Hepcidin

Hepcidin

Solution structure of hepcidin-25.
Identifiers
Symbol	Hepcidin
Pfam	PF06446
InterPro	IPR010500
SCOP	1m4f
SUPERFAMILY	1m4f
OPM family	162
OPM protein	1m4e
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

hepcidin antimicrobial peptide
Identifiers
Symbol	HAMP
Entrez	57817
HUGO	15598
OMIM	606464
RefSeq	NM_021175
UniProt	P81172
Other data
Locus	Chr. 19 q13.1

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. Hepcidin functions to increase iron storage in cells, thereby preventing an organism from losing too much iron. 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. Twenty- 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. The conversion of prohepcidin to hepcidin is mediated by the prohormone convertase furin, which conversion might be regulated by the alpha-1 antitrypsin.

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 " does not fit here. ) The structure of hepcidin has determined 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.

Function

The 25-amino acid peptide of hepcidin is secreted by the liver, which seems to be the "master regulator" of iron metabolism. Hepcidin inhibits iron transport by binding to the iron channel ferroportin, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Inhibiting ferroportin shuts off the iron transport out of these cells, which store iron. 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.

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

The peptide was initially reported as LEAP-1, for Liver-Expressed Antimicrobial Protein and later became known as hepcidin. 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"). Both groups were focused on the antimicrobial properties of the peptide.

Hepcidin was first discovered in human urine and serum in 2000. 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, new opportunities to study the regulation of hepcidin in humans have arisen. 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.

Soon after this discovery, researchers discovered that hepcidin production in mice increases 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 regulates the release of iron in the body.

Clinical significance

Beta-thalassemia is one of the most common congenital anemias arising from partial or complete lack of β-globin synthesis. Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. The serial analyses of β-thalassemic mice indicate hemoglobin levels decreases over time, while the concentration of iron in the liver, spleen, and kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. It was found that patients with β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and whether the concentration of hepcidin is increasing in the body of such patients might be therapeutic, limiting iron overload. It was demonstrated that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. The data led the researchers to suggest therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

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

• MeSH hepcidin
• Protein Data Bank Page
• Intrinsic LifeSciences - Hepcidin Research Facility, The BioIron Company