Ferritin

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Ferritin
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1fha / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Chr. 19 q13.3–13.4
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Chr. 11 q13
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ferritin mitochondrial
Chr. 5 q23.1
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Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload.[3]

Ferritin is found in most tissues as a

diagnostic test for iron-deficiency anemia.[4] Aggregated ferritin transforms into a toxic form of iron called hemosiderin.[5]

Ferritin is a globular protein complex consisting of 24 protein subunits forming a hollow nanocage with multiple metal–protein interactions.[6] Ferritin that is not combined with iron is called apoferritin.[citation needed]

Gene

Ferritin genes are highly conserved between species. All vertebrate ferritin genes have three introns and four exons.[7] In human ferritin, introns are present between amino acid residues 14 and 15, 34 and 35, and 82 and 83; in addition, there are one to two hundred untranslated bases at either end of the combined exons.[8] The tyrosine residue at amino acid position 27 is thought to be associated with biomineralization.[9]

Protein structure

Ferritin is a hollow globular protein of mass 474 kDa and comprising 24 subunits. Typically it has internal and external diameters of about 8 and 12 nm, respectively.[10] The nature of these subunits varies by class of organism:

All the aforementioned ferritins are similar, in terms of their primary sequence, with the vertebrate H-type.[11] In E. coli, a 20% similarity to human H-ferritin is observed.[11] Some ferritin complexes in vertebrates are

physiological properties. The ratio of the two homologous
proteins in the complex depends on the relative expression levels of the two genes.

Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide ions. The resulting particle is similar to ferrihydrite. Each ferritin complex can store about 4500 iron (Fe3+) ions.[8][11]

A human

introns in its genetic code. An X-ray diffraction study has revealed that its diameter is 1.70 angstroms (0.17 nm), it contains 182 residues, and is 67% helical. The mitochondrial ferritin's Ramachandran plot[14] shows its structure to be mainly alpha helical with a low prevalence of beta sheets
.

Function

Iron storage

Iron uptake through the 3-fold channel of ferritin

Ferritin is present in every cell type.[8] It serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas where it is required.[15] The function and structure of the expressed ferritin protein varies in different cell types. This is controlled primarily by the amount and stability of messenger RNA (mRNA), but also by changes in how the mRNA is stored and how efficiently it is transcribed.[8] One major trigger for the production of many ferritins is the mere presence of iron;[8] an exception is the yolk ferritin of Lymnaea sp., which lacks an iron-responsive unit.[11]

Free iron is

blood serum correlates with total body stores of iron; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores.[citation needed
]

Because iron is an important mineral in mineralization, ferritin is employed in the shells of organisms such as

polyplacophora, where it serves to rapidly transport iron to the mineralizing radula.[19]

Iron is released from ferritin for use by ferritin degradation, which is performed mainly by lysosomes.[20]

Ferroxidase activity

Vertebrate ferritin consists of two or three subunits which are named based on their molecular weight: L "light", H "heavy", and M "middle" subunits. The M subunit has only been reported in bullfrogs. In bacteria and archaea, ferritin consists of one subunit type.

Fenton reaction which produces the highly damaging hydroxyl radical. The ferroxidase activity occurs at a diiron binding site in the middle of each H-type subunits.[21][22] After oxidation of Fe(II), the Fe(III) product stays metastably in the ferroxidase center and is displaced by Fe(II),[22][23] a mechanism that appears to be common among ferritins of all three domains of life.[21] The light chain of ferritin has no ferroxidase activity but may be responsible for the electron transfer across the protein cage.[24]

Immune response

Ferritin concentrations increase drastically in the presence of an infection or cancer.

Endotoxins are an up-regulator of the gene coding for ferritin, thus causing the concentration of ferritin to rise. By contrast, organisms such as Pseudomonas, although possessing endotoxin, cause plasma ferritin levels to drop significantly within the first 48 hours of infection. Thus, the iron stores of the infected body are denied to the infective agent, impeding its metabolism.[25]

Stress response

The concentration of ferritin has been shown to increase in response to stresses such as

acute phase protein.[27]

Mitochondria

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.[citation needed]

Yolk

In some snails, the protein component of the egg yolk is primarily ferritin.[28] This is a different ferritin, with a different genetic sequence, from the somatic ferritin. It is produced in the midgut glands and secreted into the haemolymph, whence it is transported to the eggs.[28]

Tissue distribution

In vertebrates, ferritin is usually found within cells, although it is also present in smaller quantities in the plasma.[25]

Diagnostic uses

Serum ferritin levels are measured in medical laboratories as part of the iron studies workup for iron-deficiency anemia.[6] They are measured in nanograms per milliliter (ng/mL) or micrograms per liter (μg/L); the two units are equivalent.

