scholarly journals Arabidopsis inositol polyphosphate kinases regulate COP9 signalosome functions in phosphate-homeostasis

2020 ◽  
Author(s):  
Yashika Walia ◽  
Kishor D Ingole ◽  
Mritunjay Kasera ◽  
Swaroop Peddiraju ◽  
Debabrata Laha ◽  
...  
Keyword(s):  
Molecular Level ◽  
Inositol Phosphate ◽  
Phosphate Starvation ◽  
Early Response ◽  
Cop9 Signalosome ◽  
Adaptation To Stress ◽  
Inositol Polyphosphate ◽  
Phosphate Homeostasis ◽  
E3 Ligases ◽  
Kinetics Of

AbstractTargeted protein degradation is essential for physiological development and adaptation to stress. Mammalian INOSITOL PENTAKISPHOSPHATE KINASE (IP5K) and INOSITOL HEXAKISPHOSPHATE KINASE 1 (IP6K1) pair modulates functions of Cullin RING Ubiquitin E3 ligases (CRLs) that execute targeted degradation of substrates. Coordinated activities of these kinases protect CRLs on a COP9 signalosome (CSN) platform and stimulates deneddylation-dependent disassembly to maintain continuity of its functions. In plants, CRL regulations on CSN by inositol phosphate (InsP) kinases are not known. Here, we show interactions of Arabidopsis thaliana INOSITOL PENTAKISPHOSPHATE 2-KINASE 1 (IPK1) and INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE 1 (ITPK1), counterparts of the above InsP-kinase pair, with CSN subunits and its positive influences on the dynamics of cullin deneddylation. We identify neddylation enhancements on CRLs as an early response to phosphate-starvation and its orchestration by perturbed IPK1/ITPK1 activities. At a molecular level, specific kinetics of CSN5 deneddylase is affected by the above InsP-kinases. Overall, our data reveal conserved InsP-kinase involvements on CRL-CSN synergism in plants.

scholarly journals Disruption of inositol biosynthesis through targeted mutagenesis in Dictyostelium discoideum: generation and characterization of inositol-auxotrophic mutants

2006 ◽  
Vol 397 (3) ◽  
pp. 509-518 ◽  
Author(s):  
Andreas Fischbach ◽  
Stephan Adelt ◽  
Alexander Müller ◽  
Günter Vogel
Keyword(s):  
Dictyostelium Discoideum ◽  
Genetic Manipulation ◽  
Inositol Phosphate ◽  
Targeted Mutagenesis ◽  
Inositol Polyphosphate ◽  
Fluid Medium ◽  
Physiological Processes ◽  
Evolutionarily Conserved ◽  
Cellular Slime

myo-Inositol and its downstream metabolites participate in diverse physiological processes. Nevertheless, considering their variety, it is likely that additional roles are yet to be uncovered. Biosynthesis of myo-inositol takes place via an evolutionarily conserved metabolic pathway and is strictly dependent on inositol-3-phosphate synthase (EC 5.5.1.4). Genetic manipulation of this enzyme will disrupt the cellular inositol supply. Two methods, based on gene deletion and antisense strategy, were used to generate mutants of the cellular slime mould Dictyostelium discoideum. These mutants are inositol-auxotrophic and show phenotypic changes under inositol starvation. One remarkable attribute is their inability to live by phagocytosis of bacteria, which is the exclusive nutrient source in their natural environment. Cultivated on fluid medium, the mutants lose their viability when deprived of inositol for longer than 24 h. Here, we report a study of the alterations in the first 24 h in cellular inositol, inositol phosphate and phosphoinositide concentrations, whereby a rapidly accumulating phosphorylated compound was detected. After its identification as 2,3-BPG (2,3-bisphosphoglycerate), evidence could be found that the internal disturbances of inositol homoeostasis trigger the accumulation. In a first attempt to characterize this as a physiologically relevant response, the efficient in vitro inhibition of a D. discoideum inositol-polyphosphate 5-phosphatase (EC 3.1.3.56) by 2,3-BPG is presented.

