Inhibition of E. coli CTP synthase by the “positive” allosteric effector GTP

MacDonnell, Jennifer E.; Lunn, Faylene A.; Bearne, Stephen L.

doi:10.1016/j.bbapap.2004.03.002

Cited by 16 publications

(19 citation statements)

References 35 publications

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“…Negative cooperativity for L-glutamine has also been described for Ec CTPS (Levitzki and Koshland, 1972 ) and Sc CTP1S (Yang et al, 1994 ). The activity of Tg CTPS depended on GTP concentration, as observed for other CTP synthases (Levitzki and Koshland, 1972 ; MacDonnell et al, 2004 ; Endrizzi et al, 2005 ; Steeves and Bearne, 2011 ). We observed activation at GTP <0.5 mM, and inhibition at >0.5 mM (Figure 3D ).…”

Section: Resultssupporting

confidence: 52%

“…Nucleotide metabolism is energetically costly and usually tightly controlled (Berg et al, 2002 ). CTP synthase is regulated at the transcriptional level (Wylie et al, 1996a ; Meng and Switzer, 2001 ; Jørgensen et al, 2003 ), allosterically at the enzymatic level (Willemoes and Larsen, 2003 ; MacDonnell et al, 2004 ; Endrizzi et al, 2005 ; Willemoes et al, 2005 ), and by post-translational modifications (Park et al, 2003 ; Chang et al, 2007 ; Choi and Carman, 2007 ; Kassel et al, 2010 ). The assembly of CTP synthase into cytoophidia has been proposed to be an additional mechanism of regulation, in which the enzymatic activity is controlled by storing the protein in polymers composed of inactive or less active protein in E. coli, S. cerevisiae and Drosophila (Aughey et al, 2014 ; Barry et al, 2014 ; Noree et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

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A CTP Synthase Undergoing Stage-Specific Spatial Expression Is Essential for the Survival of the Intracellular Parasite Toxoplasma gondii

Narvaez-Ortiz

Lopez

Gupta

et al. 2018

Front. Cell. Infect. Microbiol.

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Cytidine triphosphate synthase catalyzes the synthesis of cytidine 5′-triphosphate (CTP) from uridine 5′-triphosphate (UTP), the final step in the production of cytidine nucleotides. CTP synthases also form filamentous structures of different morphologies known as cytoophidia, whose functions in most organisms are unknown. Here, we identified and characterized a novel CTP synthase (TgCTPS) from Toxoplasma gondii. We show that TgCTPS is capable of substituting for its counterparts in the otherwise lethal double mutant (ura7Δ ura8Δ) of Saccharomyces cerevisiae. Equally, recombinant TgCTPS purified from Escherichia coli encodes for a functional protein in enzyme assays. The epitope-tagged TgCTPS under the control of its endogenous promoter displays a punctate cytosolic distribution, which undergoes spatial reorganization to form foci or filament-like structures when the parasite switches from a nutrient-replete (intracellular) to a nutrient-scarce (extracellular) condition. An analogous phenotype is observed upon nutrient stress or after treatment with a glutamine analog, 6-diazo-5-oxo-L-norleucine (DON). The exposure of parasites to DON disrupts the lytic cycle, and the TgCTPS is refractory to a genetic deletion, suggesting an essential requirement of this enzyme for T. gondii. Not least, this study, together with previous studies, supports that CTP synthase can serve as a potent drug target, because the parasite, unlike human host cells, cannot compensate for the lack of CTP synthase activity.

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Section: Resultssupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

A CTP Synthase Undergoing Stage-Specific Spatial Expression Is Essential for the Survival of the Intracellular Parasite Toxoplasma gondii

Narvaez-Ortiz

Lopez

Gupta

et al. 2018

Front. Cell. Infect. Microbiol.

