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At least 19 recordsLinked to original sources
PubMed1975

Human plasma R-type vitamin B12-binding proteins. I. Isolation and characterization of transcobalamin I. TRANSCOBALAMIN III. and the normal granulocyte vitamin B12-binding protein.

Transcobalamin I and transcobalamin III have been purified approximately 6,000,000- and 3,000,000-fold, respectively, from normal human plasma using a purification scheme consisting of immunoadsorption, dialysis against 7.5 M guanidine HCl to remove endogenous vitamin B12, and affinity chromatography on vitamin B12-Sepharose. The two proteins were separated from each other subsequently by chromatography on DEAE-cellulose. The vitamin B12-binding protein present in granulocytes obtained from normal subjects has been purified approximately 5000-fold using affinity chromatography on vitamin B12-Sepharose as the sole purification technique. The final preparations of all three proteins were homogeneous based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Transcobalamin I and transcobalamin III belong to the R-typed class of vitamin B12-binding proteins and are indistinguishable from each other, and from the human granulocyte, milk, and saliva R-type vitamin B12-binding proteins, when studied by immunodiffusion with rabbit anti-human milk vitamin B12-binding protein sera. The carbohydrate compositions, expressed as moles of carbohydrate per mole of vitamin B12, of transcobalamin I, transcobalamin III, and the normal granulocyte vitamin B12-binding protein, respectively, are: sialic acid, 18, 11, 11; fucose, 9, 20, 24; galactose, 41, 51, 46; mannose, 24, 22, 20; galactosamine, 2, 2, 2; and glucosamine, 46, 54, 46. The high sialic acid content of transcobalamin I appears to account for the fact that this protein elutes after transcobalamin III and the normal granulocyte vitamin B12-binding protein during chromatography on DEAE-cellulose. This observation provides support for the hypothesis that differences among the R-type vitamin B12-binding proteins are due to differences in carbohydrate content. The similarities in carbohydrate composition and other properties of transcobalamin III and the granulocyte vitamin B12-binding protein provide support for the hypothesis that human plasma transcobalamin III is derived from granulocytes. The differences observed between transcobalamin I and the normal granulocyte vitamin B12-binding protein suggest that transcobalamin I may not be derived from granulocytes.

Blood Proteins↗
PubMed1975

Human plasma R-type vitamin B12-binding proteins. II. The role of transcobalamin I, transcobalamin III, and the normal granulocyte vitamin B12-binding protein in the plasma transport of vitamin B12.

The normal human granulocyte vitamin B12-binding protein, transcobalamin I, and transcobalamin III, have been labeled with 125I-labeled N-succinimidyl 3-(4-hydroxyphenyl)propionate and utilized for plasma clearance studies performed with rabbits. Both moieties of 125I-labeled granulocyte vitamin B12-binding protein-[57Co]vitamin B12 were cleared rapidly from the plasma (is less than 90% by 5 min) by the liver. After 30 min, the bulk of the 125I reappeared in the plasma in small molecular weight (less than 1000) form and was rapidly excreted in the urine. After 60 min the bulk of the [57Co]vitamin B12 reappeared in the plasma bound to rabbit transcobalamin II and was subsequently taken up by a variety of tissues. Approximately 15% of the 125I-labeled granulocyte vitamin B12-binding protein-[57Co-a1vitamin B12 was excreted intact into the bile during the period from 10 to 80 min after injection. The hepatic uptake of the protein-vitamin B12 complex was blocked by the prior injection of desialyzed fetuin but not by native fetuin. Similar results were obtained with 125I-labeled transcobalamin III-[57Co]vitamin B12. Approximately 90% of both moieties of 125I-labeled transcobalamin I-[57Co]vitamin B12 had prolonged plasma survivals similar to that of 125I-labeled bovine serum albumin. After treatment with neuraminadase, both moieties of the 125I-labeled transcobalamin I-[57Co]vitamin B12 complex were cleared rapidly from the plasma by the liver in a manner that was indistinguishable from that observed in the case of untreated granulocyte vitamin B12-binding protein and transcobalamin III. These observations indicate that desialyzed transcobalamin I and the native forms of the granulocyte vitamin B12-binding protein and transcobalamin III are cleared from plasma by the mechanism elucidated by Ashwell and Morell (Ashwell, G., and Morell A. G. (1974) Adv. Enzymol. 41, 99-128) that is capable of clearing a wide variety of asialoglycoproteins. These observations have implications concerning the function of the human R-type vitamin B12-binding proteins, the nature of the enterohepatic circulation of vitamin B12, the biological significance of the mechanism described by Ashwell and Morell, and the etiology of the increased plasma concentration of human R-type protein that occurs frequently in chronic myelogenous leukemia and occasionally in hepatocellular carcinoma and other solid tumors.

