Cycles, sources, and sinks: Conceptualizing how phosphate balance modulates carbon flux using yeast metabolic networks

Gupta, Ritu; Laxman, Sunil

doi:10.7554/elife.63341

Cited by 15 publications

(26 citation statements)

References 67 publications

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“…In agreement with these studies, we observed reductions in nucleotides and late glycolytic intermediates and increased nucleoside and nucleobase levels. These changes can be explained by simple mass action (58, 59) because they reduce phosphate-containing metabolites under conditions of intracellular P i shortage. By contrast, early TCA cycle metabolites, such as citric acid, isocitric acid, and oxoglutaric acid, strongly increased during P i starvation.…”

Section: Discussionmentioning

confidence: 99%

Metabolic consequences of polyphosphate synthesis and imminent phosphate limitation

Kim

Qiu

Jessen

et al. 2022

Preprint

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Cells stabilize intracellular inorganic phosphate (Pi) to compromise between large biosynthetic needs and detrimental bioenergetic effects of Pi. Pihomeostasis in eukaryotes employs SPXs domains, which are receptors for inositol pyrophosphates. We explored how polymerization and storage of Pi in acidocalcisome-like vacuoles supports S. cerevisiae metabolism and how these cells recognize Piscarcity. Whereas Pistarvation affects numerous metabolic pathways, beginning Piscarcity affects few metabolites. These include inositol pyrophosphates and ATP, a low-affinity substrate for inositol pyrophosphate-synthesizing kinases. Declining ATP and inositol pyrophosphates may thus be indicators of impending Pilimitation. Actual Pistarvation triggers accumulation of the purine synthesis intermediate 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which activates Pi-dependent transcription factors. Cells lacking polyphosphate show Pistarvation features already under Pi-replete conditions, suggesting that vacuolar polyphosphate supplies Pifor metabolism even when Piis abundant. However, polyphosphate deficiency also generates unique metabolic changes that are not observed in starving wildtype cells. Polyphosphate in acidocalcisome-like vacuoles may hence be more than a global phosphate reserve and channel Pito preferred cellular processes.

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Section: Discussionmentioning

confidence: 99%

Metabolic consequences of polyphosphate synthesis and imminent phosphate limitation

Kim

Qiu

Jessen

et al. 2022

Preprint

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“…ATP itself fulfills many regulatory roles acting as an allosteric effector of some enzymes and regulators and as a trigger factor of proteins phosphorylation cascades. Since phosphate is often limited in the environment, the consequences of a limitation in phosphate (Pi) has been extensively studied in microorganisms and plants ( Abel et al, 2002 ; Gupta and Laxman, 2021 ). This research field was especially active in Streptomyces species since the production of antibiotics by these Gram-positive filamentous soil bacteria is usually triggered in a condition of Pi limitation and strongly repressed in Pi proficiency ( Martin, 2004 ; Martin and Liras, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A Proteomic Analysis Indicates That Oxidative Stress Is the Common Feature Triggering Antibiotic Production in Streptomyces coelicolor and in the pptA Mutant of Streptomyces lividans

et al. 2022

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In most Streptomyces species, antibiotic production is triggered in phosphate limitation and repressed in phosphate proficiency. However, the model strain, Streptomyces coelicolor, escapes this general rule and produces actinorhoddin (ACT), a polyketide antibiotic, even more abundantly in phosphate proficiency than in phosphate limitation. ACT was shown to bear “anti-oxidant” properties suggesting that its biosynthesis is triggered by oxidative stress. Interestingly, Streptomyces lividans, a strain closely related to S. coelicolor, does not produce ACT in any phosphate condition whereas its pptA/sco4144 mutant produces ACT but only in phosphate limitation. In order to define the potentially common features of the ACT producing strains, these three strains were grown in condition of low and high phosphate availability, and a comparative quantitative analysis of their proteomes was carried out. The abundance of proteins of numerous pathways differed greatly between S. coelicolor and the S. lividans strains, especially those of central carbon metabolism and respiration. S. coelicolor is characterized by the high abundance of the complex I of the respiratory chain thought to generate reactive oxygen/nitrogen species and by a weak glycolytic activity causing a low carbon flux through the Pentose Phosphate Pathway resulting into the low generation of NADPH, a co-factor of thioredoxin reductases necessary to combat oxidative stress. Oxidative stress is thus predicted to be high in S. coelicolor. In contrast, the S. lividans strains had rather similar proteins abundance for most pathways except for the transhydrogenases SCO7622-23, involved in the conversion of NADPH into NADH. The poor abundance of these enzymes in the pptA mutant suggested a deficit in NADPH. Indeed, PptA is an accessory protein forcing polyphosphate into a conformation allowing their efficient use by various enzymes taking polyphosphate as a donor of phosphate and energy, including the ATP/Polyphosphate-dependent NAD kinase SCO1781. In phosphate limitation, this enzyme would mainly use polyphosphate to phosphorylate NAD into NADP, but this phosphorylation would be inefficient in the pptA mutant resulting in low NADP(H) levels and thus high oxidative stress. Altogether, our results indicated that high oxidative stress is the common feature triggering ACT biosynthesis in S. coelicolor and in the pptA mutant of S. lividans.

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“…We next asked if the increased Pi in ubp3Δ cells is because of altered G6P allocations towards different end-points. In particular, the Pi release from trehalose synthesis (conversion of trehalose 6-phosphate to trehalose) can be a major source of cytosolic Pi (Gupta et al, 2019; Gupta & Laxman, 2021). We therefore assessed the contribution of increased trehalose synthesis towards the high Pi levels observed in ubp3Δ cells, by estimating Pi levels in WT and ubp3Δ cells in the absence of trehalose 6-phosphate phosphatase (Tps2), which catalyzes the Pi releasing step in trehalose synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…This study highlights the importance of intracellular Pi balance in maintaining metabolic states. Because phosphates are required everywhere, it is challenging to identify hierarchies of Pi-dependent processes in metabolic state regulation (Gupta & Laxman, 2021). Phosphate transfer reactions are the foundation of metabolism, driving multiple, thermodynamically unfavorable reactions (Kamerlin et al, 2013; Westheimer, 1987).…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting

Vengayil

Niphadkar

Adhikary

et al. 2022

Preprint

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Many cells growing in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. A parsimonious biochemical explanation for this phenomenon is missing. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for proper mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, with downregulated glycolytic enzymes, rewired glucose metabolism, and increased trehalose. Utilizing ∆ubp3 cells, along with orthogonal approaches, we find that the Crabtree effect is driven mechanistically by controling mitochondrial access of inorganic phosphate (Pi), as determined by glycolytic flux. High glycolytic flux consumes free Pi, limiting available Pi for entry into the mitochondria. Cytosolic Pi-dependent mitochondrial Pi entry is necessary and sufficient to derepress mitochondria, driving synchronous requirements to sustain mitochondrial activity. Restricting Pi entry to the mitochondria prevents mitochondrial derepression. Collectively, we propose a biochemical basis of mitochondrial repression in high-glucose based on intracellular Pi budgeting.

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Cycles, sources, and sinks: Conceptualizing how phosphate balance modulates carbon flux using yeast metabolic networks

Cited by 15 publications

References 67 publications

Metabolic consequences of polyphosphate synthesis and imminent phosphate limitation

Metabolic consequences of polyphosphate synthesis and imminent phosphate limitation

A Proteomic Analysis Indicates That Oxidative Stress Is the Common Feature Triggering Antibiotic Production in Streptomyces coelicolor and in the pptA Mutant of Streptomyces lividans

The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting

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