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PubMed1998

Cobalamin-dependent methionine synthase and serine hydroxymethyltransferase: targets for chemotherapeutic intervention?

Chemotherapeutic drugs targeted at folate-dependent reactions have typically been directed at a limited number of target enzymes: dihydrofolate reductase, thymidylate synthase, and GAR and AICAR transformylase. This review discusses two other potential targets for chemotherapeutic inhibition: cobalamin-dependent methionine synthase and serine hydroxymethyltransferase. Brief reviews of the catalytic properties of these two enzymes are presented, and possible strategies for chemotherapeutic intervention are discussed.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1986

In-vitro test of haptocorrin degradation for biological diagnosis of exocrine pancreatic dysfunction using duodenal juice collected during endoscopy.

An in-vitro test of degradation of haptocorrin, a cobalamin-binding glycoprotein, was used to diagnose exocrine pancreatic dysfunction. This radioisotopic test (TDH) required only 50 microliters duodenal juice collected during endoscopy after stimulation with 1 U/kg secretin intravenously. The initial reaction mixture, composed of salivary haptocorrin saturated with cobalt-57-labelled cyanocobalamin and unsaturated intrinsic factor, was incubated with 25 microliters duodenal juice. The percentage of degraded haptocorrin was estimated from the proportion of labelled cyanocobalamin that was transferred from haptocorrin to intrinsic factor. The TDH result was 41.6 +/- 31.7% (SD) in a group of chronic pancreatitis patients (n = 22) and 91.5 +/- 4.8% in the control group (n = 47). The sensitivity and specificity for exocrine pancreatic dysfunction were estimated as 0.91 and 0.96, respectively, for a lower limit of normal values of 81.7%. A hyperbolic relation was found between the TDH and the trypsin or chymotrypsin activity in duodenal juice (p less than 0.001). In this study, the N-benzoyl-tyrosyl-p-aminobenzoic acid test was less sensitive than the TDH, since its result was abnormal in only 64% of the patients. The TDH was easier to carry out and less time-consuming than the determination of pancreatic enzyme output in duodenal juice collected after hormonal stimulation.

Adult↗
PubMed1998

Heteronuclear NMR studies of cobalt corrinoids. 20. 31P chemical shift anisotropy of aquacobalamin and its complex with a haptocorrin from chicken serum.

Static light scattering measurements have been used to determine the molecular mass (65.3 kDa) and second virial coefficient (3.66 x 10(-4) mol mL g-2) for the complex between chicken serum haptocorrin (HC) and aquacobalamin (H2OCbl). Dynamic light scattering measurements have also been used to determine the translational diffusion coefficient of the H2OCbl-HC complex as a function of concentration. From the diffusion coefficient at infinite dilution (4.71 x 10(-7) cm2 s-1), the hydrodynamic radius (45.5 A) and rotational correlation time (85.4 ns) have been calculated. Using the latter, and measured values of the 31P NMR linewidths of the H2OCbl-HC complex at several field strengths, a detailed analysis of the 31P nuclear relaxation is possible. The chemical shift anisotropy term from the transverse relaxation equation is determined to be 95.7 ppm, and the average phosphorus-proton internuclear distance is 2.05 A. For comparison to protein-free H2OCbl, the chemical shift anisotropy of the phosphorus atom was studied by solid state NMR spectroscopy and the 31P relaxation by solution T1 measurements. These studies give values of 110.3 ppm for the chemical shift anisotropy term and 2.45 A for the average phosphorus-proton internuclear distance. The results are consistent with a significant change in the conformation of the H2OCbl phosphodiester upon binding to haptocorrin which could be due to a shortening of the axial Co-N bond.

Animals↗
PubMed1990

Immunohistochemical localization of vitamin B12 R-binder in salivary gland tumors. Implications for cell differentiation.

