Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway

Nature Reviews Gastroenterology & Hepatology volume 9, pages 345–354 (2012)Cite this article

Subjects

Abstract

Vitamin B12 (B12; also known as cobalamin) is a cofactor in many metabolic processes; deficiency of this vitamin is associated with megaloblastic anaemia and various neurological disorders. In contrast to many prokaryotes, humans and other mammals are unable to synthesize B12. Instead, a sophisticated pathway for specific uptake and transport of this molecule has evolved. Failure in the gastrointestinal part of this pathway is the most common cause of nondietary-induced B12 deficiency disease. However, although less frequent, defects in cellular processing and further downstream steps in the transport pathway are also known culprits of functional B12 deficiency. Biochemical and genetic approaches have identified novel proteins in the B12 transport pathway—now known to involve more than 15 gene products—delineating a coherent pathway for B12 trafficking from food to the body's cells. Some of these gene products are specifically dedicated to B12 transport, whereas others embrace additional roles, which explains the heterogeneity in the clinical picture of the many genetic disorders causing B12 deficiency. This Review describes basic and clinical features of this multistep pathway with emphasis on gastrointestinal transport of B12 and its importance in clinical medicine.

Key Points

  • A coherent vitamin B12 (B12) transport pathway from food to the body's cells has now been delineated; the pathway includes an ABC transporter for cellular B12 efflux and a receptor for uptake of B12-bound transcobalamin

  • More than 15 gene products are involved in B12 transport and/or processing; several new genes encoding intracellular proteins (including a potential lysosomal transporter of B12) have been identified

  • Gastrointestinal uptake of B12 is via cubam, the complex of cubilin and amnionless

  • Novel genetic causes of B12 deficiency disease have been clarified; many of the new proteins have been identified by positional cloning of the genes harbouring the disease-causing mutations

  • New diagnostic assays for B12 deficiency are being developed; plasma level of holo-transcobalamin is a promising biomarker in combination with existing markers

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: B12 structure and coenzyme function.
Figure 2: Schematic overview of uptake and transport of B12 in humans.
Figure 3: Schematic representation of the cubam receptor complex and its binding to intrinsic factor–B12.
Figure 4: Schematic model of pathways for B12 cellular uptake and exit.

Similar content being viewed by others

References

  1. McLean, E., de Benoist, B. & Allen, L. H. Review of the magnitude of folate and vitamin B12 deficiencies worldwide. Food Nutr. Bull. 29 (2 Suppl.), S38–S51 (2008).

    Article  PubMed  Google Scholar 

  2. Dali-Youcef, N. & Andres, E. An update on cobalamin deficiency in adults. QJM 102, 17–28 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Reynolds, E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 5, 949–960 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Stubbe, J. Binding site revealed of nature's most beautiful cofactor. Science 266, 1663–1664 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Rickes, E. L., Brink, N. G., Koniuszy, F. R., Wood, T. R. & Folkers, K. Crystalline vitamin B12. Science 107, 396–397 (1948).

    Article  CAS  PubMed  Google Scholar 

  6. Rickes, E. L., Brink, N. G., Koniuszy, F. R., Wood, T. R. & Folkers, K. Vitamin B12, a cobalt complex. Science 108, 134 (1948).

    Article  CAS  PubMed  Google Scholar 

  7. Smith, E. L. Purification of anti-pernicious anaemia factors from liver. Nature 161, 638 (1948).

    Article  CAS  PubMed  Google Scholar 

  8. Kamper, M. J. & Hodgkin, D. C. Some observations on the crystal structure of a chlorine-substituted vitamin B12. Nature 176, 551–553 (1955).

    Article  CAS  PubMed  Google Scholar 

  9. Lindstrand, K. Isolation of methylcobalamin from natural source material. Nature 10, 188–189 (1964).

    Article  Google Scholar 

  10. Hodgkin, D. C. et al. Structure of vitamin B12. Nature 178, 64–66 (1956).

    Article  CAS  PubMed  Google Scholar 

  11. Martens, J. H., Barg, H., Warren, M. J. & Jahn, D. Microbial production of vitamin B12. Appl. Microbiol. Biotechnol. 58, 275–285 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Mathews, F. S. et al. Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution. Proc. Natl Acad. Sci. USA 104, 17311–17316 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wuerges, J. et al. Structural basis for mammalian vitamin B12 transport by transcobalamin. Proc. Natl Acad. Sci. USA 103, 4386–4391 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Birn, H. et al. Characterization of an epithelial approximately 460 kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein. J. Biol. Chem. 272, 26497–26504 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Kozyraki, R. et al. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood 91, 3593–3600 (1998).

