The inhibition of enzymes by beryllium.
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ABSTRACT:
SUBMITTER: Thomas M
PROVIDER: S-EPMC1264799 | biostudies-other | 1966 Jan
REPOSITORIES: biostudies-other
Similar Datasets
Project description:1. The inhibition of phosphoglucomutase by beryllium has been examined. 2. Inhibition by beryllium does not occur unless a complex-forming agent such as cysteine or imidazole is present. It is therefore similar to activation by magnesium. 3. The inhibition is progressive and the rate follows first-order kinetics, which may be defined by a bimolecular rate constant. 4. In the presence of magnesium the rate of inhibition is less. By using a fixed time for inhibition competition between beryllium and magnesium may be demonstrated. After inhibition has taken place, the addition of magnesium does not reverse it.
| S-EPMC1264800 | biostudies-other
Project description:1. Cyclic AMP-independent casein kinase 1 in liver cytoplasm and nuclei was inhibited by Be2+ in vitro (Ki 2.5 microM and 29 microM respectively). Casein kinase 2 (phosvitin kinase) and cyclic AMP-dependent protein kinase were unaffected. 2. The inhibition of casein kinase 1 by Be2+ was competitive with respect to the protein substrate; at non-saturating concentrations of casein, inhibition was non-competitive with respect to ATP. 3. In rats given LD50 doses of Be2+ 24 h before death, the activities of cytoplasmic and nuclear casein kinase 1 in livers from partially hepatectomized animals were diminished approx. 50%; with intact rats, nuclear casein kinase 1 was inhibited at concentrations of casein less than the Km.
| S-EPMC1153939 | biostudies-other
Project description:1. The incorporation of thymidine into DNA of regenerating rat liver was measured at various times after partial hepatectomy. A single intravenous injection of 30mumol of beryllium/kg given immediately after the operation inhibited DNA synthesis 12, 16, 20, 24 and 28h later. 2. The activity of several enzymes critical to DNA synthesis (thymidine kinase, thymidylate kinase, thymidylate synthetase, deoxycytidylate deaminase and DNA polymerase) increased in control rats 20-24h after partial hepatectomy severalfold over the activity found in resting livers. After beryllium treatment this rise in activity was much less and it seemed as if beryllium would partially block the induction of DNA-synthesizing enzymes after partial hepatectomy. 3. Enzymes whose activities do not rise during liver regeneration were not affected by beryllium (aspartate transcarbamoylase, carbamoyl phosphate synthetase, uridine kinase and glucose 6-phosphatase). 4. No evidence was found in vitro that beryllium would specifically inhibit thymidine kinase or DNA polymerase. 5. The time-effect relationship between beryllium administration and thymidine kinase activity in vivo was examined. Measured 24h after partial hepatectomy, thymidine kinase activity was only affected if beryllium was given within the first 9-12h after partial hepatectomy. Beryllium given later, even in greatly increased doses, failed to have any effect on thymidine kinase. The possibility is discussed that beryllium inhibits enzyme induction at the transcriptional level.
| S-EPMC1179644 | biostudies-other
Project description:Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4? T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4? T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4? T cells specific for these ligands in all HLADP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4? T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.
| S-EPMC3698527 | biostudies-literature
Project description:Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by a hypersensitivity to beryllium and characterized by the accumulation of beryllium-specific CD4(+) T cells in the lung. Genetic susceptibility to beryllium-induced disease is strongly associated with HLA-DP alleles possessing a glutamic acid at the 69th position of the ?-chain (?Glu69). The structure of HLA-DP2, the most prevalent ?Glu69-containing molecule, revealed a unique solvent-exposed acidic pocket that includes ?Glu69 and represents the putative beryllium-binding site. The delineation of mimotopes and endogenous self-peptides that complete the ??TCR ligand for beryllium-specific CD4(+) T cells suggests a unique role of these peptides in metal ion coordination and the generation of altered self-peptides, blurring the distinction between hypersensitivity and autoimmunity.
| S-EPMC3883670 | biostudies-literature
Project description:Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung disease, beryllium-induced hypersensitivity is the best-studied to date. This review focuses on the interaction between innate and adaptive immunity that leads to the development of chronic beryllium disease. After beryllium exposure, activation of the innate immune system occurs through the engagement of pattern-recognition receptors. This activation leads to cell death, release of alarmins, and activation and migration of dendritic cells to lung-draining lymph nodes. These events culminate in the development of an adaptive immune response that is characterized by beryllium-specific, T-helper type 1-polarized, CD4+ T-cells and granuloma formation in the lung. The unique ability of beryllium to bind to human leukocyte antigen-DP molecules that express a glutamic acid at position 69 of the ?-chain alters the charge and conformation of the human leukocyte antigen-DP-peptide complex. These changes induce post-translational modifications that are recognized as non-self. In essence, the ability of beryllium to create neoantigens underlies the genesis of chronic beryllium disease, and demonstrates the similarity between beryllium-induced hypersensitivity and autoimmunity.