The ferritin levels measured usually have a direct correlation with the total amount of iron stored in the body. However, ferritin levels may be artificially high in cases of

acute phase protein and not as a marker for iron overload.[citation needed
]

Normal ranges

A normal ferritin blood level, referred to as the

reference interval is determined by many testing laboratories. The ranges for ferritin can vary between laboratories but typical ranges would be between 40 and 300 ng/mL (=μg/L) for males, and 20–200 ng/mL (=μg/L) for females.[29]

Normal ferritin blood levels according to sex and age[citation needed]
Adult males 40–300 ng/mL (μg/L)[29]
Adult females 20–200 ng/mL (μg/L)[29]
Children (6 months to 15 years) 50–140 ng/mL (μg/L)
Infants (1 to 5 months) 50–200 ng/mL (μg/L)
Neonates 25–200 ng/mL (μg/L)

Deficiency

According to a 2014 review in the New England Journal of Medicine stated that a ferritin level below 30 ng/mL indicates iron deficiency, while a level below 10 ng/mL indicates iron-deficiency anemia.[29] A 2020 World Health Organization guideline states that ferritin indicates iron deficiency below 12 ng/mL in apparently-healthy children under 5 and 15 ng/mL in apparently-healthy individuals of 5 and over.[30]

Some studies suggest that women with fatigue and ferritin below 50 ng/mL see reduced fatigue after iron supplementation.[31][32]

In the setting of anemia, low serum ferritin is the most specific lab finding for

false positive test) is very uncommon,[34] but can result from a hook effect of the measuring tools in extreme cases.[35]

Low ferritin may also indicate

celiac disease.[citation needed
]

Low serum ferritin levels are seen in some patients with restless legs syndrome, not necessarily related to anemia, but perhaps due to low iron stores short of anemia.[37][38]

Vegetarianism is not a cause of low serum ferritin levels, according to the American Dietetic Association's position in 2009: "Incidence of iron-deficiency anemia among vegetarians is similar to that of non-vegetarians. Although vegetarian adults have lower iron stores than non-vegetarians, their serum ferritin levels are usually within the normal range."[39]

Excess

If ferritin is high, there is iron in excess or else there is an acute inflammatory reaction in which ferritin is mobilized without iron excess. For example, ferritins may be high in infection without signaling body iron overload.

Ferritin is also used as a

porphyrias, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome
are diseases 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. [citation needed
]

Ferritin has been shown to be elevated in some cases of COVID-19 and may correlate with worse clinical outcome.[40][41] Ferritin and IL-6 are considered to be possible immunological biomarkers for severe and fatal cases of COVID-19. Ferritin and C-reactive protein may be possible screening tools for early diagnosis of systemic inflammatory response syndrome in cases of COVID-19.[42][43]

According to a study of anorexia nervosa patients, ferritin can be elevated during periods of acute malnourishment, perhaps due to iron going into storage as intravascular volume and thus the number of red blood cells falls.[44]

Another study suggests that due to the catabolic nature of

oxidative damage. The rise of these isoferritins may contribute to an overall increase in ferritin concentration. The measurement of ferritin through immunoassay or immunoturbidimeteric methods may also be picking up these isoferritins thus not a true reflection of iron storage status.[45]

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.[46][47]

In chronic liver diseases

Hematological abnormalities often associate with chronic liver diseases. Both iron overload and iron deficient anemia have been reported in patients with liver cirrhosis.[48][49] The former is mainly due to reduced hepcidin level caused by the decreased synthetic capacity of the liver, while the latter is due to acute and chronic bleeding caused by portal hypertension. Inflammation is also present in patients with advanced chronic liver disease. As a consequence, elevated hepatic and serum ferritin levels are consistently reported in chronic liver diseases.[50][51][52]

Studies showed association between high serum ferritin levels and increased risk of short-term mortality in cirrhotic patients with acute decompensation[53] and acute-on-chronic liver failure.[54] An other study found association between high serum ferritin levels and increased risk of long-term mortality in compensated and stable decompensated cirrhotic patients.[55] The same study demonstrated that increased serum ferritin levels could predict the development of bacterial infection in stable decompensated cirrhotic patients, while in compensated cirrhotic patients the appearance of the very first acute decompensation episode showed higher incidence in patients with low serum ferritin levels. This latter finding was explaind by the association between chronic bleeding and increased portal pressure.[55]

Applications

Ferritin is used in materials science as a precursor in making iron nanoparticles for carbon nanotube growth by chemical vapor deposition.

