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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence that the calcium ion plays a critical role in both toxic cell killing and programmed cell death. Thus, in a variety of experimental systems a perturbation of intracellular Ca2+ homeostasis due to increased Ca2+ influx and/or inhibition of Ca2+ extrusion has been found to be an early event in the development of cell injury. It is clear that sustained increases in intracellular Ca2+ can activate cytotoxic mechanisms which result in perturbations of cellular structure and function. For example, the stimulation of Ca(2+)-dependent proteases can result in a disruption of cytoskeletal organization and the formation of surface protrusions (blebs) and Ca(2+)-mediated phospholipase activation can result in an impairment of mitochondrial function with collapse of membrane potential and cessation of ATP synthesis. The activation of a Ca2+, Mg(2+)-dependent nuclear endonuclease is associated with chromatin cleavage and appears to play a crucial role in programmed cell death (apoptosis) in the immune system and other tissues. There is also recent evidence that this process may be responsible for the immunotoxicity of dioxins and organotin compounds and involved in the killing of adenocarcinoma cells by tumor necrosis factor alpha. Although calcium ions appear to be required for endonuclease activity during apoptosis, this process is also influenced by other factors, e.g. protein kinase C activity, intracellular polyamine and Zn2+ levels, chromatin structure, etc. Thus, the regulation of endonuclease activity under both physiological and toxicological conditions appears to be complex and to involve multiple factors.
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PMID:Ca(2+)-dependent mechanisms of cytotoxicity and programmed cell death. 133 78

Structural information on an atomic scale has been obtained for a Langmuir-Blodgett (LB) trilayer system by means of long-period x-ray standing waves. The LB trilayer of zinc and cadmium arachidate was deposited on a layered synthetic microstructure (LSM) consisting of 200 tungsten/silicon layer pairs with a 25 A period. A 30 A thermally induced inward collapse of the zinc atom layer that was initially located in the LB trilayer at 53 A above the LSM surface has been observed. The mean position and width of the zinc atom layer was determined with a precision of +/- 0.3 A.
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PMID:X-ray standing waves: a molecular yardstick for biological membranes. 317 19

Understanding the roles of zinc in the liver is likely to lead to improved therapy of some clinical conditions. Zinc appears to stimulate protein synthesis in the liver where it increases the binding and inhibits the degradation of insulin. Stimulating or maintaining protein synthesis in the liver is crucial to the outcome of parturition, injury or hepatotoxin challenge. A critical liver protein in circulatory collapse is angiotensinogen. This paper describes the observations of animal responses, in a practical farm situation, to zinc medication.
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PMID:The pharmacological role of zinc: evidence from clinical studies on animals. 721 45

In the presence of KCl and only at low phosphate concentrations, ATP stimulated state 4 of the respiration of isolated yeast mitochondria. This effect could be related to a partial collapse of the transmembrane potential which was created by the respiratory chain or the F0F1-ATPase. Sodium and lithium could not replace potassium ion. Atractyloside prevented the opening of this K+ pathway, suggesting that only matricial ATP operated. All these effects were inhibited by increasing phosphate concentration, or by adding propranolol, quinine, Zn2+ or Mg2+.
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PMID:ATP opens an electrophoretic potassium transport pathway in respiring yeast mitochondria. 775 May 62

Fibrolase is an active fibrinolytic agent and possesses potential for use in thrombolytic therapy. Its mode of action had been characterized, both in vitro and in vivo. Possessing three disulfide bonds, native fibrolase is nonglycosylated and binds an intrinsic zinc atom. The zinc is essential for retention of activity and structural integrity. In solution, fibrolase is sensitive to changes in pH and temperature (Pretzer et al., 1991). At neutral to basic pH (pH 5-9), the solubility and stability of fibrolase is nearly constant. Little structural variation can be detected by CD spectroscopy. However, decrease in pH below 5 leads to a pronounced reduction in both the solubility and activity of fibrolase. At pH 3 and below, the solubility of fibrolase returns but the activity does not. This solubility profile is unusual in that the minimal solubility is well removed from the pI (which is 6.7). It is proposed that the behavior of fibrolase with variation in pH can be understood in terms of capacity to bind zinc. At pH 5 to 9, the protein binds zinc and the structure and activity are preserved. Near pH 5, the histidine residues which serve as ligands for the zinc become protonated and zinc binding is lost. Loss of zinc leads to local unfolding of a helical segment of fibrolase, exposing hydrophobic groups which allow the protein to rapidly aggregate. At lower pH values (1-3), the protein again adopts a more globular structure, similar to molten globule states, and the solubility increases. However, without the zinc, fibrolase remains inactive. Changes in pH also affect thermal stability. The Tm for fibrolase moves from 50 degrees C at pH 8 to 43 degrees C at pH 5. Increases in temperature also lead to removal of the zinc ion, again producing a partially denatured protein with a marked tendency to aggregate. In both cases (decrease in pH and increase in temperature), analysis of the CD spectra indicates that the protein has primarily lost alpha-helical secondary structure. A major change in structure can also be observed using NMR spectroscopy. At temperatures below 35 degrees C, the globular structure of fibrolase remains intact, although some increase in chain mobility can be noted with increased temperature. Upon melting, numerous signals collapse as the protein unfolds. Transition temperatures (Tm) as measured by CD and NMR are in good agreement. Similar structural changes can be induced by adding zinc chelators such as EDTA and DTT. This leads to complete loss of activity at EDTA concentrations above 1.0 mM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrolase. A fibrinolytic protein from snake venom. 801 98

