scholarly journals Methionine coordinates a hierarchically organized anabolic program enabling proliferation

2018 ◽  
Vol 29 (26) ◽  
pp. 3183-3200 ◽  
Author(s):  
Adhish S. Walvekar ◽  
Rajalakshmi Srinivasan ◽  
Ritu Gupta ◽  
Sunil Laxman
Keyword(s):  
Amino Acid ◽  
Metabolic Flux ◽  
Response Regulator ◽  
Pentose Phosphate ◽  
Dependent Manner ◽  
Comparative Transcriptome ◽  
Starvation Stress ◽  
Acid Biosynthesis ◽  
Underlying Basis ◽  
Rate Limiting

Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here we construct the organization of this methionine-mediated anabolic program using yeast. Combining comparative transcriptome analysis and biochemical and metabolic flux-based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of a key regulatory node. This comprises the pentose phosphate pathway (PPP) coupled with reductive biosynthesis, the glutamate dehydrogenase (GDH)-dependent synthesis of glutamate/glutamine, and pyridoxal-5-phosphate (PLP)-dependent transamination capacity. This PPP-GDH-PLP node provides the required cofactors and/or substrates for subsequent rate-limiting reactions in the synthesis of amino acids and therefore nucleotides. These rate-limiting steps in amino acid biosynthesis are also induced in a methionine-dependent manner. This thereby results in a biochemical cascade establishing a hierarchically organized anabolic program. For this methionine-mediated anabolic program to be sustained, cells co-opt a “starvation stress response” regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch.

scholarly journals Methionine coordinates a hierarchically organized anabolic program enabling proliferation

2018 ◽  
Author(s):  
Adhish S. Walvekar ◽  
Rajalakshmi Srinivasan ◽  
Ritu Gupta ◽  
Sunil Laxman
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Flux ◽  
Response Regulator ◽  
Pentose Phosphate ◽  
Dependent Manner ◽  
Comparative Transcriptome ◽  
Starvation Stress ◽  
Underlying Basis ◽  
Rate Limiting

AbstractMethionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here, we construct the organization of this methionine mediated anabolic program, using yeast. Combining comparative transcriptome analysis, biochemical and metabolic flux based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of three key regulatory nodes. These are: the pentose phosphate pathway coupled with reductive biosynthesis, and overall transamination capacity, including the synthesis of glutamate/glutamine. These provides the cofactors or substrates that enhance subsequent rate-limiting reactions in the synthesis of costly amino acids, and nucleotides, which are also induced in a methionine dependent manner. This thereby results in a biochemical cascade establishing an overall anabolic program. For this methionine mediated anabolic program leading to proliferation, cells co-opt a “starvation stress response” regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch.

scholarly journals Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity

2021 ◽  
Vol 7 (16) ◽  
pp. eabe5544
Author(s):  
Zeenat Rashida ◽  
Rajalakshmi Srinivasan ◽  
Meghana Cyanam ◽  
Sunil Laxman
Keyword(s):  
Amino Acid ◽  
Nutrient Limitation ◽  
Carbon Flux ◽  
Metabolic Flux ◽  
Carbon Allocation ◽  
Carbon Utilization ◽  
Acid Biosynthesis ◽  
Control Growth ◽  
Ampk Activity ◽  
Delayed Growth

In changing environments, cells modulate resource budgeting through distinct metabolic routes to control growth. Accordingly, the TORC1 and SNF1/AMPK pathways operate contrastingly in nutrient replete or limited environments to maintain homeostasis. The functions of TORC1 under glucose and amino acid limitation are relatively unknown. We identified a modified form of the yeast TORC1 component Kog1/Raptor, which exhibits delayed growth exclusively during glucose and amino acid limitations. Using this, we found a necessary function for Kog1 in these conditions where TORC1 kinase activity is undetectable. Metabolic flux and transcriptome analysis revealed that Kog1 controls SNF1-dependent carbon flux apportioning between glutamate/amino acid biosynthesis and gluconeogenesis. Kog1 regulates SNF1/AMPK activity and outputs and mediates a rapamycin-independent activation of the SNF1 targets Mig1 and Cat8. This enables effective glucose derepression, gluconeogenesis activation, and carbon allocation through different pathways. Therefore, Kog1 centrally regulates metabolic homeostasis and carbon utilization during nutrient limitation by managing SNF1 activity.

scholarly journals Key Maize Drought-Responsive Genes and Pathways Revealed by Comparative Transcriptome and Physiological Analyses of Contrasting Inbred Lines

2019 ◽  
Vol 20 (6) ◽  
pp. 1268 ◽  
Author(s):  
Tinashe Zenda ◽  
Songtao Liu ◽  
Xuan Wang ◽  
Guo Liu ◽  
Hongyu Jin ◽  
...  
Keyword(s):  
Amino Acid ◽  
Drought Stress ◽  
Stress Tolerance ◽  
Amino Acid Biosynthesis ◽  
Molecular Networks ◽  
Comparative Transcriptome ◽  
Rna Seq ◽  
Acid Biosynthesis ◽  
Drought Treatment ◽  
Drought Stress Tolerance

