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Background
Discovered in 1937 by French scientist Laufberger, ferritin was first detected in horse spleen and a few years later in humans (7). Ferritin is a protein that is responsible for iron storage and iron homeostasis, as well as various physiologic and pathological processes in prokaryotes and eukaryotes. Iron homeostasis is essential to maintaining life because iron can be toxic to DNA and proteins if not properly regulated. If there is an overload of iron, reactive oxygen species can be produced, lipid peroxidation can occur, and there can be damage to DNA. Typically, ferritin presents as a cytosolic protein, but there are also mitochondrial and nuclear forms that have recently been discovered. The most common measurement of ferritin is collected from serum ferritin, which is ferritin stored in red blood cells. Many variations of ferritin exist, as it is presumed that evolutionary adaptations were made in order to allow certain organisms to survive.
Structure
The structure of ferritin consists of a spherical apoferritin shell that has 24 subunits to form a cage that contains two types of subunits: H and L. The ratio of H to L subunits is dependent upon inflammation and tissue type, and varies greatly. H-subunits are mostly found in the kidneys and heart while the L-subunits are mostly found in the liver and spleen. The genes that encode for these H and L subunits are found on chromosomes 11q and 19q (7). Each subunit is constructed from four α-helices, A, B, C, and D, which combine to form helix E. This can be seen in the tertiary structure of ferritin. In the quaternary structure, eukaryotic ferritin presents as spherical with 4-3-2 symmetry. Within the apoferritin shell is where sequestered iron is kept. It contains insoluble iron (III) oxide hydroxide and iron (III) phosphate. Ferritin is able to be degraded through lysosomal or proteasomal mechanisms depending on if degradation is needed.
Function
Ferritin’s main function is to convert Fe(II) to Fe(III) by acting as a ferroxidase. In a clinical setting, ferritin is used as an indicator for an iron deficiency (4). Any extracellular ferritin can act as a carrier for iron in order to transport iron to cells. This is because each ferritin molecule can sequester a maximum of 4500 iron atoms (7). There has also been research to show that ferritin H can suppress immune activity by inducing IL-10 in lymphocytes, and can inhibit delayed-type hypersensitivity (DTH) without having any effect of antibody mediated inflammatory responses. Ferritin has protective cages that are very large and stable, but if all of the iron is released from ferritin, then ferritin cages are degraded within the cytoplasm. If there is too much iron for ferritin to store, the iron could be stored as hemosiderin, which is a mixture of lipids and denatured proteins. The mechanism representing ferritin function is summarized in six steps: assembly of subunits, entry of Fe (II) to ferritin, binding to catalytic centers, oxidation of Fe (II), storage of Fe (III), and release of Fe (III) from the core of ferritin. High iron organs, like the heart, participate more in ferroxidase activity versus organs, like the liver, which are meant more for iron storage in the core of ferritin.
Bacterioferritin
Bacterioferritin is another ferritin molecule found in bacteria. The structure remains relatively similar with the 24 subunits that form a sphere and consist of four helix bundles surrounding a ferroxidase center. Bacterioferritin also consists of 12 hemes that are bound at 2-fold intersubunit sites (5). B-pores, which are formed as asymmetric sites between three subunits, are lined with negatively charged residues that are also hydrophilic and are found in bacterioferritin. In studies using P. aeruginosa, it was found that there are two distinct genes that code for bacterioferritin (bfr): bfrA and bfrB. The research showed that bfrB levels were increased in response to high iron conditions and bfrA had no response to changed iron concentrations. This is due to the difference in binding sites for heme in bfrA and bfrB. BfrA has a binding site at M48, but it is too far to bind heme iron. BfrB has a binding site at M52, which is located at the center of helix B and can bind heme. Both bacterioferritin also have different ferroxidase center structures, which could have an effect on binding. In fact, there has been research to show that bfrA is a bacterial ferritin that is now referred to as ftnA. The protein that is created from bfrB still remains a true bacterioferritin (5).
Clinical Uses
Relevance to Disease/Illness
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