Cavities formed by ferritin and mini-ferritins (

nanoparticles (NPs).[56][57][58][59] 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.[6][60]

Experimental COVID-19 vaccines have been produced that display the spike protein's receptor binding domain on the surface of ferritin nanoparticles.[61]

Notes

The primary peptide sequence of human ferritin is:[62] 

MTTASTSQVR QNYHQDSEAA INRQINLELY ASYVYLSMSY YFDRDDVALK NFAKYFLHQS HEEREHAEKL MKLQNQRGGR IFLQDIKKPD CDDWESGLNA MECALHLEKN VNQSLLEFPS PISPSPSCWH HYTTNRPQPQ HHLLRPRRRK RPHSIPTPIL IFRSP.

See also

References

  1. S2CID 20756710
    .
  2. PMID 15201052
    .
  3. ^ Casiday R, Frey R. "Iron Use and Storage in the Body: Ferritin and Molecular Representations". Department of Chemistry, Washington University in St. Louis.
  4. PMID 20304033
    .
  5. PMID 18327971
    .
  6. ^
    PMID 24198751
    .
  7. PMID 11986201
    .
  8. ^
    PMID 3304136
    .
  9. PMID 17442591
    .
  10. ^ "Ferritin Structure and Its Biomedical Implications". Metallic BioNano Particles. Universidad de Granada. Archived from the original on 2016-08-27. Retrieved 2016-01-16.
  11. ^
    PMID 1431878
    .
  12. PMID 12781972
    .
  13. PMID 11323407
    .
  14. S2CID 8358424. Archived from the original
    (PDF) on 12 October 2012. MolProbity Ramachandran analysis
  15. doi:10.1080/01904168209362966
    .
  16. PMID 11415455
    .
  17. PMID 17845714
    .
  18. PMID 16626988
    .
  19. doi:10.1016/0304-4165(86)90188-1
    .
  20. PMID 20406137
    .
  21. ^
    PMID 25418839
    .
  22. ^
    PMID 23001032
    .
  23. S2CID 41485685
    .
  24. PMID 25348725
    .
  25. ^
    PMID 16262999
    .
  26. PMID 15010486
    .
  27. PMID 11687259
    .
  28. ^
    S2CID 34033340
    .
  29. ^
    S2CID 17628280
    .
  30. OCLC 1265083396.{{cite book}}: CS1 maint: location missing publisher (link
    )
  31. PMID 12763985
    .
  32. PMID 22777991
    .
  33. PMID 2178409
    .
  34. ^
    doi:10.18773/austprescr.1997.063. Archived from the original
    on 2012-03-25.
  35. ISBN 978-1-899066-62-9
    .
  36. PMID 36158423
    .
  37. PMID 14592231
    .
  38. S2CID 12959227
    .
  39. S2CID 7906168
    .
  40. PMID 32217835
    .
  41. PMC 8108185
    .
  42. PMID 34185801
    .
  43. ^ Dance A (10 April 2020). "What is a cytokine storm?". Knowable Magazine. Annual Reviews. Retrieved 9 August 2021.
  44. S2CID 26269832
    .
  45. S2CID 9927714
    .
  46. PMID 21452290
    .
  47. ^ "Hemochromatosis". guidelinecentral.com.
  48. PMID 9722207
    .
  49. PMID 28655976
    .
  50. PMID 17156889
    .
  51. PMID 9575444
    .
  52. S2CID 23125116
    .
  53. PMID 24681346
    .
  54. PMID 25475192
    .
  55. ^
    PMID 33653274
    .
  56. PMID 20170158
    .
  57. PMID 17177411
    .
  58. PMID 17768776
    .
  59. PMID 15127443
    .
  60. ^ Stanford's Single-Dose Nanoparticle Vaccine for COVID-19. On: SciTechDaily. January 10, 2021. Source: Stanford University
  61. PMID 33580169
    .
  62. ^ "Ferritin - Homo sapiens (Human)".

External links

Look up ferritin or apoferritin in Wiktionary, the free dictionary.
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