Heme transporter

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

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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]

References

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  1. ^ a b 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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