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Ferroportin
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<h2 id="structure">Structure</h2> <p>Members of the ferroportin family consist of 400-800 <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> residues,<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> with a <a href="/facts/Conserved_sequence/YAxy2Xa2">highly conserved</a> <a href="/facts/Histidine/le7781NF">histidine</a> at residue position 32 (H32), and exhibit 8-12 putative <a href="/facts/Transmembrane_domain/D1j0PwSR">transmembrane domains</a>. Human Fpn consists of 571 amino acid residues.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> When H32 is mutated in mice, iron transport activity is impaired.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Recent crystal structures generated from a bacterial <a href="/facts/Homology_(biology)/muctKlyT">homologue</a> of ferroportin (from <a href="/facts/Bdellovibrio/UmaWIERt"><i>Bdellovibrio bacteriovorus</i></a>) revealed that the Fpn structure resembles that of <a href="/facts/Major_facilitator_superfamily/aEbAPdfN">major facilitator superfamily</a> (MFS) transporters.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The prospective substrate binding site is located at the interface between the <a href="/facts/N-terminus/yKYpuaBJ">N-terminal</a> and <a href="/facts/C-terminus/ws4scHgT">C-terminal</a> halves of the protein, and is alternately accessible from either side of the cell membrane,<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> consistent with MFS transporters. </p> <h2 id="function">Function</h2> <p>Ferroportin-mediated iron efflux is <a href="/facts/Calcium/hf252CC0">calcium</a>-activated; studies of human Fpn expressed in <i><a href="/facts/African_clawed_frog/khG1KPrd">Xenopus laevis</a></i> oocytes demonstrated that calcium is a required <a href="/facts/Cofactors_and_coenzymes/DSI1Fh7y">cofactor</a> for Fpn, but that Fpn does not transport calcium.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> Thus, Fpn does not function as an iron/calcium antiporter. The thermodynamic driving force for Fpn remains unknown. </p><p>In addition to iron, human ferroportin has been shown to transport <a href="/facts/Cobalt/gqhScEw4">cobalt</a>, <a href="/facts/Zinc/80b1qgk3">zinc</a>,<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> and <a href="/facts/Nickel/KwMCHYRP">nickel</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Ferroportin may also function as a <a href="/facts/Manganese/j9ELd1TL">manganese</a> exporter.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="tissue-distribution">Tissue distribution</h2> <p>Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <ul><li><a href="/facts/Enterocytes/NfAsbB9s">Enterocytes</a> in the <a href="/facts/Duodenum/IAIgHBmq">duodenum</a></li> <li><a href="/facts/Hepatocytes/USpvDz1n">Hepatocytes</a></li> <li><a href="/facts/Macrophages/z7hkQu3o">Macrophages</a> of the <a href="/facts/Reticuloendothelial_system/bSp95EjA">reticuloendothelial system</a></li> <li><a href="/facts/Adipocytes/FuM7LlaK">Adipocytes</a></li></ul> <h2 id="role-in-development">Role in development</h2> <p>Ferroportin-1 plays an important role in <a href="/facts/Neural_tube/xv4a9Il7">neural tube</a> closure and <a href="/facts/Forebrain/X3H1IqLq">forebrain</a> patterning.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Mouse embryos lacking the <i>Slc40a1</i> gene are aborted before <a href="/facts/Gastrulation/kN8X10mK">gastrulation</a> occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> Fpn1 is expressed in the <a href="/facts/Syncytiotrophoblast/ULNKTpDg">syncytiotrophoblast</a> cells in the placenta and visceral <a href="/facts/Endoderm/6UhPjVnt">endoderm</a> of mice at E7.5.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Further, several retrospective studies have noted an increased incidence of <a href="/facts/Spina_bifida/fwKLsxfI">spina bifida</a> occurring after low maternal intake of iron during embryonic and fetal development.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>A study examining the consequences of several different mutations of the <i>Slc40a1</i> mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, <a href="/facts/Exencephaly/d1WAWcQN">exencephaly</a>, and forebrain truncations, among others.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> 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 <i>Fpn1</i> product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="role-in-fertility">Role in fertility</h2> <p>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 <a href="/facts/Granulosa_cell/8KhMa9I3">granulosa cells</a>. What's more, low expression of ferroportin is also associated with infertility 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.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h2 id="role-in-iron-metabolism">Role in iron metabolism</h2> <p>Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> This results in the retention of iron within <a href="/facts/Enterocyte/NfAsbB9s">enterocytes</a>, <a href="/facts/Hepatocyte/USpvDz1n">hepatocytes</a>, and <a href="/facts/Macrophage/z7hkQu3o">macrophages</a> 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. Hepcidin is synthesized in response to various cytokines, as described in the <a href="/facts/Hepcidin/VyFxxtGx">Hepcidin</a> article, as well as in this article by Ganz.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p><p>Ferroportin expression is also regulated by the <a href="/facts/Iron-responsive_element-binding_protein/8xYey55A">IRP</a> regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation and increasing intracellular iron and <a href="/facts/Ferritin/w7G85xJg">ferritin</a> concentrations. The ferroportin translation is also down regulated post-transcriptionally by the micro RNA miR-485-3p, which is produced in response to iron deficiency.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p>Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as <a href="/facts/Hemochromatosis_type_4/XKrYlo8h">Hemochromatosis type 4</a> 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 <a href="/facts/African_iron_overload/6D0aolPn">African iron overload</a>. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. </p> <h2 id="protein-family">Protein family</h2> <p>Ferroportin is part of the ferroportin (Fpn) family. Members of the family are found across eukaryotes in animals and plants as well as in <a href="/facts/Proteobacteria/m7SfxPus">Proteobacteria</a>, a group of bacteria.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, et al. (May 2005). <a href="https://doi.org/10.1182%2Fblood-2004-11-4502">"In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations"</a>. <i>Blood</i>. 105 (10): 4096–4102. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1182%2Fblood-2004-11-4502">10.1182/blood-2004-11-4502</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15692071">15692071</a>.</li> <li>Pietrangelo A (2004). "The ferroportin disease". <i>Blood Cells, Molecules & Diseases</i>. 32 (1): 131–138. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.bcmd.2003.08.003">10.1016/j.bcmd.2003.08.003</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14757427">14757427</a>.