Hepcidin
| Hepcidin | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 Structure of Hepcidin-25.[1] | |||||||||||
| Identifiers | |||||||||||
| Symbol | Hepcidin | ||||||||||
| Pfam | PF06446 | ||||||||||
| InterPro | IPR010500 | ||||||||||
| SCOP2 | 1m4f / SCOPe / SUPFAM | ||||||||||
| OPM protein | 1m4e | ||||||||||
| |||||||||||
| hepcidin antimicrobial peptide | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | HAMP | ||||||
| NCBI gene | 57817 | ||||||
| HGNC | 15598 | ||||||
| OMIM | 606464 | ||||||
| RefSeq | NM_021175 | ||||||
| UniProt | P81172 | ||||||
| Other data | |||||||
| Locus | Chr. 19 q13.1 | ||||||
| |||||||
Template:FixBunching Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals.[2] In humans, HAMP is the gene that encodes for hepcidin.
Structure
Hepcidin preprohormone, prohormone and hormone size are 84, 60 and 25 amino acids respectively. 20 and 22 amino acid forms of Hepcidin also exist in the urine. The N terminal region is required for function, and deletion of 5 N-terminal peptides results in a loss of function.
Hepcidin is also a tightly folded polypeptide containing 25 residues in length and is 32% beta sheets. The 25 amino acids have a hairpin structure and are stabilized by 4 disulfide bonds, which has been shown to act as the principal regulator of iron homeostasis in vertebrates. The structure of hepcidin was discovered through the method of solution NMR. The different NMR studies showed a new model for hepcidin. Revealing at ambient temperatures, interconverts between two different conformations, which could be individually resolved by temperature variation. Using the different methods, the solution structure of hepcidin was determined at 325 and 253 K in supercooled water. The hepcidin conformation had appeared to be stabilized when the X-ray analysis of a co-crystal with Fab study was completed. This is similar to the high temperature NMR structure [3].
Function
The 25-amino acid peptide of hepcidin is secreted by the liver, which seems to be the "master regulator" of iron metabolism. This binds the iron channel ferroportin, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells, and the degrading ferroportin shuts off the iron transport out of these cells that store it [4]. Ferroportin is also present on enterocytes and macrophages. By inhibiting ferroportin, hepcidin prevents enterocytes of the intestines from secreting iron into the hepatic portal system, thereby functionally reducing iron absorption. The iron release from macrophages is also prevented by ferroportin inhibition, therefore the hepcidin maintains iron homeostasis. Hepcidin activity is also partially responsible for iron sequestration seen in anemia of chronic disease and levels are elevated in people with renal failure.[5]
Several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin, a regulator of hepcidin production.
Hepcidin has shown fairly consistent antifungal activity. Hepcidin's antibacterial activity currently seems to be inconsistent. The current scientific evidence suggests that hepcidin is a central regulatory hormone and its main action is to regulate systemic iron homeostasis.
History
Initially, the peptide was reported as LEAP-1, for Liver-Expressed Antimicrobial Protein and later became known as hepcidin.[6] Independently, in a search for antimicrobial peptides, researchers working in the lab of Tomas Ganz discovered a peptide associated with inflammation, and named it "hepcidin" after observing that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing").[7] Both groups were focused on the antimicrobial properties of the peptide.
It was in the year 2000 when hepcidin was first discovered in human urine and serum. Most understandings of hepcidin regulation and action comes from in vitro and mice studies that often use hepcidin mRNA expression as a read out. Carrying out studies in humans is difficult due to the lack of suitable hepcidin assay. With the recent developments of assays to measure hepcidin in serum and urine, it has offered new opportunities to study the regulation of hepcidin in humans. Only a few laboratories are able to perform these assays at the current moment. The aim of the studies is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.[8]
Soon after this discovery, researchers discovered that hepcidin production in mice increased in conditions of iron overload as well as in inflammation. Genetically modified mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting a central and not redundant role in iron regulation. The first evidence that linked hepcidin to the clinical condition known as the anemia of inflammation came from the lab of Nancy Andrews in Boston when researchers looked at tissue from two patients with liver tumors with a severe microcytic anemia that did not respond to iron supplementation. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidin mRNA. Removing the tumors surgically cured the anemia.
Taken together, these discoveries suggested that hepcidin regulated the release of iron in the body.
References
- ^ Hunter HN, Fulton DB, Ganz T, Vogel HJ (2002). "The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis". J. Biol. Chem. 277 (40): 37597–603. doi:10.1074/jbc.M205305200. PMID 12138110.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Ganz T (2003). "Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation". Blood. 102 (3): 783–8. doi:10.1182/blood-2003-03-0672. PMID 12663437.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Jordan, J., Poppe, L., Haniu, M., Arvedson, T., & Syed, R. (2009). Hepcidin revisited, disulfide connectivity, dynamics, and structure. J.biol.chem, 284(36), 24155-24167. Retrieved November 29, 2010, from http://www.ncbi.nlm.nih.gov/pubmed/19553669?dopt=Abstract
- ^ What is hepcidin? . (2008, August 18). In Renal Fellow Network National Kidney Foundation. Retrieved November 29, 2010, from http://renalfellow.blogspot.com/2008/08/what-is-hepcidin.html.
- ^ Ashby DR, Gale DP, Busbridge M; et al. (2009). "Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease". Kidney Int. 75 (9): 976–81. doi:10.1038/ki.2009.21. PMID 19212416.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K (2000). "LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity". FEBS Lett. 480 (2–3): 147–50. doi:10.1016/S0014-5793(00)01920-7. PMID 11034317.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Park CH, Valore EV, Waring AJ, Ganz T (2001). "Hepcidin, a urinary antimicrobial peptide synthesized in the liver". J. Biol. Chem. 276 (11): 7806–10. doi:10.1074/jbc.M008922200. PMID 11113131.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Kemna EH, Tjalsma H, Willems HL, Swinkels DW (2008). "Hepcidin: from discovery to differential diagnosis". Haematologica. 93 (1): 90–7. doi:10.3324/haematol.11705. PMID 18166790.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Further reading
- Camaschella C (2005). "Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders". Blood. 106 (12): 3710–7. doi:10.1182/blood-2005-05-1857. PMID 16030190.
External links
- http://www.hepcidinanalysis.com
- hepcidin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Protein Data Bank Page