Meta-Biol

• Pathways

In cells throughout the body that have taken up TCN2:RCbl from the blood, 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 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).