    CAS  PubMed  Google Scholar 

  16. Hurlimann, J. & Zuber, C. Vitamin B12-binders in human body fluids. I. Antigenic and physico-chemical characteristics. Clin. Exp. Immunol. 4, 125–140 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gordon, M. M., Hu, C., Chokshi, H., Hewitt, J. E. & Alpers, D. H. Glycosylation is not required for ligand or receptor binding by expressed rat intrinsic factor. Am. J. Physiol. 260, G736–G742 (1991).

    CAS  PubMed  Google Scholar 

  18. Drennan, C. L., Huang, S., Drummond, J. T., Matthews, R. G. & Lidwig, M. L. How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase. Science 266, 1669–1674 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Mancia, F. et al. How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 A resolution. Structure 4, 339–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Schwartz, M. Intrinsic factor antibody in serum from patients with pernicious anaemia. Lancet 2, 1263–1267 (1960).

    Article  CAS  PubMed  Google Scholar 

  21. Tanner, S. M. et al. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc. Natl Acad. Sci. USA 102, 4130–4133 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Castle, W. B. The etiology of pernicious and related macrocytic anemias. Science 82, 159–164 (1935).

    Article  CAS  PubMed  Google Scholar 

  23. Li, N., Rosenblatt, D. S. & Seetharam, B. Nonsense mutations in human transcobalamin II deficiency. Biochem. Biophys. Res. Commun. 204, 1111–1118 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Li, N., Rosenblatt, D. S., Kamen, B. A., Seetharam, S. & Seetharam, B. Identification of two mutant alleles of transcobalamin II in an affected family. Hum. Mol. Genet. 3, 1835–1840 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Namour, F. et al. Transcobalamin deficiency due to activation of an intra exonic cryptic splice site. Br. J. Haematol. 123, 915–920 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Nissen, P. H., Nordwall, M., Hoffmann-Lucke, E., Sorensen, B. S. & Nexo, E. Transcobalamin deficiency caused by compound heterozygosity for two novel mutations in the TCN2 gene: a study of two affected siblings, their brother, and their parents. J. Inherit. Metab. Dis. http://dx.doi.org/10.1007/s10545-010-9145-z.

  27. Qian, L., Quadros, E. V., Regec, A., Zittoun, J. & Rothenberg, S. P. Congenital transcobalamin II deficiency due to errors in RNA editing. Blood Cells Mol. Dis. 28, 134–142 (2002).

    Article  PubMed  Google Scholar 

  28. Hygum, K. et al. Mouse transcobalamin has features resembling both human transcobalamin and haptocorrin. PLoS ONE 6, e20638 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morkbak, A. L., Poulsen, S. S. & Nexo, E. Haptocorrin in humans. Clin. Chem. Lab. Med. 45, 1751–1759 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Allen, R. H. & Stabler, S. P. Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am. J. Clin. Nutr. 87, 1324–1335 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Hardlei, T. F. & Nexo, E. A new principle for measurement of cobalamin and corrinoids, used for studies of cobalamin analogs on serum haptocorrin. Clin. Chem. 55, 1002–1010 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Green, R. Ins and outs of cellular cobalamin transport. Blood 115, 1476–1477 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Quadros, E. V. Advances in the understanding of cobalamin assimilation and metabolism. Br. J. Haematol. 148, 195–204 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Nexo, E. & Hoffmann-Lucke, E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am. J. Clin. Nutr. 94, 359S–365S (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hvas, A. M. & Nexo, E. Diagnosis and treatment of vitamin B12 deficiency—an update. Haematologica 91, 1506–1512 (2006).

    CAS  PubMed  Google Scholar 

  36. Green, R. Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies. Food Nutr. Bull. 29, S52–S63 (2008).

    Article  PubMed  Google Scholar 

  37. Refsum, H. et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin. Chem. 50, 3–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Savage, D. G., Lindenbaum, J., Stabler, S. P. & Allen, R. H. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am. J. Med. 96, 239–246 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Allen, R. H., Seetharam, B., Podell, E. & Alpers, D. H. Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. J. Clin. Invest. 61, 47–54 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Seetharam, B., Levine, J. S., Ramasamy, M. & Alpers, D. H. Purification, properties, and immunochemical localization of a receptor for intrinsic factor-cobalamin complex in the rat kidney. J. Biol. Chem. 263, 4443–4449 (1988).

