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Cobalamin transport
About: Cobalamin transport is a research topic. Over the lifetime, 72 publications have been published within this topic receiving 3088 citations.
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TL;DR: The most common disorder of folate metabolism, 5,10-methylenetetrahydrofolate deficiency, also affects remethylation and presents with leukodystrophy, and all are treatable, although with variable outcome.
Abstract: Disorders of cobalamin and folate intracellular metabolism that result in defective remethylation of homocysteine to methionine are associated with leukodystrophy, whereas disorders of cobalamin transport generally are not. Cobalamin derivatives are needed for only two reactions in man; remethylation of homocysteine to methionine, with methylcobalamin as a cofactor for methionine synthase, and the conversion of methylmalonyl-coenzyme A to succinyl coenzyme A by methylmalonyl-CoA mutase, with adenosylcobalamin as a cofactor. Mutations at various metabolic steps affect the synthesis of adenosylcobalamin (CblA, CblB, and CblD2), methylcobalamin (CblE, CblG, and CblD1), or both of these (CblF, CblD, and CblC). The most common disorder of folate metabolism, 5,10-methylenetetrahydrofolate deficiency, also affects remethylation and presents with leukodystrophy. Pathways of cobalamin and folate metabolism intersect at one site, methionine synthase. Patients with the remethylating disorders present acutely or chronically with significant neurologic, hematologic, vascular, and other symptoms. Circulating levels of cobalamin and folate are usually normal in these disorders, and initial diagnosis is aided by measurement of homocysteine and methylmalonic acid in blood or urine, together with hematologic tests. Current diagnosis is often by newborn screening. These disorders all show autosomal recessive inheritance, and all are treatable, although with variable outcome.
10 citations
TL;DR: It is concluded that intact function of LMBD1 is essential for the initiation of gastrulation in mice generating Lmbrd1 deficient mice using the Cre/LoxP system.
Abstract: The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl-CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia. LMBRD1 encodes for LMBD1, a predicted lysosomal cobalamin transport protein. In this study, we determine the physiological function of LMBRD1 during embryogenesis by generating Lmbrd1 deficient mice using the Cre/LoxP system. Complete loss of Lmbrd1 function is accompanied by early embryonic death in mice. Whole mount in situ hybridization studies against bone morphogenetic protein 4 and Nodal show that initial formation of the proximal–distal axis is unaffected in early embryonic stages whereas the initiation of gastrulation is disturbed shown by the expression pattern of even skipped homeotic gene 1 and fibroblast growth factor 8 in Lmbrd1 deficient mice. We conclude that intact function of LMBD1 is essential for the initiation of gastrulation.
10 citations
TL;DR: Results suggest that there may be a close link between TC II-mediated cobalamin transport and intracellular synthesis of adenosylcobalamin (Ado-Cbl).
Abstract: Cobalamin metabolism has been investigated in a new case of transcobalamin II (TC II) deficiency. Using the chromatobioautographic technique, an abnormal distribution of cobalamins was detected in the child's erythrocytes and reduced synthesis of adenosylcobalamin but not of methylcobalamin in cultured fibroblasts. These results suggest that there may be a close link between TC II-mediated cobalamin transport and intracellular synthesis of adenosylcobalamin (Ado-Cbl).
10 citations
TL;DR: The invariably tight interaction of the DNA–Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells.
Abstract: The synthesis and structural characterization of Co-(dN)25 -Cbl (Cbl: cobalamin; dN: deoxynucleotide) and Co-(dN)39 -Cbl, which are organometallic DNA-B12 conjugates with single DNA strands consisting of 25 and 39 deoxynucleotides, respectively, and binding studies of these two DNA-Cbl conjugates to three homologous human Cbl transporting proteins, transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are reported. This investigation tests the suitability of such DNA-Cbls for the task of eventual in vivo oligonucleotide delivery. The binding of DNA-Cbl to TC, IF, and HC was investigated in competition with either a fluorescent Cbl derivative and Co-(dN)25 -Cbl, or radiolabeled vitamin B12 (57 Co-CNCbl) and Co-(dN)25 -Cbl or Co-(dN)39 -Cbl. Binding of the new DNA-Cbl conjugates was fast and tight with TC, but poorer with HC and IF, which extends a similar original finding with the simpler DNA-Cbl, Co-(dN)18 -Cbl. The contrasting affinities of TC versus IF and HC for the DNA-Cbl conjugates are rationalized herein by a stepwise mechanism of Cbl binding. Critical contributions to overall affinity result from gradual conformational adaptations of the Cbl-binding proteins to the DNA-Cbl, which is first bound to the respective β domains. This transition is fast with TC, but slow with IF and HC, with which weaker binding results. The invariably tight interaction of the DNA-Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells.
8 citations
Book•
01 Jan 2012
TL;DR: This work focuses on the study of niacin status and genomic instability in bone marrow cells, which favors the progression of leukemogenesis and the role of folic acid in this process.
Abstract: Preface.- 1. Biotin: Biochemical, Physiological and Clinical Aspects.- 2. Niacin status and genomic instability in bone marrow cells Mechanisms favoring the progression of leukemogenesis.- 3. Niacin: Vitamin and Antidyslipidemic Drug.- 4. Beyond the antioxidant: the double life of vitamin C.- 5. Vitamin C in Sepsis.- 6. Vitamin C transport and its role in the central nervous system.- 7. Genetic aspects of folate metabolism.- 8. Enzymatic and non-enzymatic antioxidative effects of folic acid and its reduced derivates.- 9. Folate-linked drugs for the treatment of cancer and inflammatory diseases.- 10. Folate in Skin Cancer Prevention.- 11. Thiamin(E): The spark of life.- 12. Riboflavin in development and cell fate.- 13. Vitamins B6 and Cancer.- 14. Vitamin B6 and cardiovascular disease.- 15.- Vitamin B6: Beyond coenzyme functions.- 16.- Cobalamin Deficiency.- 17. Biochemistry of B12-Cofactors in Human Metabolism.- 18. Physiological and molecular aspects of cobalamin transport.- Index.
8 citations