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PubMed1984

Influence of metal substitution on vitamin B12 binding to human intrinsic factor and transcobalamins I and II.

Metal-free, zinc, copper, and rhodium analogues of vitamin B12 were synthesized to further characterize structural requirements for the binding to human intrinsic factor, transcobalamin I, and transcobalamin II. Binding affinities of the various analogues were studied by competition against cyano[57Co]cobalamin. When albumin-coated charcoal was used for the separation of free and bound corrinoids, the relative 50% inhibition indexes were determined. The influence of metal substitution was similar among the three binding proteins. For analogues with a strong coordinative linkage between the heterocyclic base and the central metal ion, similar to that with cobalt (e.g., zincobalamin and cyanorhodibalamin), the indexes range from 0.65 to 2.35 for all three binding proteins. Analogues in which coordination is impossible (hydrogenobalamin and dicyanorhodibalamin) exhibit markedly reduced binding with indexes between 10 and 160. Cupribalamin shows 50% inhibition indexes ranging from 2.3 to 5.0, thus suggesting a weak coordinative bond between the copper ion and the 5,6-dimethylbenzimidazole moiety. These results emphasize the importance of the coordinative linkage between the central metal ion and the nucleotide moiety for optimal recognition by vitamin B12 binding proteins.

Binding Sites↗
PubMed2001

Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects.

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTD). Homocysteine levels are elevated in mothers of NTD children, which may be due to decreased cellular vitamin B12 levels, as vitamin B12 is a cofactor for the methylation of homocysteine. Transcobalamin II (TC II) transports vitamin B12 to the tissues. To examine whether altered plasma transcobalamin levels are a risk factor for NTD, we determined the apo and holo form of TC II and haptocorrin (TCI+TCIII), vitamin B12 and homocysteine concentrations in the plasma of 46 mothers with NTD children, and in 73 female controls. Holo-tc II levels and holo-tc II percentages (holo-tc II/total tc II) in the first quartile of the control distribution were related to a three-fold (OR 2.9, 95%CI 0.9-9.2) and five-fold (OR 5.0, 95%CI 1.3-19.3) risk, respectively, for having a child with NTD, when compared with the last quartile. Homocysteine levels were significantly higher among individuals with low holo-tc II, low total vitamin B12 concentrations and low holo-tc II percentages. These low holo-tc II percentages are probably caused by reduced affinity of TC II for vitamin B12, which may be explained by genetic variation in the TC II gene. Vitamin B12 supplementation might therefore be warranted, in addition to folate, in the prevention of NTD.

Adult↗
PubMed2001

Crystallization and preliminary X-ray diffraction analysis of human transcobalamin, a vitamin B12-transporting protein.

Transcobalamin is a cobalamin-binding protein in mammalian plasma that facilitates the cellular uptake of vitamin B(12). Human transcobalamin was crystallized using polyethylene glycol and ethanol as precipitants. Crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 49.04, b = 145.27, c = 164.96 A. A complete data set to 3.2 A resolution was collected from a single crystal using synchrotron radiation. Estimation of the crystal packing (V(M) = 3.2 A(3) Da(-1)) and self-rotation function analysis suggest the presence of two molecules in the asymmetric unit related by non-crystallographic twofold symmetry.

Biological Transport↗
PubMed1979

Inherited lack of transcobalamin II in serum and megaloblastic anaemia: a further patient.

We have studied a patient, unrelated to the patients previously described, with inherited lack of the vitamin B12 binding protein Transcobalamin II. Severe haematological abnormalities were found within a few weeks of birth and responded to treatment with both vitamin B12 and folic acid. He was maintained in partial remission with such treatment until adolescence, except for a time in early childhood when folic acid alone was given and he suffered severe neurological deterioration. A the age of 18 years he was admitted to hospital because of convulsions; the deoxyuridine suppression test showed intracellular deficiency of B12 despite a normal serum B12 and normal haemoglobin concentration. His serum failed to promote the uptake of radioactive B12 by bone marrow cells, and analysis of serum B12 binding proteins demonstrated the lack of Transcobalamin II. Treatment with injections of 1000 micrograms of B12 three times weekly corrected the abnormality shown in the deoxyuridine suppression test; following this treatment, together with changes in anticonvulsive therapy, he remains healthy without occurrence of further convulsions, and is haematologically normal.

