Dataset Information

Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor.

ABSTRACT: Cellular uptake of cobalamin is facilitated by a receptor-mediated endocytosis process involving transcobalamin, a plasma protein that binds cobalamin and a cell surface receptor that specifically binds transcobalamin saturated with cobalamin. Intracellular Cbl concentration is maintained by modulating the expression of the receptor, which is cell cycle associated with highest expression in actively proliferating cells and an efflux system that shunts the excess cobalamin out of the cells for mobilization to other tissues where it is most needed. This review describes the process, proteins involved and genes encoding these proteins.

SUBMITTER: Quadros EV

PROVIDER: S-EPMC3902480 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor.

Quadros Edward V EV Sequeira Jeffrey M JM

Biochimie 20130214 5

Cellular uptake of cobalamin is facilitated by a receptor-mediated endocytosis process involving transcobalamin, a plasma protein that binds cobalamin and a cell surface receptor that specifically binds transcobalamin saturated with cobalamin. Intracellular Cbl concentration is maintained by modulating the expression of the receptor, which is cell cycle associated with highest expression in actively proliferating cells and an efflux system that shunts the excess cobalamin out of the cells for mo ...[more]

PMID: 23415653

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Project description:BACKGROUND:Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS:Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS:Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS:Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.

Dataset Information

Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor.

Publications

Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor.

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