oyster Pinctada fucata". Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 144 (2): 254–262. doi:10.1016/j.cbpb.2006.03.004. PMID 16626988.
- ^ Kyungsukkim; Webb, J.; Macey, D. (1986). "Properties and role of ferritin in the hemolymph of the chiton Clavarizona hirtosa". Biochimica et Biophysica Acta (BBA) - General Subjects 884: 387. doi:10.1016/0304-4165(86)90188-1.
- ^ a b c Ong, D.; Wang, L.; Zhu, Y.; Ho, B.; Ding, J. (2005). "The response of ferritin to LPS and acute phase of Pseudomonas infection". Journal of endotoxin research 11 (5): 267–280. doi:10.1179/096805105X58698. PMID 16262999.
- ^ Larade, K.; Storey, K. B. (2004). "Accumulation and translation of ferritin heavy chain transcripts following anoxia exposure in a marine invertebrate". Journal of Experimental Biology 207 (Pt 8): 1353. doi:10.1242/jeb.00872. PMID 15010486.
- ^ Beck, G; Ellis, TW; Habicht, GS; Schluter, SF; Marchalonis, JJ (2002). "Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule". Developmental and comparative immunology 26 (1): 11–26. PMID 11687259.
- ^ Kryger MH, Otake K, Foerster J (March 2002). "Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers". Sleep Med. 3 (2): 127–32. doi:10.1016/S1389-9457(01)00160-5. PMID 14592231.
- ^ Guyatt G, Patterson C, Ali M, Singer J, Levine M, Turpie I, Meyer R (1990). "Diagnosis of iron-deficiency anemia in the elderly". Am J Med 88 (3): 205–9. doi:10.1016/0002-9343(90)90143-2. PMID 2178409.
- ^ Greene MD, Alan (2004-12-17). "Iron and ADHD". http://www.drgreene.com/21_1864.html. Retrieved 2008-08-19.
- ^ Kennedy A, Kohn M, Lammi A, Clarke S (2004). "Iron status and haematological changes in adolescent female inpatients with anorexia nervosa". J Paediatr Child Health 40 (8): 430–2. doi:10.1111/j.1440-1754.2004.00432.x. PMID 15265182.
- ^ Kasyutich, O.; Ilari, A.; Fiorillo, A.; Tatchev, D.; Hoell, A.; Ceci, P. (2010). "Silver Ion Incorporation and Nanoparticle Formation inside the Cavity ofPyrococcus furiosusFerritin: Structural and Size-Distribution Analyses". Journal of the American Chemical Society 132 (10): 3621. doi:10.1021/ja910918b. PMID 20170158. Kasyutich, O.; Ilari, A.; Fiorillo, A.; Tatchev, D.; Hoell, A.; Ceci, P. (2010). "Silver Ion Incorporation and Nanoparticle Formation inside the Cavity ofPyrococcus furiosusFerritin: Structural and Size-Distribution Analyses". Journal of the American Chemical Society 132 (10): 3621. doi:10.1021/ja910918b. PMID 20170158.
- ^ Uchida, M.; Flenniken, M. L.; Allen, M.; Willits, D. A.; Crowley, B. E.; Brumfield, S.; Willis, A. F.; Jackiw, L. et al. (2006). "Targeting of Cancer Cells with Ferrimagnetic Ferritin Cage Nanoparticles". Journal of the American Chemical Society 128 (51): 16626. doi:10.1021/ja0655690. PMID 17177411. Uchida, M.; Flenniken, M. L.; Allen, M.; Willits, D. A.; Crowley, B. E.; Brumfield, S.; Willis, A. F.; Jackiw, L. et al. (2006). "Targeting of Cancer Cells with Ferrimagnetic Ferritin Cage Nanoparticles". Journal of the American Chemical Society 128 (51): 16626. doi:10.1021/ja0655690. PMID 17177411.
- ^ Li, M.; Viravaidya, C.; Mann, S. (2007). "Polymer-Mediated Synthesis of Ferritin-Encapsulated Inorganic Nanoparticles". Small 3 (9): 1477. doi:10.1002/smll.200700199. PMID 17768776. Li, M.; Viravaidya, C.; Mann, S. (2007). "Polymer-Mediated Synthesis of Ferritin-Encapsulated Inorganic Nanoparticles". Small 3 (9): 1477. doi:10.1002/smll.200700199. PMID 17768776.
- ^ Ueno, T.; Suzuki, M.; Goto, T.; Matsumoto, T.; Nagayama, K.; Watanabe, Y. (2004). "Size-Selective Olefin Hydrogenation by a Pd Nanocluster Provided in an Apo-Ferritin Cage". Angewandte Chemie International Edition 43: 2527. doi:10.1002/anie.200353436. Ueno, T.; Suzuki, M.; Goto, T.; Matsumoto, T.; Nagayama, K.; Watanabe, Y. (2004). "Size-Selective Olefin Hydrogenation by a Pd Nanocluster Provided in an Apo-Ferritin Cage". Angewandte Chemie International Edition 43: 2527. doi:10.1002/anie.200353436.
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The content of this section is licensed under the GNU Free Documentation License (local copy). It uses material from the Wikipedia article "Ferritin" modified November 23, 2009 with previous authors listed in its history.