Animals↗
PubMed1995

Transcobalamin II and the membrane receptor for the transcobalamin II-cobalamin complex.

Transcobalamin II is a plasma protein that binds vitamin B12 (cobalamin) as it is absorbed in the terminal ileum and distributes it to tissues. The circulating transcobalamin II-cobalamin complex binds to receptors on the plasma membrane of tissue cells and is then internalized by receptor-mediated endocytosis. A number of genetic abnormalities are characterized either by a failure to express transcobalamin II or by synthesis of an abnormal protein. These disorders result in cellular cobalamin deficiency and megaloblastic anaemia. In this chapter we review the structural and functional properties of transcobalamin II, the receptor for the transcobalamin-cobalamin complex and the clinical disorders that are associated with perturbation of circulating transcobalamin II. In addition, we provide emerging data about the molecular genetics of transcobalamin II which has emanated from our own and other laboratories.

Animals↗
PubMed1977

Characterization of the cobalamins attached to transcobalamin I and transcobalamin II in human plasma.

Insolubilized antibody to transcobalamin I was used to separate transcobalamin I and transcobalamin II. By bioautography of the extracted cobalamins it was shown that transcobalamin II bound more deoxyadenosylcobalamin than did transcobalamin I, and that methylcobalamin accounts for most of the cobalamins attached to transcobalamin I. This finding may indicate that transcobalamin I has a function in the metabolism of methylcobalamin in man.

Blood Proteins↗
PubMed1976

Mammalian transcobalamin II metabolism. The immunological and the biological cross-reactivity of mammalain transcobalamin II.

Assay of the reactivity between the chicken anti-rabbit transcobalamin II antiserum and the sera of 19 vertebrate species was carried out by both immuno-diffusion and Sephadex G-200 gel filtration column chromatography. Mammalian transcobalamin II cross-reacted with the antiserum whereas the serum vitamin B-12 binders of the bird, amphibian reptile and fish did not. The biological activity of the purified rabbit transcobalamin II was assessed using reticulocytes or erythrocytes of human, rabbit, guinea pig and rat. The purified rabbit transcobalamin II promoted the uptake of vitamin B-12 by the cells but showed a great variation in its activity. It is suggested that the rabbit transcobalamin II is immunologically and biologically similar to the serum transcobalamin II of the mammalian species studied.

Animals↗
PubMed1989

Isoelectric focusing of apo- and holo-transcobalamin present in human blood. Identification of a protein complexing with transcobalamin.

By means of isoelectric focusing we studied the factors influencing the isoelectric point of transcobalamin. Upon binding of cobalamin, the transcobalamin isopeptides M, X and S increase their isoelectric points by 0.4 pH units. Serum protein different from gammaglobulin changes the isoelectric point of transcobalamin, but the attachment of the transcobalamin-cobalamin complex to its acceptor is unchanged. Transcobalamin bound to auto-antibodies shows a characteristic pattern upon isoelectric focusing.

Agammaglobulinemia↗
PubMed1984

Congenital transcobalamin II deficiency presenting atypically with a low serum cobalamin level: studies demonstrating the coexistence of a circulating transcobalamin I (R binder) complex.

A case of transcobalamin II deficiency with several unique features is described. The clinical presentation was typical, except for a slightly delayed age at presentation and the occurrence of apparent neurologic dysfunction from the beginning. The unusual biochemical feature was a low serum cobalamin level (97 pg/ml). Several cobalamin-binding protein abnormalities coexisted and antedated cobalamin therapy. Chief among these was the complexing of all serum R binder (transcobalamin I), leaving the patient with no detectable R binder. This defect appeared to be transient. Noteworthy, too, was a prominent binder of 70,000 mol wt that also carried the bulk of his serum cobalamin after therapy; it was prominent in his presumably heterozygous relatives too. The interrelationship between all these abnormalities is intriguing but unclear. The abnormality in transcobalamin II deficiency is clearly not limited solely to deficiency of transcobalamin II. It is also evident that this entity must now be considered in the differential diagnosis of low serum cobalamin levels in infancy.

Carrier Proteins↗
PubMed1980

The concentration of vitamin B12, transcobalamins and folate in blood in a Greenland Eskimo population sample. Increased cobalamin and transcobalamin II in plasma compared with a Danish reference group.

The concentrations of cobalamin and transcobalamin I and II in plasma and of folate in erythrocytes were determined in a Greenlander population sample. Compared with the Danish reference group, cobalamin and transcobalamin II were increased in the Eskimos, whereas there were no differences in transcobalamin I and erythrocyte folate.

