ABCD4:LMBRD1 transports RCbl from lysosomal lumen to cytosol (gut mucosal cells)

Stable Identifier
Reaction [transition]
Homo sapiens
an R-cob(III)alamin(out) + ATP + H2O => ADP + an R-cob(III)alamin(in) + H(+) + phosphate
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In the mucosal cells of the distal ileum, ATP binding cassette sub family D member 4 (ABCD4) associated with lysosomal cobalamin transport escort protein (LMBRD1) mediates the ATP-dependent export of cobalamins (RCbl) from the lysosome into the cytosol. ABCD4 by itself in liposomes can mediate RCbl transport, indicating that ABCD4, not LBRD1, is directly responsible for intracellular RCbl transport (Kitai et al. 2021). Consistent with this in vitro observation, mutations affecting the ATPase activity of ABCD4 inhibit RCbl transport from the lysosome to the cytosol (Coelho et al. 2012), causing methylmalonic aciduria and homocystinuria type CblJ (MAHCJ; MIM:614857), a disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). LMBRD1 stabilizes ABCD4 in the lysosomal membrane (Kawaguchi et al. 2016) and defects in this protein are associated with a disease phenotype (CblF; MAHCF; MIM: 277380) that mimics CblJ (Rosenblatt et al. 1985, Rutsch et al. 2009).

Literature References
PubMed ID Title Journal Year
22922874 Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism

Pasquali, M, Rosenblatt, DS, Mengel, E, Frapolli, M, Burda, P, du Moulin, M, Miousse, IR, Shoubridge, EA, Watkins, D, Stucki, M, Fung, S, Fowler, B, Nürnberg, P, Thiele, H, Kim, JC, Coelho, D, Baumgartner, MR, Höhne, W, Suormala, T, Rutsch, F, Buers, I, Majewski, J, Longo, N, Robenek, H

Nat. Genet. 2012
33845046 The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro

Kitai, K, So, T, Kawaguchi, K, Morita, M, Tomohiro, T, Imanaka, T

J Biol Chem 2021
27456980 Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1

Kawaguchi, K, Morita, M, Okamoto, T, Imanaka, T

Sci Rep 2016
19136951 Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism

Becker, C, Toliat, MR, Rosenblatt, DS, Baumgartner, M, Gailus, S, Miousse, IR, Stucki, M, Fowler, B, Nürnberg, P, Wittkampf, T, Höhne, W, Nürnberg, G, Suormala, T, Rutsch, F, Buers, I, Sagné, C, Marquardt, T, Robenek, H, Sharifi, A, Gasnier, B

Nat. Genet. 2009
4001945 Defect in vitamin B12 release from lysosomes: newly described inborn error of vitamin B12 metabolism

Matiaszuk, NV, Rosenblatt, DS, Laframboise, R, Cooper, BA, Hosack, A

Science 1985
Catalyst Activity

ABC-type vitamin B12 transporter activity of ABCD4:LMBRD1 [lysosomal membrane]

Orthologous Events
Cross References
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