Pathway of cellular processing of cobalamin and the relationship of the metabolic steps of propionyl-CoA metabolism

Bound cobalamin (CN-cbl, OH-CBL) is transported from the phagolysosomal compartment after release from transcobalamin 2. The central cobalt atom likely undergoes reductive processing after export into the cytosol. The reduced cobalamin species, designated Cbl(II) in the diagram, is transported across the outer and inner mitochondrial membranes and enters the matrix, where it is converted into adenosylcobalamin, the cofactor required for the methylmalonyl-CoA mutase reaction. The complementation class and genes known to be associated with isolated methylmalonic acidemia are: cblA (MMAA); cblB (MMAB); cblD variant 2; mut (L-methylmalonyl-CoA mutase). Combined homocysteinemia/methylmalonic acidemia is caused by: cblC deficiency (MMACHC); cblD deficiency, unknown gene(s); cblF deficiency, unknown gene. Steps that affect only the synthesis of methylcobalamin and cause homocysteinemia without methylmalonic aciduria; cblE deficiency, methionine synthase reductase; cblG deficiency, methionine synthase; cblD variant 1 deficiency, unknown gene. The cblH is allelic to cblD variant 2. The precise location of the cblD variant 1 and variant 2 steps are uncertain. (Contributed by Dr. Gerard Berry.)