scholarly journals Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Megan T. Lewno ◽  
Taixing Cui ◽  
Xuejun Wang
Keyword(s):  
Ubiquitin Proteasome System ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Cop9 Signalosome ◽  
E3 Ligases ◽  
Protein Subunits ◽  
Unique Protein ◽  
Recent Advances ◽  
Regulated Necrosis ◽  
Ubiquitin Proteasome ◽  
Apoptosis And Necrosis

Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

scholarly journals Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

2015 ◽  
Vol 112 (31) ◽  
pp. 9751-9756 ◽  
Author(s):  
Ishrat Ahmed ◽  
Juan I. Sbodio ◽  
Maged M. Harraz ◽  
Richa Tyagi ◽  
Jonathan C. Grima ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Kinase Activity ◽  
Inositol Phosphate ◽  
Cell Model ◽  
Inositol Polyphosphate ◽  
Interacting Protein ◽  
Lipid Kinase ◽  
Inositol Polyphosphate Multikinase ◽  
Neural Dysfunction

Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.

THE ALTERATION OF INTRACELLULAR ENZYMES: IV. KINETICS OF CATALASE ALTERATION INDUCED BY CHEMICAL AGENTS

1956 ◽  
Vol 34 (1) ◽  
pp. 25-38
Author(s):  
J. Gordin Kaplan ◽  
Woon-Ki Paik
Keyword(s):  
Molecular Level ◽  
Narrow Range ◽  
Intact Cell ◽  
Cellular Level ◽  
Causal Connection ◽  
Rate Limiting Step ◽  
Chemical Agents ◽  
The Difference ◽  
Rate Limiting ◽  
Kinetics Of

The rate with which n-butanol alters the properties of yeast catalase has been studied as a function of temperature and concentration of altering agent. Activation energies for catalase alteration lay within the rather narrow range of 20–23 kcal./mole, thus confirming a prediction made previously on the basis of the difference in energies of activation for heat destruction of altered and unaltered catalases. Alteration by optimal concentration of butanol was a reaction of zero order. Chloroform also altered yeast catalase with an activation energy within this range of μ values. The close agreement in μ values leads us to conclude that the action of these two altering agents, at all concentrations, is characterized by the same rate-limiting step, even though their action differs in other respects. It was concluded that catalase alteration is probably all-or-none on the molecular level, rather than on the cellular level. Alteration was invariably accompanied by a decrease in the size of the treated cells; alteration was sometimes accompanied by changes in the cytochrome spectrum, but there was no causal connection between these two events. These data are consistent with the interfacial hypothesis, which, in its present crude form, pictures alteration as consisting essentially in the desorption of catalase from some intracellular interface at which it is normally bound in the intact cell.

scholarly journals Structure of Fission Yeast Transcription Factor Pho7 Bound to pho1 Promoter DNA and Effect of Pho7 Mutations on DNA Binding and Phosphate Homeostasis

2019 ◽  
Vol 39 (13) ◽  
Author(s):  
Angad Garg ◽  
Yehuda Goldgur ◽  
Ana M. Sanchez ◽  
Beate Schwer ◽  
Stewart Shuman
Keyword(s):  
Dna Binding ◽  
Fission Yeast ◽  
Dna Sequences ◽  
Phosphate Starvation ◽  
Transcriptional Factor ◽  
Target Site ◽  
Site Specificity ◽  
Phosphate Homeostasis ◽  
Content Type ◽  
Promoter Dna

ABSTRACT Pho7 is the Schizosaccharomyces pombe fission yeast Zn2Cys6 transcriptional factor that drives a response to phosphate starvation in which phosphate acquisition genes are upregulated. Here we report a crystal structure at 1.6-Å resolution of the Pho7 DNA-binding domain (DBD) bound at its target site 2 in the pho1 promoter (5′-TCGGAAATTAAAAA). Comparison to the previously reported structure of Pho7 DBD in complex with its binding site in the tgp1 promoter (5′-TCGGACATTCAAAT) reveals shared determinants of target site specificity as well as variations in the protein-DNA interface that accommodate different promoter DNA sequences. Mutagenesis of Pho7 amino acids at the DNA interface identified nucleobase contacts at the periphery of the footprint that are essential for the induction of pho1 expression in response to phosphate starvation and for Pho7 binding to site 1 in the pho1 promoter.

