Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three different phosphatases ("slow", "middle" and "fast") were found in Amoeba proteus (strain B) after PAGE and a subsequent gel staining in 1-naphthyl phosphate containing incubation mixture (pH 9.0). Substrate specificity of these phosphatases was determined in supernatants of homogenates using inhibitors of phosphatase activity. All phosphatases showed a broad substrate specificity. Of 10 tested compounds, p-nitrophenyl phosphate was a preferable substrate for all 3 phosphatases. All phosphatases were able to hydrolyse bis-p-nitrophenyl phosphate and, hence, displayed phosphodiesterase activity. All phosphatases hydrolysed O-phospho-L-tyrosine to a greater or lesser degree. Only little differences in substrate specificity of phosphatases were noticed: 1) "fast" and "middle" phosphatases hydrolysed naphthyl phosphates and O-phospho-L-tyrosine less efficiently than did "slow" phosphatase; 2) "fast" and "middle" phosphatases hydrolysed 2- naphthyl phosphate to a lesser degree than 1-naphthyl phosphate 3) "fast" and "middle" phosphatases hydrolysed O-phospho-L-serine and O-phospho-L-threonine with lower intensity as compared with "slow" phosphatase; 4) as distinct from "middle" and "slow" phosphatases, the "fast" phosphatase hydrolysed glucose-6-phosphate very poorly. The revealed broad substrate specificity of "slow" phosphatase together with data of inhibitory analysis and results of experiments with reactivation of this phosphatase by Zn2+-ions after its inactivation by EDTA strongly suggest that only the "slow" phosphatase is a true alkaline phosphatase (EC 3.1.3.1). The alkaline phosphatase of A. proteus is secreted into culture medium where its activity is low. The enzyme displays both phosphomono- and phosphodiesterase activities, in addition to supposed protein phosphatase activity. It still remains unknown, to which particular phosphatase class the amoeban "middle" and "fast" phosphatases (pH 9.0) may be assigned.
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PMID:[Substrate specifity in Amoeba proteus]. 1708 51

Elevation of the zinc-binding protein metallothionein (MT) in the heart inhibits doxorubicin (DOX)-induced myocardial apoptosis and heart hypertrophy. Zinc release from MT in response to oxidative stress has been suggested as a mechanism of action of MT protection from DOX toxicity, and calcineurin is involved in the signaling pathways leading to myocardial apoptosis and heart hypertrophy. The present study was undertaken to determine if zinc can modulate the DOX-activated calcineurin signaling pathway. H9c2 cells were treated with 1 muM DOX, and zinc release was monitored by a zinc ion-specific fluorophore, zinquin ethyl ester. Additionally, DOX-activated calcineurin signaling was detected by a calcineurin-dependent nuclear factor of activated T-cell reporter. DOX treatment induced an increase in intracellular labile zinc and activated calcineurin signaling. Pretreatment of H9c2 cells with a zinc-specific, membrane-permeable chelating agent, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), inhibited the increase in intracellular labile zinc and increased the DOX-activated calcineurin signaling. Pretreatment of H9c2 cells with exogenously added zinc attenuated the DOX-activated calcineurin signaling in a dose-dependent manner. However, neither TPEN nor addition of exogenous zinc affected DOX-induced cellular hypertrophy or DOX-induced decrease in cell viability. Additionally, inhibition of DOX-induced calcineurin signaling with the calcineurin inhibitors cyclosporine A or tacrolimus (FK506) failed to restrict the DOX-induced decrease in cell viability. These results indicate that zinc suppresses DOX-induced calcineurin signaling in H9c2 cells; however, calcineurin signaling is not involved in the DOX-induced decrease in cell viability in H9c2 cells. (It had been shown previously that calcineurin is also not necessary for DOX-induced H9c2 cell hypertrophy.).
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PMID:Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells. 1746 65

