Fdtxjr

HAMP
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1M4E, 1M4F, 2KEF, 3H0T, 4QAE
Identifiers
Aliases	HAMP, HEPC, HFE2B, LEAP1, PLTR, hepcidin antimicrobial peptide
External IDs	OMIM: 606464 HomoloGene: 81623 GeneCards: HAMP
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.12 Start 35,280,716 bp[1] End 35,285,143 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • hormone activity • iron channel inhibitor activity • receptor binding Cellular component • cytoplasm • extracellular region • apical cortex • intercalated disc • cell • extracellular space Biological process • negative regulation of ferrous iron export • negative regulation of intestinal absorption • positive regulation of receptor internalization • negative regulation of transcription from RNA polymerase II promoter • negative regulation of iron channel activity • response to iron ion • multicellular organismal iron ion homeostasis • defense response to bacterium • immune response • positive regulation of receptor catabolic process • positive regulation of protein polyubiquitination • negative regulation of ion transmembrane transporter activity • cellular iron ion homeostasis • cellular response to lipopolysaccharide • aging • cellular response to tumor necrosis factor • liver regeneration • cellular response to bile acid • cellular response to interleukin-6 • response to iron ion starvation • response to vitamin A • response to erythropoietin • positive regulation of cell growth involved in cardiac muscle cell development • response to ethanol • acute-phase response • cellular response to X-ray • response to zinc ion • negative regulation of iron ion transmembrane transport • antimicrobial humoral immune response mediated by antimicrobial peptide • killing of cells of other organism • defense response to fungus • regulation of receptor activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	57817	n/a
Ensembl	ENSG00000105697	n/a
UniProt	P81172	n/a
RefSeq (mRNA)	NM_021175	n/a
RefSeq (protein)	NP_066998	n/a
Location (UCSC)	Chr 19: 35.28 – 35.29 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Hepcidin
Solution structure of hepcidin-25.[3]
Identifiers
Symbol	Hepcidin
Pfam	PF06446
InterPro	IPR010500
SCOP	1m4f
SUPERFAMILY	1m4f
OPM superfamily	153
OPM protein	1m4e
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.^[4]

During conditions in which the hepcidin level is abnormally high, such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red blood cells. When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.

Structure

Hepcidin exists as a preprohormone (84 amino acids), prohormone (60 amino acids), and hormone (25 amino acids). Twenty- and 22-amino acid metabolites of hepcidin also exist in the urine. Deletion of 5 N-terminal amino acids results in loss of function. The conversion of prohepcidin to hepcidin is mediated by the prohormone convertase furin.^[5] This conversion may be regulated by alpha-1 antitrypsin.^[6]

Hepcidin is a tightly folded polypeptide with 32% beta sheet character and a hairpin structure stabilized by 4 disulfide bonds. The structure of hepcidin has been determined through solution NMR.^[3] NMR studies showed a new model for hepcidin: at ambient temperatures, the protein interconverts between two conformations, which could be individually resolved by temperature variation. The solution structure of hepcidin was determined at 325 K and 253 K in supercooled water. X-ray analysis of a co-crystal with Fab revealed a structure similar to the high-temperature NMR structure.^[7]

Function

Diagram showing how hepcidin controls ferroportin (FPN) levels which in turn control entry of iron into the circulation

Hepcidin is a regulator of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Hepcidin ultimately breaks down the transporter protein in the lysosome. Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells.^[8][9] By inhibiting ferroportin, hepcidin prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption. The iron release from macrophages is also reduced by ferroportin inhibition. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such as renal failure.^[10]

Any one of several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin.^[11] Mutations in TMPRSS6 can cause anemia through dysregulation of Hepcidin.^[12]

Hepcidin has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker antimicrobial activity against S.epidermidis, S.aureus and Group B streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.^[13]

Regulation

Hepcidin synthesis and secretion by the liver is controlled by iron stores within macrophages, inflammation, hypoxia, and erythropoiesis. Macrophages communicate with the hepatocyte to regulate hepcidin release into the circulation via eight different proteins: hemojuvelin, heriditrary hemochromatosis protein, transferrin receptor 2, bone morphogenic protein 6 (BMP6), matriptase-2, neogenin, BMP receptors, and transferrin.^[14]

Erythroferrone, produced in erythroblasts, has been identified as inhibiting hepcidin and so providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis.^[15][16]

Vitamin D has been shown to decrease hepcidin, in cell models looking at transcription and when given in big doses to human volunteers. Optimal function of hepcidin may be predicated upon the adequate presence of vitamin D in the blood.^[17]

History

The peptide was initially named LEAP-1, for Liver-Expressed Antimicrobial Protein, when it was first described in the year 2000.^[18] Later, a peptide associated with inflammation was discovered, and named "hepcidin" after it was observed that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing").^[19] Although it is primarily synthesized in the liver, smaller amounts are synthesised in other tissues such as fat cells.^[20]

Hepcidin was first discovered in human urine and serum in 2000.^[21]

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 supplements. 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 absorption of iron into the body.

Clinical significance

There are many diseases where failure to adequately absorb iron contributes to iron deficiency and iron deficiency anaemia. The treatment will depend on the hepcidin levels that are present, as oral treatment will be unlikely to be effective if hepcidin is blocking enteral absorption, in which cases parenteral iron treatment would be appropriate. Studies have found that measuring hepcidin would be of benefit to establish optimal treatment,^[22] although as this is not widely available, C-reactive protein (CRP) is used as a surrogate marker.

β-thalassemia, one of the most common congenital anemias, arises 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. 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. Increasing expression of hepcidin in β-thalassemic mice limits iron overload, and also decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia.^[23] 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. From these data, researchers suggested that therapeutics to increase hepcidin levels or act as hepcidin agonists could help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.^[24] In later studies in mice,^[25]erythroferrone has been suggested to be the factor that is responsible for the hepcidin suppression. Correcting hepcidin and iron levels in these mice did not improve their anemia.

References

Further reading

External links

• 
  hepcidin at the US National Library of Medicine Medical Subject Headings (MeSH)


• Intrinsic LifeSciences - Hepcidin Research Facility, The BioIron Company


• Hepcidinanalysis.com - Service for Hepcidin measurements: Scientific Research, Patients and Clinical Trials


• Protein Data Bank Page