Adult↗
PubMed1991

Transcobalamins in the etiology of neural tube defects.

In a sample of 79 pregnant women at risk offspring with neural tube defects (NTDs) and 158 controls, significantly increased median values were found for apo-transcobalamins I and II in amniotic fluid in the group at risk, thus confirming previous results. The findings may reflect a genetic disposition to NTDs associated with altered levels of apo-transcobalamins, and research on the etiology and mechanisms of NTDs should focus on these proteins.

Adult↗
PubMed1976

An improved procedure for automated Edman degradation used for determination of the N-terminal amino acid sequence of human transcobalamin I and human intrinsic factor.

An improved procedure for automated Edman degradation is presented. Three programs are described, one with double cleavage and two with single cleavage. The programs presented are characterized by a reversed delivery scheme for buffer and phenyl isothiocyanate, and by reduced cleavage times. The modified procedures applied on automated Edman degradation of the vitamin B12-binding proteins human transcobalamin I and human intrinsic factor, containing approximately 390 and 350 amino residues respectively, gave the following N-terminal amino acid sequences: Human transcobalamin I Glu-Ile-Cys-Glu-Val-Ser-Glu-Glu-Asn-Tyr-Ile-Arg-Leu-Lys-Pro-Leu-Leu-Asn-Thr-Met-Ile-Gln-Ser-Asn-Tyr-Asn-?-Gly- Human intrinsic factor Ser-Thr-Gln-Thr-Gln-Ser-Ser-Cys-Ser-Val-Pro-Ser-Ala-Gln-Glu-Pro-Leu-Val-Asn-Gly-Ile-Gln-?-Leu-Met-Glu-Thr- The background accumulation seems to be related not only to the length of the polypeptide chain being degraded, but also to the content of serine (and possibly threonine). A possible N leads to O acyl shift during the cleavage is a tentative explanation. The programs here represented lead to a significant reduction in background compared to conventional programs and allowed considerable prolongation of the degradations.

Amino Acid Sequence↗
PubMed1978

Increased concentration of transcobalamin I in a patient with metastatic carcinoma of the breast.

A patient with metastatic carcinoma of the breast and increased plasma cobalamin binding capacity (about 50 nmol/1) is described. The binding protein was identified as transcobalamin I (TCI) by DEAE cellulose ion-exchange chromatography, Sephadex G200 gel filtration and agar gel electrophoresis. Although the total plasma cobalamin concentration (about 20 nmol/1) was elevated, the patient complained of neurological symptoms in accordance with a functional vitamin B12 deficiency. Hence, an inactivation of the coenzyme is suggested by the demonstration of considerable amounts of 5'-deoxyadenosylcobalamin bound to the plasma TCI. Both urinary excretion of FIGLU and methylmalonic acid were within the reference ranges. Reported cases of increased cobalamin binding in patients with nonhaematological malignancy are reviewed. Further investigations to characterize the function of the cobalamin dependent metabolic pathways are necessary to determine the importance of the increased transcobalamin binding in these patients.

Blood Proteins↗
PubMed1983

Abnormalities of serum transcobalamins in sickle cell disease (HbSS) in Black Africa.

The unsaturated vitamin B12 binding capacity (UBBC) of serum, the three transcobalamins (TC I, TC II, TC III), and the total leucocyte and neutrophil counts have been studied in paediatric patients with sickle cell disease (SCD). Increase in the level of the binding capacities of TC I and TC II with concomitant increase of UBBC was observed in these children who also had increased total white blood and neutrophil counts. There was a significant reduction in the level of endogenous B12. These abnormalities are discussed in relation to the deficiency of the splenic reticuloendothelial function, immunologic defect, hepatic degenerative changes and aplastic crisis observed in SCD. These results lend support to the view that transcobalamins are involved in the defence mechanism of the body. The significant reduction in serum cobalamin in SCD suggests a higher demand on this vitamin for metabolic functions, especially for the sparing of folate.

