A schematic model for the tentative cellular pathways of Cbl. (A) Polarized ileal cell. After binding of Cbl to gastric IF in the gut lumen, the IF-Cbl complex binds to the IF-Cbl receptor, cubam, located in the ileal apical brush border. Once bound, IF-Cbl is internalized and processed via the classic endosome-lysosomal pathway. In the endosome IF-Cbl is released from cubam, which is recycled back to the cell surface in receptosomes (dashed line). In the lysosome, the lysosomal proteases degrade IF, releasing the vitamin for transport by the lysosomal transmembrane protein LMBD1. From the cytosol Cbl is exported at the basolateral side of the ileal cell by the ATP-driven exporter MRP1 or alternatively by a yet unknown mechanism. The vitamin remaining intracellularly is largely enzyme bound and serves as coenzyme for methionine synthase in the cytoplasm or for methylmalonyl CoA mutase in the mitochondria. Some Cbl may also be associated to the recently identified MMACHC protein involved in decyanation of CNCbl and the dealkylation of alkylcobalamins before conversion to coenzyme forms.^35,36  In the plasma, free Cbl is immediately bound to transcobalamin (TC), synthesized and excreted in vesicles by the cells. (B) Nonpolarized cell expressing the TC receptor.