The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite

Huergo, Luciano F.; Dixon, Ray

doi:10.1128/mmbr.00038-15

Cited by 240 publications

(242 citation statements)

References 172 publications

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“…cAMP activates the transcription factor CRP, which controls the expression of hundreds of proteins, including many carbon catabolic enzymes17 and is also involved in coordinating nitrogen and carbon metabolism418. High internal carbon concentrations negatively affect cAMP concentrations forming a negative feedback circuit419 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Optimality and sub-optimality in a bacterial growth law

et al. 2017

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Organisms adjust their gene expression to improve fitness in diverse environments. But finding the optimal expression in each environment presents a challenge. We ask how good cells are at finding such optima by studying the control of carbon catabolism genes in Escherichia coli. Bacteria show a growth law: growth rate on different carbon sources declines linearly with the steady-state expression of carbon catabolic genes. We experimentally modulate gene expression to ask if this growth law always maximizes growth rate, as has been suggested by theory. We find that the growth law is optimal in many conditions, including a range of perturbations to lactose uptake, but provides sub-optimal growth on several other carbon sources. Combining theory and experiment, we genetically re-engineer E. coli to make sub-optimal conditions into optimal ones and vice versa. We conclude that the carbon growth law is not always optimal, but represents a practical heuristic that often works but sometimes fails.

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Section: Resultsmentioning

confidence: 99%

Optimality and sub-optimality in a bacterial growth law

et al. 2017

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“…The metabolite 2-oxoglutarate (aka α-ketoglutarate, 2-OG) is a key intermediate of the tricarboxylic acid (TCA) cycle, building block for amino acids and nitrogen transporter. Due to its involvement in both carbon and nitrogen metabolism and multiple signaling pathways, 2-OG has been suggested to act as a master regulator metabolite [76]. One example of this is highlighted by the discovery that 2-OG can extend the lifespan of Caenorhabditis elegans by inhibiting ATP synthase and target of rapamycin (TOR) downstream [77].…”

Section: -Oxoglutarate Enzymesmentioning

confidence: 99%

Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy. Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

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“…Nutrient depletion results in immediate metabolic changes leading to the accumulation of various reserve compounds, such as cyanophycin (CP), in the case of phosphorus or potassium starvation in certain strains (Watzer and Forchhammer, 2018), or the accumulation of glycogen in the case of nitrogen starvation. When nondiazotrophic cyanobacteria experience the lack of combined nitrogen, the ammonia assimilating reaction, carried out by the glutamine synthetase-glutamate synthase cycle (GS-GOGAT cycle), can no longer cope with the supply of 2-oxoglutarate (2-OG), a major metabolic status reporter of carbon-nitrogen balance (Muro-Pastor et al, 2001;Fokina et al, 2010;Huergo and Dixon, 2015). Consequently, the level of 2-OG increases, which alters the activities of key enzymes and transcription factors.…”

Section: Metabolic Responses To Nitrogen Starvationmentioning

confidence: 99%

Nitrogen chlorosis in unicellular cyanobacteria – a developmental program for surviving nitrogen deprivation

Forchhammer

Schwarz

2018

Environmental Microbiology

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Summary Cyanobacteria evolved sophisticated mechanisms allowing them to cope with environmental depletion of combined nitrogen. Here, we describe progress in understanding the processes involved in acclimation of nondiazotrophic cyanobacteria to nitrogen shortage, known as nitrogen chlorosis. The process includes immediate metabolic changes and degradation of light harvesting complexes as well as long‐term acclimation responses. Consequently, quiescent cells substantially differing from vegetative cells are obtained. Thus, the process leading to these considerable metabolic and morphological changes is referred to as a developmental program. Current understanding of the relevant regulatory processes depicts an intricate mechanism involving modulation of transcription activators by proteinaceous interacting components, as well as by small metabolites reporting the energy status and carbon–nitrogen balance of the cell. In addition, we describe in detail the quiescent state characterizing cells under prolonged starvation and the process of recovery from this dormant chlorotic state. Accumulated data provide an in depth understanding of the mechanisms accompanying the cycling of cyanobacterial cells between vegetative growth, the quiescent‐state and the recovery program, allowing them to regain proliferative growth upon nutrient replenishment.

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The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite

Cited by 240 publications

References 172 publications

Optimality and sub-optimality in a bacterial growth law

Optimality and sub-optimality in a bacterial growth law

Mitochondrial protein interaction landscape of SS-31

Nitrogen chlorosis in unicellular cyanobacteria – a developmental program for surviving nitrogen deprivation

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