Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1gene, and is part of the Ferroportin (Fpn)Family (TC# 2.A.100).[1] Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. After iron is absorbed into the cells of the intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Ferroportin is the only known iron exporter.[2]
Members of the FPN family consist of 400-800 amino acid residues,[3] with a highly conservedhistidine at residue position 32 (H32), and exhibit 8-11 putative transmembrane segments (TMSs). When H32 is mutated, lower activity in its iron transport role is observed.[4] Ferroportin can also function as a manganese exporter.[5] Because ferroportin extrudes Fe2+ from the cell, ferroportin is presumed to function by cation (H+ or Na+) antiport.
Transport reaction
The transport reaction catalyzed by ferroportin is:
Ferroportin-1 plays an important role in neural tube closure and forebrain patterning.[8] Mouse embyros lacking the Scl40a1 gene are aborted before gastrulation occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development.[6] Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5.[1][6] Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.[9][10]
A study examining the consequences of several different mutations of the Slc40a1 mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others.[8] Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.[8]
Role in fertility
It is known that ferroportin (SLC40A1) gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in granulosa cells. What's more, low expression of ferroportin is also associated with infertily when some features like age and smoking habits are considered.
It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status.[11]
Role in iron metabolism
Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell.[12] This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels.[13]
Ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation. The ferroportin translation is also regulated by the micro RNA miR-485-3p.[14]
Clinical significance
Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as type IV haemochromatosis or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis.
References
↑ 1.01.1Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (February 2000). "Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter". Nature. 403 (6771): 776–81. Bibcode:2000Natur.403..776D. doi:10.1038/35001596. PMID10693807.
↑ 6.06.16.2Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (March 2005). "The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis". Cell Metabolism. 1 (3): 191–200. doi:10.1016/j.cmet.2005.01.003. PMID16054062.
↑Delaby C, Pilard N, Puy H, Canonne-Hergaux F (April 2008). "Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression". The Biochemical Journal. 411 (1): 123–31. doi:10.1042/BJ20071474. PMID18072938.
↑Felkner MM, Suarez L, Brender J, Scaife B, Hendricks K (December 2005). "Iron status indicators in women with prior neural tube defect-affected pregnancies". Maternal and Child Health Journal. 9 (4): 421–8. doi:10.1007/s10995-005-0017-3. PMID16315101.
↑Groenen PM, van Rooij IA, Peer PG, Ocké MC, Zielhuis GA, Steegers-Theunissen RP (June 2004). "Low maternal dietary intakes of iron, magnesium, and niacin are associated with spina bifida in the offspring". The Journal of Nutrition. 134 (6): 1516–22. doi:10.1093/jn/134.6.1516. PMID15173422.
↑Moreno-Navarrete JM, López-Navarro E, Candenas L, Pinto F, Ortega FJ, Sabater-Masdeu M, et al.Ferroportin mRNA is down-regulated in granulosa and cervical cells from infertile women.Fertil Steril. 2017 Jan;107(1):236-242.
↑Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (December 2004). "Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization". Science. 306 (5704): 2090–3. Bibcode:2004Sci...306.2090N. doi:10.1126/science.1104742. PMID15514116.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Abboud S, Haile DJ (June 2000). "A novel mammalian iron-regulated protein involved in intracellular iron metabolism". The Journal of Biological Chemistry. 275 (26): 19906–12. doi:10.1074/jbc.M000713200. PMID10747949.
Haile DJ (2000). "Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization". Cytogenetics and Cell Genetics. 88 (3–4): 328–9. doi:10.1159/000015522. PMID10828623.
McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (February 2000). "A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation". Molecular Cell. 5 (2): 299–309. doi:10.1016/S1097-2765(00)80425-6. PMID10882071.
Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P (July 2001). "A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis". Nature Genetics. 28 (3): 213–4. doi:10.1038/90038. PMID11431687.
Press RD (December 2001). "Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin". Molecular Diagnosis. 6 (4): 347–349. doi:10.1054/modi.2001.0060347. PMID11774199.
Lee PL, Gelbart T, West C, Halloran C, Felitti V, Beutler E (2001). "A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin". Blood Cells, Molecules & Diseases. 27 (5): 783–802. doi:10.1006/bcmd.2001.0445. PMID11783942.
Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA (April 2002). "Intestinal expression of genes involved in iron absorption in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology. 282 (4): G598–607. doi:10.1152/ajpgi.00371.2001. PMID11897618.
Thomas C, Oates PS (April 2002). "IEC-6 cells are an appropriate model of intestinal iron absorption in rats". The Journal of Nutrition. 132 (4): 680–7. doi:10.1093/jn/132.4.680. PMID11925460.
Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (July 2002). "Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3)". Blood. 100 (2): 695–7. doi:10.1182/blood-2001-11-0132. PMID12091367.
Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, Piga A, Mackie PH, Robson KJ, Camaschella C (July 2002). "A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4". Blood. 100 (2): 733–4. doi:10.1182/blood-2002-03-0693. PMID12123233.