Vitamin B12 R-binder, a specific binding protein for vitamin B12, was studied immunohistochemically in normal and 106 neoplastic salivary gland tissues with a monoclonal antibody against vitamin B12 R-binder (R-binder). In normal salivary glands, R-binder localization was restricted to the ductal systems and to mucous acinar cells; serous acinar cells, myoepithelial cells and stromal connective tissues were consistently negative. Among salivary gland tumors, R-binder was present in 87% of pleomorphic adenomas, 100% of monomorphic adenomas, and 40% of adenoid cystic carcinomas; positivity was observed only on luminal surfaces of small ductular elements, indicating that the components closely related to ductal differentiation were rather small in population. R-binder could be detected both in lacunar and non-lacunar cells within chondroid areas of pleomorphic adenomas, suggesting the possibility that chondroid regions arise from metaplastic changes in ductal epithelial cells. In mucoepidermoid tumors, mucous cells and focal squamous cells exhibited cytoplasmic staining. The staining pattern for R-binder in epithelial components of adenolymphomas showed close similarities to those found in normal large excretory ducts. Two acinic cell tumors and one case each of myoepithelioma and malignant myoepithelioma exhibited negative reactivity for R-binder, showing that these neoplasms are solely composed of tumor cells without the characteristics of ductular differentiation. The immunohistochemical examination of salivary gland tumors, employing a monoclonal anti-R-binder antibody, may have some implications for cellular heterogeneity and differentiation in various tumors.

Antibodies, Monoclonal↗
PubMed1989

Distribution of vitamin B12 R-binder in lung tumors. Implications for cell differentiation.

Expression of vitamin B12 R-binder, a specific binding protein for vitamin B12, was studied immunohistochemically in normal lung tissues and 107 lung tumors of various types. In normal tissues, vitamin B12 R-binder (R-binder) expression was restricted to the mucous cells of bronchial or bronchiolar epithelium and submucosal glands as well as to nonciliated bronchiolar (Clara) cells. Among lung carcinomas, 38% of squamous cell carcinomas, 42% of adenocarcinomas and 23% of large cell carcinomas showed positive staining for R-binder whereas small cell carcinomas did not. These findings offer the possibility that a majority of the histologic types of lung carcinoma have common histogenetical characteristics with mucous or Clara cells. Of the bronchial gland tumors, R-binder could be detected in a mucoepidermoid carcinoma but not in adenoid cystic carcinomas. Epithelial components in both pulmonary blastomas and hamartomas showed a reactivity for R-binder, suggesting that these tumors contained components composed of cells with bronchiolar cell differentiation. The immunohistochemical examination of lung tumors, using anti-R-binder antibody, may have some implications in the cell differentiation of lung tumors.

Bronchi↗
PubMed1997

Home parenteral nutrition and vitamin B12 status.

The vitamin B12 status of 20 subjects who were on home parenteral nutrition after surgical or functional small bowel resection and were given 1000 micrograms cyanocobalamin every 3 mo was studied by comparing their plasma vitamin B12, homocysteine (HS), and methylmalonic acid (MMA) concentrations. The plasma vitamin B12 concentration (median 145 pmol/L, 95% confidence interval: 123-217) was subnormal in four cases and borderline in four others. In the "4low B12" group, the concentrations of the markers of vitamin B12 deficiency were in the normal range; HS 10.7 mumol/L (8.0-12.3); and MMA, 0.15 mumol/L (0.09-0.19). References values were HS, 10.0 mumol/L (9.4-12.6); and MMA, 0.16 mumol/L (0.10-0.19). Thus, there were no metabolic signs of vitamin B12 deficiency in these subjects on parenteral nutrition, despite the fact that their plasma vitamin B12 levels were low. Analysis of individual data showed that the four patients with low circulating B12 had markers of intracellular vitamin B12 deficiency in the normal range.

Adult↗
PubMed1998

[Imerslund disease].

Explore the source record for details and available documents.

Diagnosis, Differential↗
PubMed1993

Human cobalophilin: the structure of bound methylcobalamin and a functional role in protecting methylcobalamin from photolysis.

The interactions of methylcobalamin with cobalophilin from human serum were analyzed using extended X-ray absorption fine structure (EXAFS) spectroscopy, photolysis of the cobalt-carbon bond of methylcobalamin, and a pKa determination of the protonation of the coordinated nitrogen of 5,6-dimethylbenzimidazole (DMB). These results are consistent with the idea that the DMB nitrogen is still coordinated when protein is bound; however, the ability of a methyl radical (generated by photolysis) to escape the geminate cage of the protein is considerably reduced. For methylcobalamin in solution, the DMB nitrogen ligand is at a distance of 2.20 +/- 0.03 A from cobalt [Sagi, I., & Chance, M. R. (1992) J. Am. Chem. Soc. 114, 8061-8066]. This distance to the lower axial ligand does not change when protein binds (2.20 +/- 0.04 A), nor do the optical spectra exhibit any base-off character. The average of the distance from cobalt to the four equatorial nitrogens of the corrin plane is also unchanged. The pKa for the conversion of the "base-on" to the "base-off" form of methylcobalamin, where the above DMB nitrogen becomes protonated and the Co-N axial bond is cleaved, does not deviate from the free cobalamin value of 2.7 when methylcobalamin is bound to cobalophilin. These results indicate that replacement of the DMB ligand with a ligand from the protein is unlikely. Although the background-subtracted EXAFS data sets for free methylcobalamin and for the protein complex are extremely similar, more accurate data with explicit higher shell analysis would be required to entirely rule out ligand replacement. The chemical and electronic nature of the ligand changes little.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophoresis, Polyacrylamide Gel↗
PubMed1998

The mechanism of adenosylmethionine-dependent activation of methionine synthase: a rapid kinetic analysis of intermediates in reductive methylation of Cob(II)alamin enzyme.

