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

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

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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.

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Acknowledgements

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

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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.

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Correspondence to Søren K. Moestrup.

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The authors declare no competing financial interests.

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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

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