</li> <li>Robson KJ, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, et al. (October 2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735598">"Recent advances in understanding haemochromatosis: a transition state"</a>. <i>Journal of Medical Genetics</i>. 41 (10): 721–730. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1136%2Fjmg.2004.020644">10.1136/jmg.2004.020644</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735598">1735598</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15466004">15466004</a>.</li> <li>Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". <i>Gene</i>. 138 (1–2): 171–174. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0378-1119%2894%2990802-8">10.1016/0378-1119(94)90802-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8125298">8125298</a>.</li> <li>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". <i>Gene</i>. 200 (1–2): 149–156. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0378-1119%2897%2900411-3">10.1016/S0378-1119(97)00411-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9373149">9373149</a>.</li> <li>Abboud S, Haile DJ (June 2000). <a href="https://doi.org/10.1074%2Fjbc.M000713200">"A novel mammalian iron-regulated protein involved in intracellular iron metabolism"</a>. <i>The Journal of Biological Chemistry</i>. 275 (26): 19906–19912. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M000713200">10.1074/jbc.M000713200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10747949">10747949</a>.</li> <li>Haile DJ (2000). "Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization". <i>Cytogenetics and Cell Genetics</i>. 88 (3–4): 328–329. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1159%2F000015522">10.1159/000015522</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10828623">10828623</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:6098716">6098716</a>.</li> <li>McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, et al. (February 2000). <a href="https://doi.org/10.1016%2FS1097-2765%2800%2980425-6">"A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation"</a>. <i>Molecular Cell</i>. 5 (2): 299–309. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS1097-2765%2800%2980425-6">10.1016/S1097-2765(00)80425-6</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10882071">10882071</a>.</li> <li>Hartley JL, Temple GF, Brasch MA (November 2000). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310948">"DNA cloning using in vitro site-specific recombination"</a>. <i>Genome Research</i>. 10 (11): 1788–1795. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fgr.143000">10.1101/gr.143000</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310948">310948</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11076863">11076863</a>.</li> <li>Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, et al. (July 2001). "A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis". <i>Nature Genetics</i>. 28 (3): 213–214. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F90038">10.1038/90038</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11431687">11431687</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:7345473">7345473</a>.</li> <li>Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. (August 2001). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC209405">"Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene"</a>. <i>The Journal of Clinical Investigation</i>. 108 (4): 619–623. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1172%2FJCI13468">10.1172/JCI13468</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC209405">209405</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11518736">11518736</a>.</li> <li>Press RD (December 2001). "Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin". <i>Molecular Diagnosis</i>. 6 (4): 347. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1054%2Fmodi.2001.0060347">10.1054/modi.2001.0060347</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11774199">11774199</a>.</li> <li>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". <i>Blood Cells, Molecules & Diseases</i>. 27 (5): 783–802. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fbcmd.2001.0445">10.1006/bcmd.2001.0445</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11783942">11783942</a>.</li> <li>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". <i>American Journal of Physiology. Gastrointestinal and Liver Physiology</i>. 282 (4): G598 – G607. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1152%2Fajpgi.00371.2001">10.1152/ajpgi.00371.2001</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11897618">11897618</a>.</li> <li>Thomas C, Oates PS (April 2002). <a href="https://doi.org/10.1093%2Fjn%2F132.4.680">"IEC-6 cells are an appropriate model of intestinal iron absorption in rats"</a>. <i>The Journal of Nutrition</i>. 132 (4): 680–687. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fjn%2F132.4.680">10.1093/jn/132.4.680</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11925460">11925460</a>.</li> <li>Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN (July 2002). <a href="https://doi.org/10.1182%2Fblood.v100.2.692">"Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis"</a>. <i>Blood</i>. 100 (2): 692–694. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1182%2Fblood.v100.2.692">10.1182/blood.v100.2.692</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12091366">12091366</a>.</li> <li>Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (July 2002). <a href="https://doi.org/10.1182%2Fblood-2001-11-0132">"Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3)"</a>. <i>Blood</i>. 100 (2): 695–697. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1182%2Fblood-2001-11-0132">10.1182/blood-2001-11-0132</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12091367">12091367</a>.</li> <li>Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, et al. (July 2002). <a href="https://doi.org/10.1182%2Fblood-2002-03-0693">"A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4"</a>. <i>Blood</i>. 100 (2): 733–734. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1182%2Fblood-2002-03-0693">10.1182/blood-2002-03-0693</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12123233">12123233</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=ferroportin1+protein">ferroportin1+protein</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <p><i>As of <a href="https://en.wikipedia.org/w/index.php?title=Ferroportin&oldid=699838558">this edit</a>, this article uses content from </i><a href="http://www.tcdb.org/search/result.php?tc=2.A.100">"2.A.100 The Ferroportin (Fpn) Family"</a><i>, which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed.</i> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, et al. (February 2000). "Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter". Nature. 403 (6771): 776–781. Bibcode:2000Natur.403..776D. doi:10.1038/35001596. PMID 10693807. S2CID 4429026. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Ward DM, Kaplan J (September 2012). "Ferroportin-mediated iron transport: expression and regulation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1426–1433. doi:10.1016/j.bbamcr.2012.03.004. PMC 3718258. 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