The small t antigen (ST) of DNA tumor virus SV40 facilitates cellular transformation by disrupting the functions of protein phosphatase 2A (PP2A) through a poorly defined mechanism. The crystal structure of the core domain of SV40 ST bound to the scaffolding subunit of human PP2A reveals that the ST core domain has a novel zinc-binding fold and interacts with the conserved ridge of HEAT repeats 3-6, which overlaps with the binding site for the B' (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B' for the PP2A core enzyme. Consequently, ST does not efficiently displace B' from PP2A holoenzymes in vitro. Notably, ST inhibits PP2A phosphatase activity through its N-terminal J domain. These findings suggest that ST may function mainly by inhibiting the phosphatase activity of the PP2A core enzyme, and to a lesser extent by modulating assembly of the PP2A holoenzymes.
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PMID:Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. 1752 92

Escherichia coli YfcE belongs to a conserved protein family within the calcineurin-like phosphoesterase superfamily (Pfam00149) that is widely distributed in bacteria and archaea. Superfamily members are metallophosphatases that include monoesterases and diesterases involved in a variety of cellular functions. YfcE exhibited catalytic activity against bis-p-nitrophenyl phosphate, a general substrate for phosphodiesterases, and had an absolute requirement for Mn2+. However, no activity was observed with phosphodiesters and over 50 naturally occurring phosphomonoesters. The crystal structure of the YfcE phosphodiesterase has been determined to 2.25 A resolution. YfcE has a beta-sandwich architecture similar to metallophosphatases of common ancestral origin. Unlike its more complex homologs that have added structural elements for regulation and substrate recognition, the relatively small 184-amino-acid protein has retained its ancestral simplicity. The tetrameric protein carries two zinc ions per active site from the E. coli extract that reflect the conserved di-Mn2+ active site geometry. A cocrystallized sulfate inhibitor mimics the binding of phosphate moeities in known ligand/phosphatase complexes. Thus, YfcE has a similar active site and biochemical mechanism as well-characterized superfamily members, while the YfcE phosphodiester-containing substrate is unique.
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PMID:Structural and biochemical characterization of a novel Mn2+-dependent phosphodiesterase encoded by the yfcE gene. 1758 69

The Down syndrome (DS) candidate region gene 1 (DSCR1) is localized near DS critical region on chromosome 21 and is overexpressed in the brains of DS patients. Although DSCR1 was known for a modulator of calcineurin, the overexpression of DSCR1 is thought to play a role in neuronal cell death. Zinc, one of the most abundant transition metals in the brain, may also contribute to selective neuronal cell death when present in excessive amounts. In the present study, we investigated the effect of DSCR1 overexpression on zinc-induced cell death in hippocampal neuroprogenitor cells. The overexpression of DSCR1 caused apoptotic cell death without an apparent formation of intracellular protein inclusions. Upon exposure to zinc, soluble DSCR1 levels were significantly decreased and insoluble levels were enhanced to a similar extent, which were partially caused by the zinc-induced inhibition of proteasomal activity and a consequently diminished degradation of DSCR1. Furthermore, zinc treatment induced the formation of nuclear DSCR1 aggregates, which blocked zinc-induced cell death. These findings indicate that, although the up-regulation of DSCR1 levels exerts a cytotoxic effect, the addition of zinc leads to the formation of cytoprotective nuclear aggregates in neuronal cells.
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PMID:Overexpression of DSCR1 blocks zinc-induced neuronal cell death through the formation of nuclear aggregates. 1759 61

The SV40 small t antigen (ST) is a potent oncoprotein that perturbs the function of protein phosphatase 2A (PP2A). ST directly interacts with the PP2A scaffolding A subunit and alters PP2A activity by displacing regulatory B subunits from the A subunit. We have determined the crystal structure of full-length ST in complex with PP2A A subunit at 3.1 A resolution. ST consists of an N-terminal J domain and a C-terminal unique domain that contains two zinc-binding motifs. Both the J domain and second zinc-binding motif interact with the intra-HEAT-repeat loops of HEAT repeats 3-7 of the A subunit, which overlaps with the binding site of the PP2A B56 subunit. Intriguingly, the first zinc-binding motif is in a position that may allow it to directly interact with and inhibit the phosphatase activity of the PP2A catalytic C subunit. These observations provide a structural basis for understanding the oncogenic functions of ST.
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PMID:Structural basis of PP2A inhibition by small t antigen. 1760 67

Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.
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PMID:Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase. 1800 Aug 19

Oxidative stress induced by glutathione depletion in the mouse HT22 neuroblastoma cell line and embryonic rat immature cortical neurons causes a delayed, sustained activation of extracellular signal-regulated kinase (ERK) 1/2, which is required for cell death. This sustained activation of ERK1/2 is mediated primarily by a selective inhibition of distinct ERK1/2-directed phosphatases either by enhanced degradation (i.e., for mitogen-activated protein kinase phosphatase-1) or as shown here by reductions in enzymatic activity (i.e., for protein phosphatase type 2A). The inhibition of ERK1/2 phosphatases in HT22 cells and immature neurons subjected to glutathione depletion results from oxidative stress because phosphatase activity is restored in cells treated with the antioxidant butylated hydroxyanisole. This leads to reduced ERK1/2 activation and neuroprotection. Furthermore, an increase in free intracellular zinc that accompanies glutathione-induced oxidative stress in HT22 cells and immature neurons contributes to selective inhibition of ERK1/2 phosphatase activity and cell death. Finally, ERK1/2 also functions to maintain elevated levels of zinc. Thus, the elevation of intracellular zinc within neurons subjected to oxidative stress can trigger a robust positive feedback loop operating through activated ERK1/2 that rapidly sets into motion a zinc-dependent pathway of cell death.
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PMID:Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death. 1863 68

Zinc, which is essential for many cellular processes, is controlled by zinc transporters and through buffering by metallothioneins and glutathione. Although zinc is increasingly implicated in disease states, little is known about how zinc regulates cellular biochemical pathways. Recent seminal articles have revealed discrete zinc-trafficking pathways that are linked to signalling cascades, particularly those involving protein phosphatase inhibition and downstream activation of mitogen-activated protein kinases and tyrosine kinases. Here, we discuss the mechanisms of cellular zinc homeostasis, and we propose an important role for the zinc transporter solute carrier family 39, member 7 (SLC39A7; commonly referred to as ZIP7). ZIP7 releases zinc from the endoplasmic reticulum and might be required for tyrosine kinase activation. These observations position ZIP7 at a critical node in zinc-mediated tyrosine kinase signalling and suggest that this protein might form a novel target for diseases such as cancer where prevention of tyrosine kinase activation would be therapeutically advantageous.
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PMID:Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. 1924 44

The trace element zinc is a crucial cofactor for many proteins involved in cellular processes like differentiation, proliferation and apoptosis. Zinc homeostasis is tightly regulated and disturbance of this homeostasis due to genetic defects, zinc deficiency, or supplementation influences the development and the progression of various infectious and autoimmune diseases. The immune system is strongly impaired during zinc deficiency, predominantly the cell-mediated response by T-lymphocytes. During zinc deprivation T-lymphocyte development, polarization into effector cells, and function are impaired. This leads to reduced T-cell numbers, a decreased ratio of type 1 to type 2 T-helper cells with reduced production of T-helper type 1 cytokines like interferon-gamma, and compromised T-cell mediated immune defense. Accordingly, disturbed zinc homeostasis increases the risk for infections, and zinc supplementation restores normal immune function. Furthermore, several disorders, like mycobacterial infections, asthma, diabetes, and rheumatoid arthritis are accompanied by decreased zinc levels and in some cases disease progression can be affected by zinc supplementation. On the molecular level, apoptosis of T-cell precursors is influenced by zinc via the Bcl-2/Bax ratio, and zinc ions inhibit caspases-3, -6, -7, and -8. In mature T-cells, zinc interacts with kinases involved in T-cell activation, like protein kinase C and the lymphocyte protein tyrosine kinase (Lck), while higher zinc concentrations are inhibitory, reducing the activities of the interleukin-1 receptor-associated kinase (IRAK) and calcineurin. Taken together, zinc homeostasis influences T-lymphocytes via several molecular targets, leading to a modulation of T-cell-dependent immune responses.
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PMID:T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. 1951 63


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