Mammalian metallothionein has been postulated to play a pivotal role in cellular zinc distribution. All seven of its metal atoms are bound with high thermodynamic stability in two clusters buried deeply in the molecule. If the protein is to function in metal delivery, there must be a biological mechanism to facilitate metal release. One means to achieve this would be a labilization of the clusters by interaction of metallothionein with an appropriate cellular ligand. To search for such a mediator, we have designed a rapid radiochromatographic method that can detect changes in the zinc content of 65Zn-labeled metallothionein in response to other biomolecules. Using this methodology, we have established that rabbit liver metallothionein 2 interacts with glutathione disulfide with concomitant release of zinc. Under conditions of pseudo-first-order kinetics, the monophasic reaction depends linearly on the concentration of glutathione disulfide in the range from 5 to 30 mM with a second-order rate constant k = 4.9 x 10(-3)s-1.M-1 (pH 8.6; 25 degrees C). Apparently, zinc release does not involve direct access of glutathione disulfide to the inner coordination sphere of the metals. Rather it appears that the solvent-accessible zinc-bound thiolates in two clefts of each domain of metallothionein [Robbins, A. H., McRee, D. E., Williamson, M., Collett, S. A., Xuong, N. H., Furey, W. F., Wang, B. C. & Stout, C. D. (1991) J. Mol. Biol. 221, 1269-1293] participate in a thiol/disulfide interchange with glutathione disulfide. This rate-limiting initial S-thiolation, which occurs with indistinguishable rates in both clusters, then causes the clusters to collapse and release their zinc. Such a mechanism of metal release would link the control of the metal content of metallothionein to the cellular glutathione redox status and raises important questions about the physiological implications of this observation with regard to a role of glutathione in zinc metabolism and in making zinc available for other biomolecules.
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PMID:Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. 827 72

High-temperature drying is required to remove chemisorbed water from the zinc oxide surface. High-temperature drying of a very small particle size zinc oxide powder (median particle size approximately 23 nm) resulted in a substantial decrease in the surface area. The surface areas (BET analysis of 77 K nitrogen vapor adsorption data) of ZnO samples dried at 500 degrees C decreased continually as the drying time was increased. Although the surface area decrease was fastest during the first 5 h, a 64% decrease in surface area was found after 20 h. The decrease in surface area was not due to a collapse of pore structure. Comparison of nitrogen vapor adsorption and desorption isotherms as well as geometric calculations of surface area indicated that both the original and final particles were nonporous. X-ray diffractograms of the original powder and of powders dried at two temperatures were all identical. Thus, no change in crystal structure occurred as a result of drying at 500 degrees C. Atomic force microscopy provided substantial evidence that the surface area decrease was due to a shift in the particle size distribution to a larger mean size. It was verified using two different experiments that ZnO exhibited significant sublimation at 500 degrees C. It was concluded that the increase in particle size was due to a sublimation/condensation process that obeyed the Kelvin equation. The effect of ZnO particle size on the vapor pressure ratio in the Kelvin equation was modeled at 500 degrees C for several different assumed solid surface tensions. Drying conditions for ZnO were then selected which balanced maximum removal of chemisorbed water and minimum surface area decrease. Water vapor adsorption isotherms for ZnO at 25 degrees C were subsequently obtained. Differences in the isotherms resulting from the presence or absence of a chemisorption contribution could clearly be demonstrated.
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PMID:Determination of the mechanism for the decrease in zinc oxide surface area upon high-temperature drying. 858 47