    CAS  PubMed  Google Scholar 

  41. Seetharam, B., Christensen, E. I., Moestrup, S. K., Hammond, T. G. & Verroust, P. J. Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J. Clin. Invest. 99, 2317–2322 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Moestrup, S. K. et al. The intrinsic factor—vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J. Biol. Chem. 273, 5235–5242 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Fyfe, J. C. et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103, 1573–1579 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Sahali, D. et al. Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies. J. Exp. Med. 167, 213–218 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. He, Q. et al. Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo. Blood 106, 1447–1453 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kalantry, S. et al. The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nat. Genet. 27, 412–416 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Strope, S., Rivi, R., Metzger, T., Manova, K. & Lacy, E. Mouse amnionless, which is required for primitive streak assembly, mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules. Development 131, 4787–4795 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Tanner, S. M. et al. Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat. Genet. 33, 426–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Kristiansen, M. et al. Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J. Biol. Chem. 274, 20540–20544 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Andersen, C. B., Madsen, M., Storm, T., Moestrup, S. K. & Andersen, G. R. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. Nature 464, 445–448 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Birn, H. et al. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J. Clin. Invest. 105, 1353–1361 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kozyraki, R. et al. The intrinsic factor—vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. Nat. Med. 5, 656–661 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Zhai, X. Y. et al. Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int. 58, 1523–1533 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Pedersen, G. A., Chakraborty, S., Steinhauser, A. L., Traub, L. M. & Madsen, M. AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. Traffic 11, 706–720 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Coudroy, G. et al. Contribution of cubilin and amnionless to processing and membrane targeting of cubilin-amnionless complex. J. Am. Soc. Nephrol. 16, 2330–2337 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Fyfe, J. C., Ramanujam, K. S., Ramaswamy, K., Patterson, D. F. & Seetharam, B. Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J. Biol. Chem. 266, 4489–4494 (1991).

    CAS  PubMed  Google Scholar 

  57. Namour, F. et al. Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica 96, 1715–1719 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Storm, T. et al. A patient with cubilin deficiency. N. Engl. J. Med. 364, 89–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Xu, D., Kozyraki, R., Newman, T. C. & Fyfe, J. C. Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption. Blood 94, 3604–3606 (1999).

    CAS  PubMed  Google Scholar 

  60. Grasbeck, R., Gordin, R., Kantero, I. & Kuhlback, B. Selective vitamin B12 malabsorption and proteinuria in young people. A syndrome. Acta Med. Scand. 167, 289–296 (1960).

    Article  CAS  PubMed  Google Scholar 

  61. Imerslund, O. Idiopathic chronic megaloblastic anemia in children. Acta Paediatr. Suppl. 49 (Suppl. 119), 1–115 (1960).

    Google Scholar 

  62. Aminoff, M. et al. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat. Genet. 21, 309–313 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. He, Q. et al. Canine Imerslund-Grasbeck syndrome maps to a region orthologous to HSA14q. Mamm. Genome 14, 758–764 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Kristiansen, M. et al. Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. Blood 96, 405–409 (2000).

    CAS  PubMed  Google Scholar 

  65. Rutsch, F. et al. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat. Genet. 41, 234–239 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Rosenblatt, D. S., Hosack, A., Matiaszuk, N. V., Cooper, B. A. & Laframboise, R. Defect in vitamin B12 release from lysosomes: newly described inborn error of vitamin B12 metabolism. Science 228, 1319–1321 (1985).