Adult↗
PubMed1995

Genomic structure of human transcobalamin II: comparison to human intrinsic factor and transcobalamin I.

Human transcobalamin II (TC II) gene was isolated and partially sequenced. The gene is composed of nine exons and eight introns spanning approximately 20 kb. Multiple potential transcription start sites were revealed by primer extension analysis. The 5'-flanking region of the gene contained no TATA-like motif, but a binding motif for HIP1, which is suggested to be important in the transcription of TATA-less housekeeping genes, was identified in a region very close to the initiator methionine codon. In addition, potential binding sites for a variety of transcription factors such as SP1, AP2, CF1, NF-IL6, Ets-1, Myb and E2A were also observed. Comparison of the genomic structure of TC II to other Cbl-binding proteins, human gastric intrinsic factor (IF) and transcobalamin I (TC I) revealed similar intron-exon organizations with respect to the number, position and size of exons. These results suggest that TC II, TC I and IF genes have originated by gene duplications of an ancestral gene and TC II, unlike the other two Cbl-binding proteins, is the product of a "housekeeping" gene.

Amino Acid Sequence↗
PubMed1995

Circadian variation of plasma cobalamin, transcobalamin-bound cobalamin and unsaturated binding capacity of transcobalamin and haptocorrin in healthy elderly.

Blood samples were drawn every second hour during a 24-h period from healthy elderly subjects. Plasma levels of cobalamin, albumin, transcobalamin-bound cobalamin and unsaturated binding capacity of transcobalamin and haptocorrin were determined. During night, all components decreased in parallel with plasma albumin. The nocturnal decreases were therefore ascribed to plasma volume changes due to bed-rest. Reports on the recently proposed role of cobalamin for the biological clock were reviewed, but the proposed role could not be explained by this study.

Aged↗
PubMed1991

The cDNA sequence and the deduced amino acid sequence of human transcobalamin II show homology with rat intrinsic factor and human transcobalamin I.

The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by human umbilical vein endothelial (HUVE) cells. These cells synthesize and secrete TCII and, therefore, served as the source of the complementary DNA (cDNA) library from which the TCII cDNA was isolated. This full-length cDNA consists of 1866 nucleotides that code for a leader peptide of 18 amino acids, a secreted protein of 409 amino acids, a 5'-untranslated segment of 37 nucleotides, and a 3'-untranslated region of 548 nucleotides. A single 1.9-kilobase species of mRNA corresponding to the size of the cDNA was identified by Northern blot analysis of the RNA isolated from HUVE cells. TCII has 20% amino acid homology and greater than 50% nucleotide homology with human transcobalamin I (TCI) and with rat intrinsic factor (R-IF). TCII has no homology with the amino-terminal region of R-IF that has been reported to have significant primary as well as secondary structural homology with the nucleotide-binding domain of NAD-dependent oxidoreductases. The regions of homology that are common to all three proteins are located in seven domains of the amino acid sequence. One or more of these conserved domains is likely to be involved in Cbl binding, a function that is common to all three proteins. However, the difference in the affinity of TCII, TCI, and R-IF for Cbl and Cbl analogues indicates, a priori, that structural differences in the ligand-binding site of these proteins exist and these probably resulted from divergence of a common ancestral gene.

Amino Acid Sequence↗
PubMed1994

Expression of transcobalamin II mRNA in human tissues and cultured fibroblasts from normal and transcobalamin II-deficient patients.

Transcobalamin II (TCII) is an important plasma transporter of cobalamin (Cbl; vitamin B12). In the present study, TCII gene expression in human and rat tissues and in the fibroblasts of patients with TCII deficiency was investigated. Northern-blot analyses revealed expression of TCII mRNA in many human and rat tissues. In humans, this was 14-fold higher in the kidney than in liver, whereas in the rat the levels of expression were similar in the kidney and liver. Southern-blot analysis of genomic DNA from several species revealed sequence similarity in TCII across species. Metabolic labelling and ribonuclease protection assay revealed a 43 kDa TCII protein and a fully protected TCII mRNA band in normal fibroblasts but not in fibroblasts from three TCII-deficient patients. Southern-blot analysis of genomic DNA from all these fibroblasts revealed identical restriction patterns on BamHI, HindIII, KpnI, MspI and EcoRI digestion. On the basis of these results, we suggest that TCII is expressed in multiple tissues, and its level of expression in tissues varies within the same and across species. Furthermore, the TCII deficiency characterized in this study is due to the absence of TCII protein which in turn is due to the absence or extremely low levels of its mRNA and not to detectable gross alterations in the gene structure.

Animals↗