Intraperitoneal zinc chloride was administered at 7.5 micrograms/g body weight and 15 micrograms/g body weight to 10-12 weeks old Swiss albino mice for 5 consecutive days. Control animals were given normal saline. The testis and epididymis were dissected and examined under the light microscope. Micrographs of the testes appeared normal in both treated and nontreated animals. However the group of animals treated with the higher dosage of zinc chloride showed evidence of rupture and collapse of the epididymal epithelial lining. The testes were not affected probably because of (a) known higher testicular concentration of metallothioneins which can bind the zinc and consequently detoxify the metal and (b) "stratified" epithelium comprising of spermatogenic and Sertoli cells.
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PMID:Effect of zinc on the epithelial lining of mice epididymis--a light microscopic study. 887 Apr 77

For the first time a consistent catalytic mechanism of phospholipase C from Bacillus cereus is reported based on molecular mechanics calculations. We have identified the position of the nucleophilic water molecule, which is directly involved in the hydrolysis of the natural substrate phosphatidylcholine, in phospholipase C. This catalytically essential water molecule, after being activated by an acidic residue (Asp55), performs the nucleophilic attack on the phosphorus atom in the substrate, leading to a trigonal bipyramidal pentacoordinated intermediate (and structurally similar transition state). The subsequent collapse of the intermediate, regeneration of the enzyme, and release of the products has to involve a not yet identified second water molecule. The catalytic mechanism reported here is based on a series of molecular mechanics calculations. First, the x-ray structure of phospholipase C from B cereus including a docked substrate molecule was subjected to a stepwise molecular mechanics energy minimization. Second, the location of the nucleophilic water molecule in the active site of the fully relaxed enzyme-substrate complex was determined by evaluation of nonbonded interaction energies between the complex and a water molecule. The nucleophilic water molecule is positioned at a distance (3.8 A) from the phosphorus atom in the substrate, which is in good agreement with experimentally observed distances. Finally, the stability of the complex between phospholipase C, the substrate, and the nucleophilic water molecule was verified during a 100 ps molecular dynamics simulation. During the simulation the substrate undergoes a conformational change, but retains its localization in the active site. The contacts between the enzyme, the substrate, and the nucleophilic water molecule display some fluctuations, but remain within reasonable limits, thereby confirming the stability of the enzyme-substrate-water complex. The protocol developed for energy minimization of phospholipase C containing three zinc ions located closely together at the bottom of the active site cleft is reported in detail. In order to handle the strong electrostatic interactions in the active site realistically during energy minimization, delocalization of the charges from the three zinc ions was considered. Therefore, quantum mechanics calculations on the zinc ions and the zinc-coordinating residues were carried out prior to the molecular mechanics calculations, and two different sets of partial atomic charges (MNDO-Mulliken and AMI-ESP) were applied. After careful assignment of partial atomic charges, a complete energy minimization of the protein was carried out by a stepwise procedure without explicit solvent molecules. Energy minimization with either set of charges yielded structures, which were very similar both to the x-ray structure and to each other, although using AMI-ESP partial atomic charges and a dielectric constant of 4, yielded the best protein structure.
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PMID:Substrate binding and catalytic mechanism in phospholipase C from Bacillus cereus: a molecular mechanics and molecular dynamics study. 927 25

An endonuclease named DNase gamma has been purified from the nuclei of apoptotic rat thymocytes [Shiokawa, Ohyama, Yamada and Tanuma (1997) Biochem. J. 326, 675-681]. Here we report the molecular cloning of a cDNA encoding a 35 kDa precursor protein for rat DNase gamma. A 1.6 kb mRNA coding for the DNase gamma precursor is detected at high levels in spleen, lymph nodes, thymus and liver. By using reverse transcriptase-mediated PCR, expression of DNase gamma mRNA is observed in kidney and testis but not in brain or heart. Analysis of recombinant DNase gamma reveals that full-length DNase gamma, including the N-terminal precursor, is an inactive proenzyme. The mature form of recombinant DNase gamma, from which the N-terminal precursor has been removed, has the same properties as purified DNase gamma: requirement for divalent cations, dependence on pH, sensitivity to Zn2+, and cleavage of chromosome DNA to nucleosomal units. In HeLa S3 cells stably transfected with the DNase gamma cDNA, exogenously introduced DNase gamma is activated by apoptotic stimuli; enhancement of DNA fragmentation, chromatin condensation and nuclear collapse are observed. These findings provide evidence for the involvement of DNase gamma in DNA fragmentation and nuclear structural changes during apoptosis.
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PMID:Molecular cloning and expression of a cDNA encoding an apoptotic endonuclease DNase gamma. 962 Aug 74


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