Eukaryotic Phosphate Homeostasis: The Inositol Pyrophosphate Perspective

Azevedo, Cristina; Saiardi, Adolfo

doi:10.1016/j.tibs.2016.10.008

Cited by 138 publications

(138 citation statements)

References 86 publications

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“…The (24) has shown that extracellular [P i ] is sensed by the IP6K that synthesizes the intracellular inositol pyrophosphate 5-InsP 7. During a period of P i starvation, there is a decline in cellular [ATP].…”

Section: Resultsmentioning

confidence: 99%

“…The unusually low affinity of IP6Ks for ATP compels 5-InsP 7 levels to fall in parallel (5). As noted in a recent review of this field (24), yeasts are the only organisms that have previously been used to study 5-InsP 7 turnover in response to fluctuations in extracellular P i availability. We have addressed this gap in the field by using the HCT116 human intestinal epithelial cell line as a model system.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, inositol pyrophosphates have gained considerable attention for their actions that dovetail signaling with metabolism (6,7,24,42). In our study, we add several new aspects to this important research topic by showing that InsP 8 levels sense and respond to fluctuations in the extracellular levels of a vital nutrient, P i .…”

Section: Elevated Extracellular [P I ] Specifically Promotes Inspmentioning

confidence: 88%

“…This would not be surprising considering the many interactions between inositol pyrophosphate signaling and metabolic homeostasis (6,7,24,42) and the domain complexities of the PPIP5Ks (Fig. 2).…”

Section: Elevated Extracellular [P I ] Specifically Promotes Inspmentioning

confidence: 98%

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The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

Nguyen

Hofer

et al. 2017

Journal of Biological Chemistry

292

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Edited by Alex TokerPhosphate has multiple functions that direct the survival of all living organisms: in its organic form, P i is a component of genomic material, it serves as an energy currency, and it is ubiquitous in cell signaling. Thus, P i homeostasis is essential to life, but the mechanisms by which this occurs in humans and other metazoans are largely unknown (1, 2). Most of the previous work in this field of research has focused on yeast models (3-5). In particular, recent studies with Saccharomyces cerevisiae have revealed a new function in P i homeostasis for inositol pyrophosphates (5). The latter are soluble, intracellular signals that contain multiple phosphates and diphosphates; up to seven (InsP 7 ) 4 or eight (InsP 8 ) phosphates in total are crammed around a six-carbon inositol ring (see Refs. 6 -8 and Fig. 1). In S. cerevisiae, levels of one inositol pyrophosphate, 5-InsP 7 , track perturbations to P i homeostasis (5).This P i -sensing activity of 5-InsP 7 appears to reflect it being synthesized by a kinase class (kcs1 in yeast; IP6Ks in metazoans) that exhibits an unusually low affinity for ATP (9, 10). Consequently, cellular levels of 5-InsP 7 in yeast decrease in response to the drop in [ATP] that accompanies extracellular [P i ] depletion (5, 11). Furthermore, these ATP-driven changes in 5-InsP 7 levels appear to comprise a dynamic signaling response because 5-InsP 7 regulates proteins that maintain P i homeostasis through interactions with their SPX domains (5). However, it is not known to what extent this signaling response is applicable to metazoan cells, which lack orthologs of many of the yeast genes that function in P i sensing and P i homeostasis (2).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Elevated Extracellular [P I ] Specifically Promotes Inspmentioning

confidence: 88%

Section: Elevated Extracellular [P I ] Specifically Promotes Inspmentioning

confidence: 98%

See 2 more Smart Citations

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

Nguyen

Hofer

et al. 2017

Journal of Biological Chemistry

292

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“…hosphorus is the fifth-most-abundant element in bacterial cells (1), and an inorganic phosphate compound (PO 4 3ϩ [P i for short]) is involved in a high percentage of chemical reactions (2). Phosphate is present in key biomolecules (e.g., phospholipids, nucleic acids, polyphosphate [polyPi]), is involved in regulation (e.g., signal transduction and protein phosphorylation), and plays a role in maintaining cellular energy dynamics due to inclusion in high-energy compounds (e.g., ATP).…”