Cobalamin-dependent methionine synthase catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. During this primary turnover cycle, the enzyme alternates between the active methylcobalamin and cob(I)alamin forms of the enzyme. Formation of the cob(II)alamin prosthetic group by oxidation of cob(I)alamin or photolysis of methylcobalamin renders the enzyme inactive. Methionine synthase from E. coli catalyzes its own reactivation by a reductive methylation that involves electron transfer from reduced flavodoxin and methyl transfer from AdoMet. This process has been proposed to involve formation of a transient cob(I)alamin intermediate that is then trapped by methyl transfer from AdoMet. During aerobic growth of E. coli, electrons for this process are ultimately derived from NADPH, and electron transfer does not generate a detectable level of cob(I)alamin due to the large potential difference between the NADPH/NADP+ couple and the cob(I)alamin/cob(II)alamin couple. In this paper, we show that even in the presence of the strong reductant flavodoxin hydroquinone, cob(I)alamin is not observed as a significant intermediate. We demonstrate, however, that this is due to a rate-limiting reorganization of the cobalt ligand environment from five-coordinate to four-coordinate cob(II)alamin. Mutation of aspartate 757 to glutamate results in a cob(II)alamin enzyme that is approximately 70% four-coordinate, and reductive methylation of this enzyme using flavodoxin hydroquinone as the electron donor proceeds through a kinetically competent cob(I)alamin intermediate. Furthermore, wild-type cob(I)alamin enzyme produced by chemical reduction reacts with AdoMet in a kinetically competent reaction. We provide evidence that methyl transfer from AdoMet to cob(I)alamin enzyme results initially in formation of a five-coordinate methylcobalamin enzyme that slowly decays to the active six-coordinate methylcobalamin enzyme. We propose a kinetic scheme for reductive methylation of wild-type cob(II)alamin enzyme by adenosylmethionine and flavodoxin hydroquinone in which slow conformational changes mask the relatively fast electron and methyl transfer steps.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1978

Comparative studies on intrinsic factor and cobalophilin in different parts of the gastrointestinal tract of the pig.

The vitamin B(12) binders in the pig pyloric mucosa gastric and intestinal juice from the upper gastrointestinal tract were fractionated into only two molecular forms, classified as intrinsic factor and cobalophilin. The unsaturated vitamin B(12)-binding power due to cobalophilin was lower in the intestinal than in the gastric juice. Electrofocusing revealed that intrinsic factor and cobalophilin in the intestinal juice contained more of the ;neutral'-type isoproteins, and the suggestion is made that this is due to enzyme activity. The gastric-juice intrinsic factor contained more acidic isoproteins, which supports the hypothesis that carbohydrate is added on to the polypeptide chain of this protein before it is secreted into gastric juice. The gastric- and intestinal-juice cobalophilins, studied also by electrofocusing, differed from that of pyloric mucosa and they appeared to be of salivary origin. With regard to molecular dimensions there was no significant difference between the intrinsic factors and cobalophilins from all sources studied. All cobalophilins had molecular weights by the formula of Svedberg of approx. 92500, Stokes radii of 4.62nm and sedimentation coefficients of 5.15S. The corresponding values for the intrinsic factors were 63600, 3.57nm and 4.38S. In addition, the intrinsic factors exhibited similar avidities for binding to the solubilized ileal intrinsic-factor receptor. Also the intrinsic factors and cobalophilins, irrespective of their source, bound to the analogous specific xenoantibodies with the same avidity. The present results demonstrate that intrinsic factor remains practically unaltered during its passage through the proximal intestine and render unlikely the speculations made about the presence of an endogenous binder for intrinsic factor as well as the existence of a ;pancreatic intrinsic factor'. In addition, they are compatible with the theory that the interference by undegraded cobalophilin may be the reason for the abnormal vitamin B(12) absorption observed in patients with pancreatic insufficiency.

Animals↗