To unravel the molecular mechanisms underpinning maize (Zea mays L.) drought stress tolerance, we conducted comprehensive comparative transcriptome and physiological analyses of drought-tolerant YE8112 and drought-sensitive MO17 inbred line seedlings that had been exposed to drought treatment for seven days. Resultantly, YE8112 seedlings maintained comparatively higher leaf relative water and proline contents, greatly increased peroxidase activity, but decreased malondialdehyde content, than MO17 seedlings. Using an RNA sequencing (RNA-seq)-based approach, we identified a total of 10,612 differentially expressed genes (DEGs). From these, we mined out four critical sets of drought responsive DEGs, including 80 specific to YE8112, 5140 shared between the two lines after drought treatment (SD_TD), five DEGs of YE8112 also regulated in SD_TD, and four overlapping DEGs between the two lines. Drought-stressed YE8112 DEGs were primarily associated with nitrogen metabolism and amino-acid biosynthesis pathways, whereas MO17 DEGs were enriched in the ribosome pathway. Additionally, our physiological analyses results were consistent with the predicted RNA-seq-based findings. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis and the RNA-seq results of twenty representative DEGs were highly correlated (R2 = 98.86%). Crucially, tolerant line YE8112 drought-responsive genes were predominantly implicated in stress signal transduction; cellular redox homeostasis maintenance; MYB, NAC, WRKY, and PLATZ transcriptional factor modulated; carbohydrate synthesis and cell-wall remodeling; amino acid biosynthesis; and protein ubiquitination processes. Our findings offer insights into the molecular networks mediating maize drought stress tolerance.

scholarly journals ERF-VII transcription factors induce ethanol fermentation in response to amino acid biosynthesis-inhibiting herbicides

2019 ◽  
Vol 70 (20) ◽  
pp. 5839-5851 ◽  
Author(s):  
Miriam Gil-Monreal ◽  
Beatrice Giuntoli ◽  
Ana Zabalza ◽  
Francesco Licausi ◽  
Mercedes Royuela
Keyword(s):  
Amino Acid ◽  
Ethanol Fermentation ◽  
Herbicide Tolerance ◽  
Amino Acid Biosynthesis ◽  
Dependent Manner ◽  
Low Oxygen ◽  
Acid Biosynthesis ◽  
Response Factors ◽  
Oxygen Conditions ◽  
Branched Chain

Abstract Herbicides inhibiting either aromatic or branched-chain amino acid biosynthesis trigger similar physiological responses in plants, despite their different mechanism of action. Both types of herbicides are known to activate ethanol fermentation by inducing the expression of fermentative genes; however, the mechanism of such transcriptional regulation has not been investigated so far. In plants exposed to low-oxygen conditions, ethanol fermentation is transcriptionally controlled by the ethylene response factors-VII (ERF-VIIs), whose stability is controlled in an oxygen-dependent manner by the Cys-Arg branch of the N-degron pathway. In this study, we investigated the role of ERF-VIIs in the regulation of the ethanol fermentation pathway in herbicide-treated Arabidopsis plants grown under aerobic conditions. Our results demonstrate that these transcriptional regulators are stabilized in response to herbicide treatment and are required for ethanol fermentation in these conditions. We also observed that mutants with reduced fermentative potential exhibit higher sensitivity to herbicide treatments, thus revealing the existence of a mechanism that mimics oxygen deprivation to activate metabolic pathways that enhance herbicide tolerance. We speculate that this signaling pathway may represent a potential target in agriculture to affect tolerance to herbicides that inhibit amino acid biosynthesis.

scholarly journals Underestimation of the Pentose–Phosphate Pathway in Intact Primary Neurons as Revealed by Metabolic Flux Analysis

2013 ◽  
Vol 33 (12) ◽  
pp. 1843-1845 ◽  
Author(s):  
Patricia Rodriguez-Rodriguez ◽  
Emilio Fernandez ◽  
Juan P Bolaños
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Flux ◽  
Pentose Phosphate ◽  
Flux Analysis ◽  
Primary Neurons ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Total Glucose ◽  
Rate Limiting ◽  
Glycolytic Rate

The rates of glucose oxidized at glycolysis and pentose–phosphate pathway (PPP) in neurons are controversial. Using [3-3H]-, [1-14C]-, and [6-14C]glucose to estimate fluxes through these pathways in resting, intact rat cortical primary neurons, we found that the rate of glucose oxidized through PPP was, apparently, ∼14% of total glucose metabolized. However, inhibition of PPP rate-limiting step, glucose-6-phosphate (G6P) dehydrogenase, increased approximately twofold the glycolytic rate; and, knockdown of phosphoglucose isomerase increased ∼1.8-fold the PPP rate. Thus, in neurons, a considerable fraction of fructose-6-phosphate returning from the PPP contributes to the G6P pool that re-enters PPP, largely underestimating its flux.

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