Defects in the intracellular vitamin B12 uptake - Methylmalonic aciduria
Dietary vitamin B12 (CnCbl, Cbl) is delivered to its target enzymes by a multistep process in which Cbl is permanently associated to proteins. After receptor-mediated endocytosis of protein-bound vitamin B12 (Cbl) into lysosomes, Cbl is exported from the lysosomes to the cytosol by two membrane proteins LMBD1 (LMBRD1) and ABCD4. Mutations in these genes lead to cobalamin metabolism disorders cblF and cblJ due to accumulation of Cbl in lysosomes. (PMID:27456980) In the cytosol Cbl is bound and processed by MMACHC. MMADHC binds to Cbl-laden MMACHC and targets Cbl either to the cytosolic methionine synthase (MS, MTR) or to the mitochondrial methylmalonyl-CoA mutase (MUT) (28572511). Mutations in MMACHC cause the cblC type of cobalamin metabolism disorders, with both methylmalonic aciduria (MMA) and homocystinuria (HC), whereas cblD (MMADHC) patients exhibit isolated or combined MMA and HC (PMID:23270877). MS (MTR) binds to methionine synthase reductase (MSR, MTRR), the causative for homocystinuria-megaloblastic anemia, cbl E type (PMID:27771510 ). MS (MRT) catalyzes the synthesis of methionine by transferring the methyl group from methyl-Cbl to homocysteine and subsequently the remethylation of the cofactor using methyltetrahydrofolate. Defects in MS result in homocystinuria and megaloblastic anemia (cblG type). (PMID:25526710) In mitochondria Cbl is adenosylated by MMAB, the causative for the cblB type, to form the cofactor adenosylcobalamin (AdoCbl, coabmide coenzyme). AdoCbl is then transferred to the enzyme methylmalonyl-CoA transferase (MUT). This transfer is controlled by MMAA (cblA type), which blocks or ejects non-functional Cbl forms. (PMID:28572511) MUT catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA and mutations therein result in the accumulation of methylmalonic acid in mitochondria (mut(0/-) type) (PMID:22661206). Accumulation of methylmalonic acid causes an increase of ROS levels and induces neuroinflammatory and apoptotic processes during the brain development. This might explain brain dysfunction and cognitive impairment in patients with methylmalonic acidemia. (PMID:28395089).