Kinetics and Mechanism of Cationic Micelle/Flexible Nanoparticle Catalysis: A Review

2018 ◽  
Vol 43 (1) ◽  
pp. 1-20 ◽  
Author(s):  
Mohammad Niyaz Khan ◽  
Ibrahim Isah Fagge
Keyword(s):  
Rate Increase ◽  
Molecular Level ◽  
Binding Constants ◽  
Exchange Constant ◽  
Interior Region ◽  
Bimolecular Reactions ◽  
Exterior Region ◽  
Different Shapes ◽  
Molecular Origin ◽  
Kinetics Of

The aqueous surfactant (Surf) solution at [Surf] > cmc (critical micelle concentration) contains flexible micelles/nanoparticles. These particles form a pseudophase of different shapes and sizes where the medium polarity decreases as the distance increases from the exterior region of the interface of the Surf/H2O particle towards its furthest interior region. Flexible nanoparticles (FNs) catalyse a variety of chemical and biochemical reactions. FN catalysis involves both positive catalysis ( i.e. rate increase) and negative catalysis ( i.e. rate decrease). This article describes the mechanistic details of these catalyses at the molecular level, which reveals the molecular origin of these catalyses. Effects of inert counterionic salts (MX) on the rates of bimolecular reactions (with one of the reactants as reactive counterion) in the presence of ionic FNs/micelles may result in either positive or negative catalysis. The kinetics of cationic FN (Surf/MX/H2O)-catalysed bimolecular reactions (with nonionic and anionic reactants) provide kinetic parameters which can be used to determine an ion exchange constant or the ratio of the binding constants of counterions.

Molecular-Level Kinetic Modeling of Methyl Laurate: The Intrinsic Kinetics of Triglyceride Hydroprocessing

2018 ◽  
Vol 32 (4) ◽  
pp. 5264-5270 ◽  
Author(s):  
Pratyush Agarwal ◽  
Nicholas Evenepoel ◽  
Sulaiman S. Al-Khattaf ◽  
Michael T. Klein
Keyword(s):  
Kinetic Modeling ◽  
Molecular Level ◽  
Methyl Laurate ◽  
Intrinsic Kinetics ◽  
Kinetics Of

scholarly journals Arabidopsis inositol phosphate kinases IPK1 and ITPK1 constitute a metabolic pathway in maintaining phosphate homeostasis

2018 ◽  
Vol 95 (4) ◽  
pp. 613-630 ◽  
Author(s):  
Hui-Fen Kuo ◽  
Yu-Ying Hsu ◽  
Wei-Chi Lin ◽  
Kai-Yu Chen ◽  
Teun Munnik ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Inositol Phosphate ◽  
Phosphate Homeostasis

scholarly journals Rapid accumulation and sustained turnover of inositol phosphates in cerebral-cortex slices after muscarinic-receptor stimulation

1989 ◽  
Vol 260 (1) ◽  
pp. 237-241 ◽  
Author(s):  
I H Batty ◽  
S R Nahorski
Keyword(s):  
Cerebral Cortex ◽  
Muscarinic Receptor ◽  
Metabolic Flux ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Receptor Activation ◽  
Inositol Polyphosphate ◽  
Receptor Stimulation ◽  
Cortex Slices ◽  
Rapid Kinetics

The rapid kinetics of [3H]inositol phosphate accumulation and turnover were examined in rat cerebral-cortex slices after muscarinic-receptor stimulation. Markedly increased [3H]inositol polyphosphate concentrations were observed to precede significant stimulated accumulation of [3H]inositol monophosphate. New steady-state accumulations of several 3H-labelled products were achieved after 5-10 min of continued agonist stimulation, but were rapidly and effectively reversed by subsequent receptor blockade. The results show that muscarinic-receptor activation involves phosphoinositidase C-catalysed hydrolysis initially of polyphosphoinositides rather than of phosphatidylinositol. Furthermore, prolonged carbachol stimulation is shown not to cause receptor desensitization, but to allow persistent hydrolysis of [3H]phosphatidylinositol bisphosphate and permit sustained metabolic flux through the inositol tris-/tetrakis-phosphate pathway.

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