    Article  CAS  PubMed  Google Scholar 

  67. Froese, D. S. & Gravel, R. A. Genetic disorders of vitamin B metabolism: eight complementation groups—eight genes. Expert Rev. Mol. Med. 12, e37 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Banerjee, R., Gherasim, C. & Padovani, D. The tinker, tailor, soldier in intracellular B12 trafficking. Curr. Opin. Chem. Biol. 13, 484–491 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hannibal, L. et al. Processing of alkylcobalamins in mammalian cells: a role for the MMACHC (cblC) gene product. Mol. Genet. Metab. 97, 260–266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lerner-Ellis, J. P. et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat. Genet. 38, 93–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Kim, J., Gherasim, C. & Banerjee, R. Decyanation of vitamin B12 by a trafficking chaperone. Proc. Natl Acad. Sci. USA 105, 14551–14554 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kim, J., Hannibal, L., Gherasim, C., Jacobsen, D. W. & Banerjee, R. A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J. Biol. Chem. 284, 33418–33424 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Coelho, D. et al. Gene identification for the cblD defect of vitamin B12 metabolism. N. Engl. J. Med. 358, 1454–1464 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Miousse, I. R. et al. Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J. Pediatr. 154, 551–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Suormala, T. et al. The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J. Biol. Chem. 279, 42742–42749 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Beedholm-Ebsen, R. et al. Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin. Blood 115, 1632–1639 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Bakos, E. & Homolya, L. Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1). Pflugers Arch. 453, 621–641 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Cole, S. P. et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650–1654 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Flens, M. J. et al. Tissue distribution of the multidrug resistance protein. Am. J. Pathol. 148, 1237–1247 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Peng, K. C. et al. Tissue and cell distribution of the multidrug resistance-associated protein (MRP) in mouse intestine and kidney. J. Histochem. Cytochem. 47, 757–768 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Ostray, F. & Gams, R. A. Cellular fluxes of vitamin B12. Blood 50, 877–888 (1977).

    CAS  PubMed  Google Scholar 

  82. Ramasamy, M., Alpers, D. H., Tiruppathi, C. & Seetharam, B. Cobalamin release from intrinsic factor and transfer to transcobalamin II within the rat enterocyte. Am. J. Physiol. 257, G791–G797 (1989).

    CAS  PubMed  Google Scholar 

  83. Seetharam, B. & Yammani, R. R. Cobalamin transport proteins and their cell-surface receptors. Expert Rev. Mol. Med. 5, 1–18 (2003).

    Article  PubMed  Google Scholar 

  84. Schilling, R. F. Intrinsic factor studies II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J. Lab. Clin. Med. 42, 860–866 (1953).

    CAS  PubMed  Google Scholar 

  85. Shah, N. P., Beech, C. M., Sturm, A. C. & Tanner, S. M. Investigation of the ABC transporter MRP1 in selected patients with presumed defects in vitamin B12 absorption. Blood 117, 4397–4398 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Deeley, R. G., Westlake, C. & Cole, S. P. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol. Rev. 86, 849–899 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Hall, C. A. The carriers of native vitamin B12 in normal human serum. Clin. Sci. Mol. Med. 53, 453–457 (1977).

    CAS  PubMed  Google Scholar 

  88. Quadros, E. V., Nakayama, Y. & Sequeira, J. M. The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. Blood 113, 186–192 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bose, S., Seetharam, S. & Seetharam, B. Membrane expression and interactions of human transcobalamin II receptor. J. Biol. Chem. 270, 8152–8157 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Nexo, E. & Hollenberg, M. D. Characterization of the particulate and soluble acceptor for transcobalamin II from human placenta and rabbit liver. Biochim. Biophys. Acta 628, 190–200 (1980).

    Article  CAS  PubMed  Google Scholar 

  91. Seligman, P. A. & Allen, R. H. Characterization of the receptor for transcobalamin II isolated from human placenta. J. Biol. Chem. 253, 1766–1772 (1978).

    CAS  PubMed  Google Scholar 

  92. Amagasaki, T., Green, R. & Jacobsen, D. W. Expression of transcobalamin II receptors by human leukemia K562 and HL-60 cells. Blood 76, 1380–1386 (1990).

    CAS  PubMed  Google Scholar 

  93. Cho, W. et al. Expression of CD320 in human B cells in addition to follicular dendritic cells. BMB Rep. 41, 863–867 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Park, H. J., Kim, J. Y., Jung, K. I. & Kim, T. J. Characterization of a novel nene in the nxtended MHC region of mouse, NG29/Cd320, a homolog of the human CD320. Immune Netw. 9, 138–146 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Arendt, J. F., Quadros, E. V. & Nexo, E. Soluble transcobalamin receptor, sCD320, is present in human serum and relates to serum cobalamin—establishment and validation of an ELISA. Clin. Chem. Lab Med. http://dx/doi.org/10.1515/cclm.2011.810.

