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At least 289 records · Page 16Linked to original sources
PubMed1978

Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency.

Cobalamin (Cbl; vitamin B(12)) malabsorption in pancreatic insufficiency can be partially corrected by bicarbonate and completely corrected by pancreatic proteases but the mechanisms involved are unknown. Because saliva contains enough R-type Cbl-binding protein (R protein) to bind all of the dietary and biliary Cbl, it is possible that R protein acts as an inhibitor of Cbl absorption and that pancreatic proteases are required to alter R protein and prevent such inhibition. To test this hypothesis we studied the ability of R protein and intrinsic factor (IF) to compete for Cbl binding and ability of pancreatic proteases to alter this competition. Human salivary R protein bound Cbl with affinities that were 50- and 3-fold higher than those of human IF at pH 2 and 8, respectively. Cbl bound to IF was transferred to an equal amount of R protein with t((1/2))'s of 2 and 90 min at pH 2 and 8, respectively, and within several hours respective ratios of R protein-Cbl/IF-Cbl of 50 and 2 were observed. Cbl bound to R protein was not transferred to IF at either pH 2 or 8. Incubation of R protein with pancreatic proteases at pH 8 led to a 150-fold decrease in its affinity for Cbl. Incubation of R protein-Cbl with pancreatic proteases led to complete transfer of Cbl to IF within 10 min. Gel filtration studies with R protein-[(57)Co]Cbl and (125)I-R protein showed that pancreatic proteases partially degraded R protein. Pancreatic proteases differed in their ability to effect these changes with trypsin > chymotrypsin > elastase. Pancreatic proteases did not alter IF in any of the parameters mentioned above. Pepsin failed to alter either R protein or IF. THESE STUDIES SUGGEST THE FOLLOWING: (a) that Cbl is bound almost exclusively to R protein in the acid milieu of the stomach, rather than to IF as has been assumed previously; (b) that Cbl remains bound to R protein in the slightly alkaline environment of the intestine until pancreatic proteases partially degrade R protein and enable Cbl to become bound exclusively to IF; and (c) that the primary defect in Cbl absorption in pancreatic insufficiency is a lack of pancreatic proteases and a failure to alter R protein and effect the transfer of Cbl to IF. These studies also suggest that the partial correction of Cbl malabsorption observed with bicarbonate is due to neutralization of gastric HCl, since at slightly alkaline, pH IF can partially compete with R protein for the initial binding and retention of Cbl.

Carrier Proteins↗
PubMed1979

An evaluation of simultaneously administered free and intrinsic factor bound radioactive cyanocobalamin in the diagnosis of pernicious anaemia in the elderly.

The definitive diagnosis of pernicious anaemia (PA) in the elderly is by no means always straightforward, particularly when inappropriate medication has been introduced before the institution of specific investigatory procedures. A detailed haematological study was carried out on 301 patients aged 60-95 with a serum B(12) concentration at the laboratory's lower level of normal of 150 ng per litre (Euglena gracilis assay). The diagnosis of PA was based on strict predetermined haematological criteria. All patients were subsequently studied by the simultaneous oral administration of the dual isotopes (57)Co-labelled B(12) bound to intrinsic factor and free (58)Co-labelled B(12) (Dicopac test), and urine was collected over 24 hours after an intramuscular dose of 1 mg nonradioactive B(12) for estimation of the (57)Co/(58)Co B(12) ratio; 255 patients satisfied all criteria for final analysis. The Radiochemical Centre, Amersham suggests an upper limit of the normal range for the (57)Co/(58)Co ratio of 1.3 with a lower limit for PA of 2.0. We were unable to show a sharp borderline in the (57)Co/(58)Co B(12) ratio between those patients shown by other criteria to have PA and those who do not have PA; 34% of the 71 established patients had a ratio below 2.0. From our series a ratio borderline drawn at 1.4 gave only one false negative (1.4% of the PA group). Of the 175 non-PA cases, nine (5%) gave false positive results; four of these had (58)Co excretion levels high enough to make misdiagnosis unlikely. In a proportion of patients the (57)Co/(58)Co B(12) ratio was estimated at regular intervals for 36-hour periods. Maximum accuracy of isotope measurement on a single specimen was obtained 8-20 hours after isotope dosing. The Dicopac investigation is a useful simple screening test in the differential diagnosis of patients with a megaloblastic bone marrow and combined low serum B(12) and folate concentrations. When carried out by the standard technique, the degree of discrimination between normal and abnormal ratios is of limited diagnostic significance in one-third of patients.

Aged↗
PubMed1992

[Pernicious anemia. A study of initial forms of the disease and diagnostic significance of determination of the intrinsic factor antibody and parietal cell antibody].