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“…(Sivapalan et al, 2003) found that simple models with a small number of parameters can adequately describe a majority of catchment responses. A number of studies encouraged the use of catchment classification using a small number of explanatory variables to improve understanding and predictions (Bloschl and Sivapalan, 1995;Dooge, 1986;MacDonnell et al, 2004;Olden et al, 2012). (Olden and Poff, 2003) examined the transferability of hydrologic indices across 'stream types' by identifying indices that consistently explain dominant patterns of variance across streams in varying climatic and geologic environments, such that the selected hydrologic indices are adequate to characterize flow regimes yet without redundancy information, that is, with the parsimonious selection of hydrologic indices for future hydrogeological studies.…”

Section: Introductionmentioning

confidence: 99%

Classification of hydrological parameter sensitivity and evaluation of parameter transferability across 431 US MOPEX basins

Ren

Hou

Huang

et al. 2016

Journal of Hydrology

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The Community Land Model (CLM) represents physical, chemical, and biological processes of the terrestrial ecosystems that interact with climate across a range of spatial and temporal scales. As CLM includes numerous sub-models and associated parameters, the high-dimensional parameter space presents a formidable challenge for quantifying uncertainty and improving Earth system predictions needed to assess environmental changes and risks. This study aims to evaluate the potential of transferring hydrologic model parameters in CLM through sensitivity analyses and classification across watersheds from the Model Parameter Estimation Experiment (MOPEX) in the United States. The sensitivity of CLM-simulated water and energy fluxes to hydrological parameters across 431 MOPEX basins are first examined using an efficient stochastic sampling-based sensitivity analysis approach. Linear, interaction, and high-order nonlinear impacts are all identified via statistical tests and stepwise backward removal parameter screening. The basins are then classified according to their parameter sensitivity patterns (internal attributes), as well as their hydrologic indices/attributes (external hydrologic factors) separately, using Principal component analysis (PCA) and expectation-maximization (EM)based clustering approach. Similarities and differences among the parameter sensitivity-based classification system (S-Class), the hydrologic indices-based classification (H-Class), and the Koppen climate classification systems (K-Class) are discussed. Within each parameter sensitivity-based classification system (S-Class) with similar parameter sensitivity characteristics, similar inversion modeling setups can be used for parameter calibration, and the parameters and their contribution or significance to water and energy cycling may also be more transferrable. This classification study provides guidance on identifiable parameters, and on parameterization and inverse model design for CLM but the methodology is applicable to other models. A set of 3 experiments of model calibration were conducted to evaluate the transferability of model calibration strategies and parameter values within and between the classes. It was demonstrated that inverting parameters at representative sites belonging to the same class can significantly reduce parameter calibration efforts.

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“…From UTP, CTP, 5 , was directly synthesized and purified (Scheme 1). [29] The yield for CTP from UTP was nearly quantitative after 6 hours (SI-3) and the recovery of isolated product after purification was nearly 90% with respect to UTP.…”

mentioning

confidence: 99%

Regio‐Selective Chemical‐Enzymatic Synthesis of Pyrimidine Nucleotides Facilitates RNA Structure and Dynamics Studies

et al. 2014

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Isotope labeling revolutionized NMR studies of small nucleic acids, but to extend this technology to larger RNAs requires site-specific labeling tools to expedite NMR structural and dynamics studies. Using enzymes from the pentose phosphate pathway, we couple chemically synthesized uracil nucleobase with specifically 13C-labeled ribose to synthesize both UTP and CTP with nearly quantitative yields. This chemo-enzymatic method affords a cost-effective preparation of labels that are unattainable by current methods. The methodology generates versatile 13C and 15N labeling patterns which, when employed with relaxation-optimized NMR spectroscopy, effectively mitigates problems of rapid relaxation that result in low resolution and sensitivity. The methodology is demonstrated with RNAs of various sizes, complexity, and importance: the exon splicing silencer 3 (27 nt), iron responsive element (29 nt), Pro-tRNA (76 nt), and HIV-1 core encapsidation signal (155 nt).

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Inhibition of E. coli CTP synthase by the “positive” allosteric effector GTP

Cited by 16 publications

References 35 publications

A CTP Synthase Undergoing Stage-Specific Spatial Expression Is Essential for the Survival of the Intracellular Parasite Toxoplasma gondii

A CTP Synthase Undergoing Stage-Specific Spatial Expression Is Essential for the Survival of the Intracellular Parasite Toxoplasma gondii

Classification of hydrological parameter sensitivity and evaluation of parameter transferability across 431 US MOPEX basins

Regio‐Selective Chemical‐Enzymatic Synthesis of Pyrimidine Nucleotides Facilitates RNA Structure and Dynamics Studies

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