Anemia, Sickle Cell↗
PubMed1986

Cobalamin and unsaturated transcobalamin values in pernicious anaemia: relation to treatment.

27 patients with pernicious anaemia, followed for a long period, were consecutively treated with 3 different vitamin B12 preparations while, during intervening periods, no therapy was given until signs of B12 deficiency developed. The mean of the vitamin B12-free period lasted 400 d. Some patients were 'short-reactors' whereas others were 'long-reactors'. Some patients repeatedly revealed deficiency signs at cobalamin values greater than 200 pmol/l and others at values less than 50 pmol/l, pointing to individually different cut-off points for appearance of signs of deficiency. Hypersegmentation was the first sign in about 2/3, neuropathy in 1/3 and mucosal changes in about 1/10 of the patients. The same type of deficiency was repeatedly noted in the same patient. The daily decline of plasma cobalamin values decreased during the vitamin B12-free period. In perorally treated patients the unsaturated transcobalamin values showed an inverse relationship to the cobalamin values. Marked increases in unsaturated transcobalamin I values were noted in 4 of 16 patients treated with B12 injections, resulting in prolonged high cobalamin values and prolongation of the vitamin B12-free periods.

Adult↗
PubMed1978

Evidence for intestinal origin of transcobalamin II during vitamin B12 absorption.

The plasma binding of newly absorbed, radioactively labelled vitamin B12 was studied during a urinary excretion (Schilling) test. Vitamin B12, after being absorbed from the gut, enters blood attached to transcobalamin II, which seems to be derived from the ileal enterocyte. The absorbed B12 re-enters the blood stream after the transcobalamin II-B12 complex is cleared by the liver and it is then excreted into the urine during the Schilling test.

Aged↗
PubMed2007

Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2).

BACKGROUND: A 776C-->G variant (dbSNP ID: rs1801198) in the transcobalamin gene (TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B(12). OBJECTIVE: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level. METHODS: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria. RESULTS: The frequencies of the 776G allele were the highest in China (0.607; 95% CI 0.554 to 0.659), low in West Africa (Bénin and Togo, 0.178; 0.154 to 0.206), and intermediate in France (0.445; 0.408 to 0.481), Italy (0.352; 0.299 to 0.409), Morocco (0.370; 0.300 to 0.447) and Mexico (0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York (16.7; 8.4 to 30.7) and in Afro-African patients with severe malaria (6.0%; 95% CI 3.7 to 9.6) than in healthy Afro-African volunteers (p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected (p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B(12) (<100 pmol/l). CONCLUSION: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.

Adult↗
PubMed1982

Neurological involvement in hereditary transcobalamin II deficiency.

A case of hereditary transcobalamin II deficiency with neurological involvement is described. The patient presented in early infancy with megaloblastic anaemia and was treated with folinic acid from 6 weeks of age. The diagnosis of transcobalamin II deficiency was not made until he was 2 years old when he showed severely retarded intellectual development, ataxia and pyramidal deficit in the limbs. Following treatment with hydroxocobalamin, his condition has slowly improved but he has remained with a severe neurological deficit. The consequences of vitamin B12 deficiency on neurological development in infancy are discussed.

Age Factors↗
PubMed1980

Validity of transcobalamin II-based radioassay for the determination of serum vitamin B12 concentrations.