In a prospective study of thirty five consecutive patients with decreased plasma cobalamine (P-Cbl), twenty-two (63%) were diagnosed as having pernicious anaemia (PA) (no age or sex differences) on basis of the B12-absorption test and/or megaloblastic changes in the bone marrow. In this group ten patients were anaemic (six of whom were characterized as macrocytic), sixteen of nineteen examined had megaloblastic changes in the bone marrow, and all of thirteen examined had achlorhydria with positive correlation to Parietal Cell Antibodies (PCA). Two patients with PA had normal Cbl-absorption and two had malabsorption at the time of diagnosis. Twenty-one patients (95%) had PCA and thirteen (59%) were Intrinsic Factor Antibody (IFAb) positive. Three patients IFAb-seroconverted within a year. Among the remaining thirteen patients (37%), one had PCA but not IFAb and three were IFAb-positive all of whom had normal Cbl-absorption. Of the three patients with IFAb one had also PCA, one IFAb-seroconverted within three months, and one had microcytic anaemia with iron depleted bone marrow due to coecal cancer. Among twenty two healthy adult controls four (18%) had PCA while none had IFAb. This investigation shows that at the debut half of PA patients (55%) do not have anaemia, some have normal Cbl-absorption and some have malabsorption. 95% have PCA and 59% have IFAb. So, IFAb-negative PA is often seen (41%) and seroconversion can take place. Diagnosis is even more reliable, when achlorhydria is present in PCA-positive persons. Healthy PCA-positive persons are probably predisposed to develop PA. Patients with cbl-deficiency, IFAb and/or PCA must be considered as having latent PA even if they have normal haemoglobin and normal Cbl-absorption. These patients should be followed and, in case of anaemia or signs of neuropathia, treated.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Pernicious↗
PubMed1992

Genomic structure and mapping of the chromosomal gene for transcobalamin I (TCN1): comparison to human intrinsic factor.

Transcobalamin I (TCI) is a vitamin B12 binding protein that is found in the secondary granules of mature neutrophils. The expression of the gene for TCI (TCN1) within neutrophils has been shown to be restricted to the later stages of myeloid development and can therefore be used as a marker for granulocyte differentiation. To study transcriptional control regions important in late stage myeloid gene regulation the genomic sequence for TCN1 has been cloned. Clones were isolated from a genomic library constructed in Charon 4A using homologous full-length cDNA probes. Southern blot analysis showed the gene to reside on five EcoRI fragments totaling 14 kb in length. Two overlapping phage clones, containing the entire 14 kb, were isolated and the introns and exons were mapped using Southern blotting and dideoxy sequencing of subclones. The cDNA is represented by nine exons contained within 12 kb of genomic DNA. Comparison of the genomic structure to gastric intrinsic factor (GIF), another vitamin B12 binding protein, revealed a strikingly similar intron/exon structure, with several positionally conserved splice sites. The gene was localized to chromosome 11 using in situ hybridization.

Amino Acid Sequence↗
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↗
PubMed1995

Intrinsic factors of apatite influencing its amorphization during plasma-spray coating.

Hydroxyapatite coatings were prepared from differently treated starting powders to investigate the intrinsic factors of apatite influencing its amorphization during plasma-spray coating. The joint analyses of X-ray diffraction and infrared spectra show that the vacancies located on missing hydroxyl sites retard the amorphous/crystalline conversion and enforce retention of the amorphous component; the absorbed water molecules that pre-exist in the starting powder can be incorporated into the vacancies in the hydroxyapatite lattice during plasma-spray coating and compensate for the missing hydroxyls so as to promote the transformation of amorphous into crystalline apatite in the coating process. The more vacancies there are in the apatite structure due to missing hydroxyl sites, the more amorphous the component in the resultant coatings. Moreover, the amorphous phase formed in this way is stable in room conditions.

Biodegradation, Environmental↗
PubMed1995

Decreased activity of intestinal and urinary intrinsic factor receptor in Gräsbeck-Imerslund disease [corrected].

BACKGROUND/AIMS: The pathogenesis of inherited intestinal cobalamin malabsorption (Gräsbeck-Imerslund disease) remains unknown. The authors studied whether the disease corresponds to a defective expression and/or function of the intrinsic factor-cobalamin receptor in the ileum. METHODS: Intrinsic factor-cobalamin receptor activity was measured using radioisotope assay and gel-filtration exclusion chromatography in ileal biopsy specimens and urine concentrates from 4 patients with Gräsbeck-Imerslund disease and 5 controls. RESULTS: Receptor activity was 164 +/- 13 fmol/mg of protein in control biopsy specimens and < 2.6 fmol/mg protein in specimens from patients. The association constant was estimated to be 3.8 +/- 0.4 (nmol/L)-1 in controls. A dramatic decrease in receptor activity was also observed in urine concentrate from patients with an association constant of 1.9 and 3.3 (nmol/L)-1. Isoelectrofocusing of the cross-linked intrinsic factor-cobalamin receptor complex showed an isoelectric point at 4.8 in a patient as well as in control samples. CONCLUSIONS: It is concluded that Gräsbeck-Imerslund disease is related to decreased intrinsic factor-receptor activity in intestinal mucosa; the receptor assay in urine can be helpful for diagnosis.

Adult↗
PubMed2003

Maternal macho-1 is an intrinsic factor that makes cell response to the same FGF signal differ between mesenchyme and notochord induction in ascidian embryos.

An extracellular signaling molecule acts on several types of cells, evoking characteristic and different responses depending on intrinsic factors in the signal-receiving cells. In ascidian embryos, notochord and mesenchyme are induced in the anterior and posterior margins, respectively, of the vegetal hemisphere by the same FGF signal emanating from endoderm precursors. The difference in the responsiveness depends on the inheritance of the posterior-vegetal egg cytoplasm. We show that macho-1, first identified as a localized muscle determinant, is also required for mesenchyme induction, and that it plays a role in making the cell response differ between notochord and mesenchyme induction. A zygotic event involving snail expression downstream of maternal macho-1 mediates the suppression of notochord induction in mesenchyme precursors.

Animals↗