Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcineurin, a calmodulin-activated protein phosphatase, is known to dephosphorylate certain low molecular weight phosphate esters. The low molecular weight phosphatase activity of calcineurin has been studied by utilizing tyrosine phosphate derivatives. Kinetic studies suggest that the substrate specificity is dependent upon the electronic nature of the substrate in contrast to results obtained with alkaline phosphatase from Escherichia coli. Comparison of calcineurin and acid-catalyzed hydrolyses indicates a 1:1 correlation between the rate constants for the two processes. This correlation and other model studies have been utilized to provide insight into the chemical mechanism of calcineurin. Possible chemical mechanisms for calcineurin are discussed.
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PMID:Use of fluorinated tyrosine phosphates to probe the substrate specificity of the low molecular weight phosphatase activity of calcineurin. 241 11

Similar to previous observations with cyclosporins and didemnin B, the novel immunosuppressant FK-506 inhibits the Ca2+/calmodulin-dependent phosphorylation of the eukaryotic elongation factor 2 of protein synthesis in vitro and biological effects of the phorbol ester TPA on mouse skin in vivo. These effects include the induction of the ear edema and the stimulation of alkaline phosphatase activity. FK-506 neither activates nor inhibits protein kinase C in vitro. FK-506 does not compete with cyclosporin A for the high-affinity binding sites in mouse epidermis cytosol.
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PMID:The immunosuppressant FK-506, like cyclosporins and didemnin B, inhibits calmodulin-dependent phosphorylation of the elongation factor 2 in vitro and biological effects of the phorbol ester TPA on mouse skin in vivo. 247 85

The involvement of inositol lipid metabolism in agonist-mediated Ca2+ signaling by Ins 1,4,5-P3 has become firmly established. Recent advances have led to a better understanding of the proteins associated with signal transduction in the plasma membrane. A number of specific receptors (G proteins, phospholipases and inositol lipid kinases) have now been purified and characterized. An Ins 1,4,5-P3 receptor has also been purified which is presumably involved in mediating Ca2+ efflux from intracellular stores. The morphological site of the hormone-sensitive Ca2+ pool has been tentatively identified as discrete, specialized intracellular structures (calciosomes), but further studies are required to demonstrate that these contain Ins 1,4,5-P3-gated Ca2+ channels and their possible functional relationship to the plasma membrane. Receptor occupancy by Ca2+ mobilizing agonists also stimulates Ca2+ entry into the cell, but the mechanism for activation of voltage insensitive Ca2+ channels and the possible involvement of Ins 1,4,5-P3, Ins 1,3,4,5-P4 and/or G proteins in this process has not been established. The Ca2+ signaling pathway is subject to multisite feedback regulation by Ca2+ itself and by a diacylglycerol-mediated activation of protein kinase C. Potential sites for Ca2+ interaction are displacement of Ins 1,4,5-P3 from its receptor by a Ca2+-dependent mechanism, promotion of Ins 1,3,4,5-P4 formation by the Ca2+/calmodulin-regulated Ins 1,4,5-P3 3-kinase, and efflux of Ca2+ from the cell or sequestration into intracellular Ca2+ stores by Ca2+/calmodulin-regulated Ca2+-ATPases. Protein kinase C activation potentially affects the rate of generation of Ins 1,4,5-P3 by negative feedback to the receptor-G protein-phospholipase C transduction system and possibly also the rate of Ins 1,4,5-P3 degradation by activation of an inositol polyphosphate 5-phosphomonoesterase. It may also attenuate the Ca2+ transient directly by increasing the activity of Ca2+-ATPases associated with the plasma membrane and the endoplasmic reticulum. Cell-to-cell heterogeneity in the relative control strengths of these different mechanisms may explain the differences in the Ca2+ signal in different tissues and even in different cells within a population. The ability of Ca2+ and protein kinase C to provide negative feedback at various points in the signal transduction pathway suggests that a complex mechanism involving multiple feedback loops is likely to regulate the generation of Ca2+ oscillations seen in some cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormone effects on cellular Ca2+ fluxes. 249 41