| S-EPMC5955034 | biostudies-literature
Project description:Aldehydes play a key role in the human metabolism. Therefore, it is essential to know their reactivity with beryllium compounds in order to assess its effects in the body. The reactivity of simple aldehydes towards beryllium halides (F, Cl, Br, I) was studied through solution and solid-state techniques and revealed distinctively different reactivities of the beryllium halides, with BeF2 being the least and BeI2 the most reactive. Rearrangement and aldol condensation reactions were observed and monitored by in situ NMR spectroscopy. Crystal structures of various compounds obtained by Be2+ -catalyzed cyclization, rearrangement, and aldol addition reactions or ligation of beryllium halides have been determined, including unprecedented one-dimensional BeCl2 chains and the first structurally characterized example of an 1-iodo-alkoxide. Long-term studies showed that only aldehydes without a β-H can form stable beryllium complexes, whereas other aldehydes are oligo- and polymerized or decomposed by beryllium halides.
| S-EPMC6771974 | biostudies-literature
Project description:Chronic Beryllium (Be) Disease (CBD) is a granulomatous disorder that predominantly affects the lung. The CBD is caused by Be exposure of individuals carrying the HLA-DP2 protein of the major histocompatibility complex class II (MHCII). While the involvement of Be in the development of CBD is obvious and the binding site and the sequence of Be and peptide binding were recently experimentally revealed [1], the interplay between induced conformational changes and the changes of the peptide binding affinity in presence of Be were not investigated. Here we carry out in silico modeling and predict the Be binding to be within the acidic pocket (Glu26, Glu68 and Glu69) present on the HLA-DP2 protein in accordance with the experimental work [1]. In addition, the modeling indicates that the Be ion binds to the HLA-DP2 before the corresponding peptide is able to bind to it. Further analysis of the MD generated trajectories reveals that in the presence of the Be ion in the binding pocket of HLA-DP2, all the different types of peptides induce very similar conformational changes, but their binding affinities are quite different. Since these conformational changes are distinctly different from the changes caused by peptides normally found in the cell in the absence of Be, it can be speculated that CBD can be caused by any peptide in presence of Be ion. However, the affinities of peptides for Be loaded HLA-DP2 were found to depend of their amino acid composition and the peptides carrying acidic group at positions 4 and 7 are among the strongest binders. Thus, it is proposed that CBD is caused by the exposure of Be of an individual carrying the HLA-DP2*0201 allele and that the binding of Be to HLA-DP2 protein alters the conformational and ionization properties of HLA-DP2 such that the binding of a peptide triggers a wrong signaling cascade.
| S-EPMC4219729 | biostudies-literature
Project description:RationaleBeryllium sensitization (BeS) and chronic beryllium disease (CBD) are determined by at least one genetic factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, and by exposure to beryllium. The relationship between exposure and the E69 genotype has not been well characterized.ObjectivesThe study goal was to define the relationship between beryllium exposure and E69 for CBD and BeS.MethodsWorkers (n = 386) from a U.S. nuclear weapons facility were enrolled into a case-control study (70 BeS, 61 CBD, and 255 control subjects). HLA-DPB1 genotypes were determined by sequence-specific primer-polymerase chain reaction. Beryllium exposures were reconstructed on the basis of worker interviews and historical exposure measurements.Measurements and main resultsAny E69 carriage increased odds for CBD (odds ratio [OR], 7.61; 95% confidence interval [CI], 3.66-15.84) and each unit increase in lifetime weighted average exposure increased the odds for CBD (OR, 2.27; 95% CI, 1.26-4.09). Compared with E69-negative genotypes, a single E69-positive *02 allele increased the odds for BeS (OR, 12.01; 95% CI, 4.28-33.71) and CBD (OR, 3.46; 95% CI, 1.42-8.43). A single non-*02 E69 allele further increased the odds for BeS (OR, 29.54; 95% CI, 10.33-84.53) and CBD (OR, 11.97; 95% CI, 5.12-28.00) and two E69 allele copies conferred the highest odds for BeS (OR, 55.68; 95% CI, 14.80-209.40) and CBD (OR, 22.54; 95% CI, 7.00-72.62).ConclusionsE69 and beryllium exposure both contribute to the odds of CBD. The increased odds for CBD and BeS due to E69 appear to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes.
| S-EPMC3136994 | biostudies-literature
Project description:Uracil methylation is essential for survival of organisms and passage of information from generation to generation with high fidelity. Two alternative uridyl methylation enzymes, flavin-dependent thymidylate synthase and folate/FAD-dependent RNA methyltransferase, have joined the long-known classical enzymes, thymidylate synthase and SAM-dependent RNA methyltransferase. These alternative enzymes differ significantly from their classical counterparts in structure, cofactor requirements and chemical mechanism. This review covers the available structural and mechanistic knowledge of the classical and alternative enzymes in biological uracil methylation, and offers a possibility of using inhibitors specifically aiming at microbial thymidylate production as antimicrobial drugs.
| S-EPMC3315608 | biostudies-literature