  96. Quadros, E. V. & Jacobsen, D. W. The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. Biochim. Biophys. Acta 1244, 395–403 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Youngdahl-Turner, P., Rosenberg, L. E. & Allen, R. H. Binding and uptake of transcobalamin II by human fibroblasts. J. Clin. Invest. 61, 133–141 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Quadros, E. V. et al. Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). Hum. Mutat. 31, 924–929 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Birn, H., Nexo, E., Christensen, E. I. & Nielsen, R. Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis. Nephrol. Dial. Transplant. 18, 1095–1100 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Moestrup, S. K. et al. Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis. Proc. Natl Acad. Sci. USA 93, 8612–8617 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burger, R. L., Schneider, R. J., Mehlman, C. S. & Allen, R. H. Human plasma R-type vitamin B12-binding proteins. II. The role of transcobalamin I, transcobalamin III, and the normal granulocyte vitamin B12-binding protein in the plasma transport of vitamin B12. J. Biol. Chem. 250, 7707–7713 (1975).

    CAS  PubMed  Google Scholar 

  102. Birn, H. et al. Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). Am. J. Physiol. Renal Physiol. 282, F408–F416 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Birn, H. The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins. Am. J. Physiol. Renal Physiol. 291, F22–F36 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Newmark, P., Newman, G. E. & O'Brien, J. R. Vitamin B12 in the rat kidney. Evidence for an association with lysosomes. Arch. Biochem. Biophys. 141, 121–130 (1970).

    Article  CAS  PubMed  Google Scholar 

  105. Hammad, S. M., Barth, J. L., Knaak, C. & Argraves, W. S. Megalin acts in concert with cubilin to mediate endocytosis of high density lipoproteins. J. Biol. Chem. 275, 12003–12008 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Kozyraki, R. et al. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc. Natl Acad. Sci. USA 98, 12491–12496 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Leheste, J. R. et al. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am. J. Pathol. 155, 1361–1370 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Nagai, J. et al. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am. J. Physiol. Renal Physiol. 289, F569–F576 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Green, R. Is it time for vitamin B-12 fortification? What are the questions? Am. J. Clin. Nutr. 89, 712S–716S (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hvas, A. M., Morkbak, A. L., Hardlei, T. F. & Nexo, E. The vitamin B12 absorption test, CobaSorb, identifies patients not requiring vitamin B12 injection therapy. Scand. J. Clin. Lab. Invest. 71, 432–438 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Fedosov, S. N. et al. Human intrinsic factor expressed in the plant Arabidopsis thaliana. Eur. J. Biochem. 270, 3362–3367 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Kuzminski, A. M., Del Giacco, E. J., Allen, R. H., Stabler, S. P. & Lindenbaum, J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 92, 1191–1198 (1998).

    CAS  PubMed  Google Scholar 

  113. Clardy, S. M., Allis, D. G., Fairchild, T. J. & Doyle, R. P. Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical. Expert Opin. Drug Deliv. 8, 127–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Quadros, E. V., Nakayama, Y. & Sequeira, J. M. Targeted delivery of saporin toxin by monoclonal antibody to the transcobalamin receptor, TCblR/CD320. Mol. Cancer Ther. 9, 3033–3040 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Novo Nordisk Foundation, the Lundbeck Foundation, the Danish Medical Research Council and the European Research Council.

Author information

Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Building 1170, Aarhus, 8000, Denmark

    Marianne J. Nielsen, Mie R. Rasmussen, Christian B. F. Andersen & Søren K. Moestrup

  2. Department of Clinical Biochemistry, Aarhus University Hospital, Norrebrogade, Aarhus, 8000, Denmark

    Ebba Nexø

Authors
  1. Marianne J. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mie R. Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian B. F. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ebba Nexø
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Søren K. Moestrup
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. J. Nielsen contributed to the writing and reviewing/editing of the manuscript. M. R. Rasmussen and C. B. F. Andersen researched data. E. Nexø researched data and contributed to reviewing/editing the manuscript. S. K. Moestrup contributed to all aspects of this manuscript.

Corresponding author

Correspondence to Søren K. Moestrup.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nielsen, M., Rasmussen, M., Andersen, C. et al. Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 9, 345–354 (2012). https://doi.org/10.1038/nrgastro.2012.76

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2012.76

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing