Heme transporter

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A heme transporter is a protein that delivers heme to the various parts of a biological cell that require it.

Heme is a major source of dietary iron in humans and other mammals, and its synthesis in the body is well understood, but heme pathways are not as well understood. It is likely that heme is tightly regulated for two reasons: the toxic nature of iron in cells, and the lack of a regulated excretory system for excess iron. Understanding heme pathways is therefore important in understanding diseases such as hemochromatosis and anemia.

Heme transport

Members of the SLC48 and SLC49 solute carrier family participate in heme transport across cellular membranes (heme-transporting ATPase). [1]

SLC48A1 [2] —also known as Heme-Responsive Gene 1 (HRG1)—and its orthologues were first identified as a heme transporter family through a genetic screen in C.elegans . [3] The protein plays a role in mobilizing heme from the lysosome to the cytoplasm. [4] Deletion of the gene in mice leads to accumulation of heme crystals called hemozoin within the lysosomes of bone marrow, liver and splenic macrophages [5] [6] , but the gene is not known to be associated with human disease.

FLVCR1 [7] was originally identified as the receptor for the feline leukemia virus, whose genetic disruption leads to anemia and disruption of heme transport. [8] [9] It appears to protect cells at the CFU-E stage by exporting heme to prevent heme toxicity. Rare homozygous mutations result in autosomal recessive posterior column ataxia with retinitis pigmentosa. [10] [11]

FLVCR2 [12] is closely related to FLCVR1, and genetic transfection experiments indicate that it transports heme. [13] Mutations in the gene are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, also known as Fowler syndrome). [14] [15]

Related genes SLC49A3 [16] and SLC49A4 [17] are less well characterized [1] functionally, although SLC49A4 is also known as Disrupted In Renal Cancer Protein 2 or RCC4 due to an association with renal cell cancer. [18] [19]

Related Research Articles

Glucose transporter 2 (GLUT2) also known as solute carrier family 2, member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood Unlike GLUT4, it does not rely on insulin for facilitated diffusion.

<span class="mw-page-title-main">Ferroportin</span> Protein

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 SLC40A1 gene, and is part of the Ferroportin (Fpn)Family (TC# 2.A.100). Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

<span class="mw-page-title-main">Zinc transporter 8</span> Protein-coding gene in the species Homo sapiens

Zinc transporter 8 (ZNT8) is a protein that in humans is encoded by the SLC30A8 gene. ZNT8 is a zinc transporter related to insulin secretion in humans. In particular, ZNT8 is critical for the accumulation of zinc into beta cell secretory granules and the maintenance of stored insulin as tightly-packaged hexamers. Certain alleles of the SLC30A8 gene may increase the risk for developing type 2 diabetes, but a loss-of-function mutation appears to greatly reduce the risk of diabetes.

<span class="mw-page-title-main">Neutral and basic amino acid transport protein rBAT</span> Protein-coding gene in the species Homo sapiens

Neutral and basic amino acid transport protein rBAT is a protein that in humans is encoded by the SLC3A1 gene.

<span class="mw-page-title-main">Thiamine transporter 2</span> Protein-coding gene in the species Homo sapiens

Thiamine transporter 2 (ThTr-2), also known as solute carrier family 19 member 3, is a protein that in humans is encoded by the SLC19A3 gene. SLC19A3 is a thiamine transporter.

<span class="mw-page-title-main">Sulfate transporter</span> Protein-coding gene in the species Homo sapiens

The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B was subsequently also found to be caused by genetic variants in the sulfate transporter gene. This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates. SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.

<span class="mw-page-title-main">Major facilitator superfamily</span>

The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.

<span class="mw-page-title-main">Chloride anion exchanger</span> Protein-coding gene in the species Homo sapiens

Chloride anion exchanger, also known as down-regulated in adenoma, is a protein that in humans is encoded by the SLC26A3 gene.

<span class="mw-page-title-main">Equilibrative nucleoside transporter 2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ABCB7</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family B member 7, mitochondrial is a protein that in humans is encoded by the ABCB7 gene.

<span class="mw-page-title-main">SLC22A12</span> Mammalian protein found in Homo sapiens

Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.

<span class="mw-page-title-main">FLVCR1</span> Protein-coding gene in the species Homo sapiens

Feline leukemia virus subgroup C receptor-related protein 1 is a protein that in humans is encoded by the FLVCR1 gene (SLC49A1).

<span class="mw-page-title-main">Mitoferrin-1</span> Protein-coding gene in the species Homo sapiens

Mitoferrin-1 (Mfrn1) is a 38 kDa protein that is encoded by the SLC25A37 gene in humans. It is a member of the Mitochondrial carrier (MC) Superfamily, however, its metal cargo makes it distinct from other members of this family. Mfrn1 plays a key role in mitochondrial iron homeostasis as an iron transporter, importing ferrous iron from the intermembrane space of the mitochondria to the mitochondrial matrix for the biosynthesis of heme groups and Fe-S clusters. This process is tightly regulated, given the redox potential of Mitoferrin's iron cargo. Mfrn1 is paralogous to Mitoferrin-2 (Mfrn2), a 39 kDa protein encoded by the SLC25A28 gene in humans. Mfrn1 is highly expressed in differentiating erythroid cells and in other tissues at low levels, while Mfrn2 is expressed ubiquitously in non-erythroid tissues.

<span class="mw-page-title-main">Sodium-dependent phosphate transport protein 2C</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent phosphate transport protein 2C is a protein that in humans is encoded by the SLC34A3 gene.

Haem or Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was the SLC46A1 folate transporter.

<span class="mw-page-title-main">FLVCR2</span> Protein-coding gene in the species Homo sapiens

Feline leukemia virus subgroup C cellular receptor family, member 2 is a protein that in humans is encoded by the FLVCR2 gene.

<span class="mw-page-title-main">Proton-coupled folate transporter</span> Mammalian protein found in Homo sapiens

The proton-coupled folate transporter is a protein that in humans is encoded by the SLC46A1 gene. The major physiological roles of PCFTs are in mediating the intestinal absorption of folate, and its delivery to the central nervous system.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Zinc transporter ZIP9</span> Protein-coding gene in the species Homo sapiens

Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, is a protein that in humans is encoded by the SLC39A9 gene. This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein. ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane.

<span class="mw-page-title-main">Zinc transporter ZIP12</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 39 member 12 is a protein that in humans is encoded by the SLC39A12 gene.

References

  1. 1 2 Khan AA, Quigley JG (2013). "Heme and FLVCR-related transporter families SLC48 and SLC49". Molecular Aspects of Medicine. 34 (2–3): 669–82. doi:10.1016/j.mam.2012.07.013. PMC   3602793 . PMID   23506900.
  2. ↑ GeneCard for SLC48A1
  3. ↑ Rajagopal A, Rao AU, Amigo J, Tian M, Upadhyay SK, Hall C, Uhm S, Mathew MK, Fleming MD, Paw BH, Krause M, Hamza I (June 2008). "Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins". Nature. 453 (7198): 1127–31. Bibcode:2008Natur.453.1127R. doi:10.1038/nature06934. PMC   4058867 . PMID   18418376.
  4. ↑ White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK, Campagna D, Hall C, Bishop K, Calicchio ML, Lapierre A, Ward DM, Liu P, Fleming MD, Hamza I (February 2013). "HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis". Cell Metabolism. 17 (2): 261–70. doi:10.1016/j.cmet.2013.01.005. PMC   3582031 . PMID   23395172.
  5. ↑ Pek, Rini H.; Yuan, Xiaojing; Rietzschel, Nicole; Zhang, Jianbing; Jackson, Laurie; Nishibori, Eiji; Ribeiro, Ana; Simmons, William; Jagadeesh, Jaya; Sugimoto, Hiroshi; Alam, Md Zahidul; Garrett, Lisa; Haldar, Malay; Ralle, Martina; Phillips, John D. (2019-10-01). "Hemozoin produced by mammals confers heme tolerance". eLife. 8: e49503. doi:10.7554/eLife.49503. ISSN   2050-084X. PMC   6773446 . PMID   31571584.
  6. ↑ Simmons, William R.; Wain, Lily; Toker, Joseph; Jagadeesh, Jaya; Garrett, Lisa J.; Pek, Rini H.; Hamza, Iqbal; Bodine, David M. (2020). "Normal Iron Homeostasis Requires the Transporter SLC48A1 for Efficient Heme-Iron Recycling in Mammals". Frontiers in Genome Editing. 2: 8. doi:10.3389/fgeed.2020.00008. ISSN   2673-3439. PMC   8525403 . PMID   34713217.
  7. ↑ GeneCard for FLVCR1
  8. ↑ Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL (September 2004). "Identification of a human heme exporter that is essential for erythropoiesis". Cell. 118 (6): 757–66. doi: 10.1016/j.cell.2004.08.014 . PMID   15369674. S2CID   12749187.
  9. ↑ Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, Kingsley PD, De Domenico I, Vaughn MB, Kaplan J, Palis J, Abkowitz JL (February 2008). "A heme export protein is required for red blood cell differentiation and iron homeostasis". Science. 319 (5864): 825–8. Bibcode:2008Sci...319..825K. doi:10.1126/science.1151133. PMID   18258918. S2CID   5510704.
  10. ↑ Berciano J, Polo JM (December 1998). "Autosomal recessive posterior column ataxia and retinitis pigmentosa". Neurology. 51 (6): 1772–3. doi:10.1212/wnl.51.6.1772-a. PMID   9855554. S2CID   46553303.
  11. ↑ "Online Mendelian Inheritance in Man:FLCVR1". omim.org.
  12. ↑ GeneCard for FLVCR2
  13. ↑ Duffy SP, Shing J, Saraon P, Berger LC, Eiden MV, Wilde A, Tailor CS (November 2010). "The Fowler syndrome-associated protein FLVCR2 is an importer of heme". Molecular and Cellular Biology. 30 (22): 5318–24. doi:10.1128/MCB.00690-10. PMC   2976379 . PMID   20823265.
  14. ↑ Thomas S, Encha-Razavi F, Devisme L, Etchevers H, Bessieres-Grattagliano B, Goudefroye G, Elkhartoufi N, Pateau E, Ichkou A, Bonnière M, Marcorelle P, Parent P, Manouvrier S, Holder M, Laquerrière A, Loeuillet L, Roume J, Martinovic J, Mougou-Zerelli S, Gonzales M, Meyer V, Wessner M, Feysot CB, Nitschke P, Leticee N, Munnich A, Lyonnet S, Wookey P, Gyapay G, Foliguet B, Vekemans M, Attié-Bitach T (October 2010). "High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy" (PDF). Human Mutation. 31 (10): 1134–41. doi:10.1002/humu.21329. PMID   20690116. S2CID   20452899.
  15. ↑ "Online Mendelian Inheritance in Man:FLCVR1". omim.org.
  16. ↑ GeneCard for SLC49A3
  17. ↑ GeneCard for SLC49A4
  18. ↑ Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar B, van Kessel AG (March 2002). "Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21)". Human Molecular Genetics. 11 (6): 641–9. doi: 10.1093/hmg/11.6.641 . PMID   11912179.
  19. ↑ Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB, Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K (2001). "Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation". Journal of Human Genetics. 46 (12): 685–93. doi: 10.1007/s100380170001 . PMID   11776380. S2CID   28156717.


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