The effects of phorbol ester or calmodulin on the calcium and phosphorus uptakes by rat tissues and their relationship to the alkaline phosphatase activity (ALP) were investigated in vivo. In rat tissues, ALP activity and calcium uptake in the duodenum and liver were clearly induced by phorbol ester treatment, whereas in the calvarium and ileum they were decreased. Phosphorus uptake was increased by the administration of phorbol ester only in the calvarium. In rats pretreated with an injection of indomethacin as an inhibitor of prostaglandin-synthesizing enzyme, the selective uptake of calcium by phorbol ester was eliminated in the duodenum and liver, as was the ALP activity. In contrast, rats showed a marked increase in ALP activity in the ileum after calmodulin treatment. Moreover, the increased uptake of calcium after calmodulin treatment was clearly seen in the ileum, calvarium, and kidney, and an increased uptake in phosphorus was seen in the duodenum, ileum, and calvarium, but not in kidney. Furthermore, prior injection of W-7 or calmidazolium as an antagonist of calmodulin, reduced the increased ALP activities and the uptake of calcium in all organs tested, but did not reduce the increased phosphorus uptake by the calvarium. Consequently, it is suggested that calcium uptake under the above conditions correlated well with changes in the ALP activity; however, phosphorus uptake seemed to be less in accord with ALP activity. The amount of tested other mineral metabolic markers suggests that the Ca uptake and ALP activity induced by certain effectors regulate 1,25(OH)2D3 level by the modulation of 25(OH)D3-1 alpha-hydroxylase activity.
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PMID:Relationship between the uptake of calcium or phosphorus and alkaline phosphatase activity induced by certain modulators in rat organs. 250 9

In a previous report we have shown that microtubule-associated protein tau can be induced to form paracrystals (Lichtenberg, B., E.-M. Mandelkow, T. Hagestedt, and E. Mandelkow. 1988. Nature [Lond.]. 334:359-362). A striking feature was the high degree of elasticity of the molecules. We now report that this property is related to the state of phosphorylation. When tau is dephosphorylated by alkaline phosphatase, it becomes shorter and more elastic; when it is phosphorylated by Ca++/calmodulin-dependent kinase, it becomes longer and stiffer. This may provide a model for the control of structural properties of tau-like molecules by phosphorylation.
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PMID:Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. 250 54

The mechanism of calmodulin-stimulated alkaline phosphatase activity was studied in the rat. In calmodulin-treated rats (2.5 micrograms/animal, intraperitoneally) alkaline phosphatase (ALP) activity was elevated 11-fold in the ileum, 1.5-fold in the duodenum and calvarium, 3-fold in serum, and not at all in liver. The elevated ALP activity was prevented by prior treatment with flunarizine, a calcium channel blocker, and by W-7, a calmodulin antagonist. cAMP content in ileum paralleled the timing and changes in ALP activity, but was not elevated in the duodenum or calvarium. Calcium ionophore A23187 and calcitonin treatment also increased ileal, duodenal, and calvarial ALP activity, but by less than the response to calmodulin. All of these treatments caused a 2-fold elevation in serum 1,25-dihydroxyvitamin D-3 (1,25(OH)2D3) levels. Pretreatment of the animals with parathyroid hormone prevented the rise of both ALP activity and of 1,25(OH)2D3. Administration of 1,25(OH)2D3 alone stimulated a different pattern of increased ALP activity, greater in duodenum than ileum. The uptake of 45Ca by calmodulin was also elevated in ileum and calvarium. These data suggest that shifts in calcium movement, perhaps mediated by vitamin D, can alter ALP activity, and may provide a mechanism for rapid control of the secretion of this enzyme.
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PMID:Rat ileal alkaline phosphatase activity and secretion is stimulated by alterations in calcium metabolism. 253 9

