Recognition of two intracellular cobalamin binding proteins and their identification as methylmalonyl-CoA mutase and methionine synthetase.

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Abstract
The granulocyte R-type cobalamin (Cbl) binding protein delivers Cbl exclusively to hepatocytes, and transcobalamin II delivers Cbl to various mammalian cells. Both protein-Cbl complexes enter cells by pinocytosis, and the protein moieties are rapidly degraded in lysosomes. The liberated Cbl is subsequently bound to a high-molecular-weight intracellular Cbl binding protein (ICB). The nature of ICB-Cbl is unknown but appears important because ICB-[57Co]Cbl is missing from cultured fibroblasts of a group of patients whose cells take up CN-[57Co]Cbl normally but do not convert it to either of its coenzyme forms. Supernatants of sonicated rabbit livers were examined. Of the total endogenous Cbl 65% elutes from Sephadex G-150 as ICB-Cbl; this fraction also contains the 2 mammalian Cbl-dependent enzymes, methylmalonyl-CoA mutase (EC 5.4.99.2) and methionine synthetase (EC 2.1.1.13). Gradient elution from DEAE-Sephadex reveals that 90-95% of the ICB-Cbl elutes with methylmalonyl-CoA mutase and 5-10% elutes with methionine synthetase. ICB-[57Co]Cbl 1st appears 2 h after the i.v. injection of CN-[57Co]Cbl bound to granulocyte R-type protein. This ICB-[57Co]Cbl is associated with either methylmalonyl-CoA mutase or methionine synthetase although the latter appears to be formed at a relatively faster rate. The primary abnormality in the group of patients mentioned above probably lies at a step that is common to the formation of both Cbl coenzymes and precedes the stable binding of Cbl to both methylmalonyl-CoA mutase and methionine synthetase.

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