A valid radioassay for the estimation of serum vitamin B12 in the presence of naturally occurring vitamin B12 (= cobalamin) analogues can be operated if serum transcobalamin II (TC II) is used as the binding protein. Serum samples that gave diagnostically discrepant results when their vitamin B12 content was analysed (i) by a commercial radioassay known to be susceptible to interference from cobalamin analogues, and (ii) by microbiological assay, were further analysed by an alternative radioassay which uses the transcobalamins (principally TC II) of diluted normal serum as the assay binding protein. Concordance between the results from microbiological assay and the TC II-based radioassay was found in all cases. In an extended study over a three-year period, all routine serum samples sent for vitamin B12 analysis that had a vitamin B12 content of less than 320 ng/l by the TC II-based radioassay (reference range 200-850 ng/l) were reanalysed using an established microbiological method. Over 1000 samples were thus analysed. The data are presented to demonstrate the validity of the TC II-based radioassay results in this group of patients, serum samples from which are most likely to produce diagnostically erroneous vitamin B12 results when analysed by a radioassay that is less specific for cobalamins.

Biological Assay↗
PubMed2004

Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications.

The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy.

Abortion, Spontaneous↗
PubMed2005

Circadian variation of holo-transcobalamin (holo-TC) and related markers.

We examined the circadian variation of holo-transcobalamin (holo-TC), total transcobalamin (total TC) and plasma cobalamins, and the association between food intake and fluctuations in the biochemical markers. A total of 17 healthy women (mean age 33 years; range 24-40) participated. The subjects were admitted at 08:00 h after an overnight fast, and blood samples were obtained every 20 min for 24 h from 12:00 h. Holo-TC and total TC were measured by an ELISA, and plasma cobalamins were measured by a routine method (Centaur, Bayer). All subjects, except one, had 12:00 h levels within the reference interval for all variables studied, and all subjects had normal renal function as judged from plasma creatinine. We found a small intra-individual variation (12%, 10%, 10%) and a considerable inter-individual variation (56%, 26%, 43%) in the level of holo-TC, total TC and plasma cobalamins, respectively. During the night, the absolute values of all components decreased, as did plasma albumin. There was no systematic association between intake of food and fluctuation of the biochemical markers. In conclusion, we found no significant circadian variation in serum holo-TC in healthy vitamin-replete subjects on a standard diet. This supports the view that holo-TC is a marker of long-term vitamin B(12) status, and that samples may also be obtained from non-fasting subjects.

Adult↗
PubMed1986

Isoelectric focusing of rabbit transcobalamin from serum and cerebrospinal fluid.

Isoelectric focusing in agarose gel separated rabbit transcobalamin into five to eight isopeptides with isoelectric point (pI) 5.4-6.8. Three different sets of patterns were observed in serum samples from 34 rabbits and in cerebrospinal fluid samples from 10 rabbits as a given pattern in serum corresponded to a given pattern in cerebrospinal fluid. Serum contained higher substance concentrations of acidic isopeptides than cerebrospinal fluid. No correlation was found between the isopeptide patterns and the unsaturated cobalamin-binding capacity. The unsaturated cobalamin-binding capacity of cerebrospinal fluid was high in relation to the protein concentration (0.5-1.3 nmol/l) compared to that of serum (6.6-22.8 nmol/l). The data suggest synthesis of transcobalamin into the cerebrospinal fluid.

Animals↗
PubMed1983

Vitamin B12 binding proteins (transcobalamin and haptocorrin) in serum and synovial fluid of patients with rheumatoid arthritis and traumatic synovitis.

The vitamin B12 (cobalamin) binding proteins, transcobalamin and haptocorrin, were measured in serum and synovial fluid of 12 patients with rheumatoid arthritis (RA) and 11 patients with traumatic synovitis (TS). Levels of both the cobalamin-binding proteins of synovial fluid were markedly elevated in RA compared with TS. In serum, the haptocorrin concentrations were significantly increased in RA vis-à-vis TS. In synovial fluid of RA patients, the transcobalamin and haptocorrin concentrations were positively correlated to the concentrations of macrophages and polymorphonuclear granulocytes, respectively. The demonstration of increased synovial fluid transcobalamin/total protein and haptocorrin/total protein ratios in RA vis-à-vis TS provides further evidence of a local production or liberation of the cobalamin-binding proteins in synovial fluid of patients with RA.

Arthritis, Rheumatoid↗