mentioning

confidence: 99%

PhoU Allows Rapid Adaptation to High Phosphate Concentrations by Modulating PstSCAB Transport Rate in Sinorhizobium meliloti

et al. 2017

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Maintenance of cellular phosphate homeostasis is essential for cellular life. The PhoU protein has emerged as a key regulator of this process in bacteria, and it is suggested to modulate phosphate import by PstSCAB and control activation of the phosphate limitation response by the PhoR-PhoB two-component system. However, a proper understanding of PhoU has remained elusive due to numerous complications of mutating phoU, including loss of viability and the genetic instability of the mutants. Here, we developed two sets of strains of Sinorhizobium meliloti that overcame these limitations and allowed a more detailed and comprehensive analysis of the biological and molecular activities of PhoU. The data showed that phoU cannot be deleted in the presence of phosphate unless PstSCAB is inactivated also. However, phoU deletions were readily recovered in phosphatefree media, and characterization of these mutants revealed that addition of phosphate to the environment resulted in toxic levels of PstSCAB-mediated phosphate accumulation. Phosphate uptake experiments indicated that PhoU significantly decreased the PstSCAB transport rate specifically in phosphate-replete cells but not in phosphate-starved cells and that PhoU could rapidly respond to elevated environmental phosphate concentrations and decrease the PstSCAB transport rate. Sitedirected mutagenesis results suggested that the ability of PhoU to respond to phosphate levels was independent of the conformation of the PstSCAB transporter. Additionally, PhoU-PhoU and PhoU-PhoR interactions were detected using a bacterial two-hybrid screen. We propose that PhoU modulates PstSCAB and PhoR-PhoB in response to local, internal fluctuations in phosphate concentrations resulting from PstSCAB-mediated phosphate import.IMPORTANCE Correct maintenance of cellular phosphate homeostasis is critical in all kingdoms of life and in bacteria involves the PhoU protein. This work provides novel insights into the role of the Sinorhizobium meliloti PhoU protein, which plays a key role in rapid adaptation to elevated phosphate concentrations. It is shown that PhoU rapidly responds to elevated phosphate levels by significantly decreasing the phosphate transport of PstSCAB, thereby preventing phosphate toxicity and cell death. Additionally, a new model for phosphate sensing in bacterial species which involves the PhoR-PhoB two-component system is presented. This work provides new insights into the bacterial response to changing environmental conditions and into regulation of the phosphate limitation response that influences numerous bacterial processes, including antibiotic production and virulence.KEYWORDS Pho regulon, PhoU, PstSCAB, Sinorhizobium meliloti, environmental adaptation, modulation of TCS, phosphate homeostasis, phosphate sensing, phosphate transport, transport modulation

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Fluorination Influences the Bioisostery of Myo‐Inositol Pyrophosphate Analogs

Hostachy,

Wang,

Zong

et al. 2023

Chemistry A European J

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Inositol pyrophosphates (PP‐IPs) are densely phosphorylated messenger molecules involved in numerous biological processes. PP‐IPs contain one or two pyrophosphate group(s) attached to a phosphorylated myo‐inositol ring. 5PP‐IP5 is the most abundant PP‐IP in human cells. To investigate the function and regulation by PP‐IPs in biological contexts, metabolically stable analogs have been developed. Here, we report the synthesis of a new fluorinated phosphoramidite reagent and its application for the synthesis of a difluoromethylene bisphosphonate analog of 5PP‐IP5. Subsequently, the properties of all currently reported analogs were benchmarked using a number of biophysical and biochemical methods, including co‐crystallization, ITC, kinase activity assays and chromatography. Together, the results showcase how small structural alterations of the analogs can have notable effects on their properties in a biochemical setting and will guide in the choice of the most suitable analog(s) for future investigations.

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Eukaryotic Phosphate Homeostasis: The Inositol Pyrophosphate Perspective

Cited by 138 publications

References 86 publications

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

PhoU Allows Rapid Adaptation to High Phosphate Concentrations by Modulating PstSCAB Transport Rate in Sinorhizobium meliloti

Fluorination Influences the Bioisostery of Myo‐Inositol Pyrophosphate Analogs

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