The intestinal absorption of calcium is certainly a complex process, dependent on several factors of which vitamin D, via 1,25(OH)2D3, is the major controlling hormone. The efficiency of calcium absorption is a function of calcium status and calcium need. As the body's demand for calcium increases, the process commonly termed, adaptation, is activated in which the synthesis of 1,25(OH)2D3 from precursor is increased, resulting in the stimulation of the rate of calcium absorption. The increased demand for calcium might result from the ingestion of a diet deficient in calcium, from growth, pregnancy, lactation and egg shell formation in the laying hen. Accomapanying the change in calcium absorptive efficiency are molecular modifications of the transporting enterocytes, some mentioned herein and elsewhere (Wasserman & Chandler, 1985; Wasserman, 1980; Wasserman et al., 1984). Highly correlated with the rate of calcium absorption under a wide variety of conditions is the concentration of the vitamin D-induced calcium-binding protein, calbindin-D28K (avian type) and calbindin-D9K (mammalian intestinal type). The role of calbindin-D in this transport process is not precisely known but is considered to act at the present time as a cytosolic facilitator of Ca2+ diffusion from the brush border membrane to the basolateral membrane. In addition to the induction of calbindin-D synthesis, 1,25(OH)2D3 exerts other effects on the intestinal epithelium that can have consequences on the calcium absorptive process. Some of these effects are summarized in Figure 14. Vitamin D-dependent reactions might be either direct effects of 1,25(OH)2D3 or indirect effects due to elevated intracellular Ca2+ concentrations. These include changes in the fluidity of the brush border membrane, an increase in microvillar alkaline phosphatase-low affinity Ca-activated ATPase activity, an association of calmodulin with the 105 kD brush border cytoskeletal protein and, following calbindin D synthesis, the binding of calbindin D to a 60 kD brush border protein and to microtubules. The latter has been suggested to be related to the proposed transfer of Ca2+ by an endocytotic-exocytotic mechanism. In addition, a vitamin D-dependent intestinal membrane calcium-binding protein has been identified (Kowarski & Schachter, 1980). Playing into this multi-component system is a stimulation of cyclic nucleotide synthesis by 1,25(OH)2D3 which, through activation of cyclic nucleotide-dependent protein kinases, might modify membrane Ca2+ "channels" by phosphorylation reactions.4+ Intracellular organelles, i.e., the endoplasmic reticulum, mitochondria, the Golgi apparatus, are potent sequesters of Ca2+ and could contribute to the protection of the cell from excessively high Ca2+ concentrations by transiently storing absorbed Ca2+.
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PMID:On the molecular mechanism of intestinal calcium transport. 254 94

The activities of intestinal brush border membrane (BBM) enzymes alkaline phosphatase, maltase, lactase, sucrase, gamma-glutamyl transpeptidase and leucine aminopeptidase were determined in intestinal homogenates and purified BBMs from control, heat-stable and heat-labile enterotoxin treated mice. The activities of all the enzymes except lactase were decreased significantly (p less than 0.01) in homogenates while increased significantly (p less than 0.001) in BBMs of experimental groups as compared to controls. Calmodulin activities were increased significantly (p less than 0.01) as compared to control in heat-stable enterotoxin treated mice but remained unaltered in heat-labile enterotoxin treated mice. DNA contents of intestinal homogenates were decreased in experimental groups demonstrating the decrease in cell number in these groups. The altered BBM enzyme activities could not be attributed to changes in calmodulin activities. The increase in enzyme activities in BBMs may reflect a compensatory phenomenon in the remaining cells.
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PMID:Effect of heat-stable and heat-labile enterotoxins of Escherichia coli on intestinal brush border membrane enzymes of mice. 257 May 78

During early sexual development in Dictyostelium discoideum cell and pronuclear fusion are negatively regulated by an endogenous autoinhibitor. Here, the autoinhibitor was partially purified from the culture medium and found to inhibit both cell and pronuclear fusion while augmenting gamete numbers. These developmental effects suggested that calmodulin might be an intracellular target for the autoinhibitor. In support of this data, the partially purified autoinhibitor inhibited the calmodulin-dependent activation of phosphodiesterase in a dose-dependent manner, but had no effect on either a calmodulin-insensitive form of phosphodiesterase or the calmodulin-independent enzymes acid and alkaline phosphatase. Thus, the autoinhibitor of sexual development in Dictyostelium discoideum appears to regulate cell and pronuclear fusion at least in part by a direct effect on calmodulin.
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PMID:The autoinhibitor of cell fusion in Dictyostelium inhibits calmodulin. 259 Jan 96

Calmodulin, an acidic protein that binds calcium with high affinity, has multiple roles in the activation of many enzymes involved in cellular regulation of eukaryotes. In this study we show that calmodulin binding to hen egg-white lysozyme, in a Ca2+-dependent way, was observed using electroblots incubated with biotinylated calmodulin and detected with avidin-alkaline phosphatase or for affinity chromatography on a gel calmodulin column. Antimicrobial activity of lysozyme was not modified in the presence of Ca2+-calmodulin.
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PMID:Calcium-dependent binding between calmodulin and lysozyme. 270 47


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