Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites

Laxman, Sunil; Sutter, Benjamin M.; Shi, Lei; Tu, Benjamin P.

doi:10.1126/scisignal.2005948

Cited by 47 publications

(68 citation statements)

References 68 publications

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“…Methionine levels are normally in the range of 30-60 µM, and thus not much of the excess thiol was trapped in methionine. Indeed, there are other studies as well where sulfur amino acid metabolism change also indicates that cells maintain methionine concentrations within a fairly stable steady state range 2123.…”

Section: Resultsmentioning

confidence: 95%

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

Deshpande¹,

Bhatia²,

Laxman³

et al. 2017

Microb Cell

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Cysteine is an essential requirement in living organisms. However, due to its reactive thiol side chain, elevated levels of intracellular cysteine can be toxic and therefore need to be rapidly eliminated from the cellular milieu. In mammals and many other organisms, excess cysteine is believed to be primarily eliminated by the cysteine dioxygenase dependent oxidative degradation of cysteine, followed by the removal of the oxidative products. However, other mechanisms of tackling excess cysteine are also likely to exist, but have not thus far been explored. In this study, we use Saccharomyces cerevisiae, which naturally lacks a cysteine dioxygenase, to investigate mechanisms for tackling cysteine overload. Overexpressing the high affinity cysteine transporter, YCT1, enabled yeast cells to rapidly accumulate high levels of intracellular cysteine. Using targeted metabolite analysis, we observe that cysteine is initially rapidly interconverted to non-reactive cystine in vivo. A time course revealed that cells systematically convert excess cysteine to inert thiol forms; initially to cystine, and subsequently to cystathionine, S-Adenosyl-L-homocysteine (SAH) and S-Adenosyl L-methionine (SAM), in addition to eventually accumulating glutathione (GSH) and polyamines. Microarray based gene expression studies revealed the upregulation of arginine/ornithine biosynthesis a few hours after the cysteine overload, and suggest that the non-toxic, non-reactive thiol based metabolic products are eventually utilized for amino acid and polyamine biogenesis, thereby enabling cell growth. Thus, cells can handle potentially toxic amounts of cysteine by a combination of thiol trapping, metabolic redistribution to non-reactive thiols and subsequent consumption for anabolism.

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Section: Resultsmentioning

confidence: 95%

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

Deshpande¹,

Bhatia²,

Laxman³

et al. 2017

Microb Cell

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“…A major function of TORC1 is in the regulation of autophagy, which is induced when TORC1 is inhibited, either by rapamycin or by nitrogen starvation. Thus, it is not surprising that SEACIT, which inhibits TORC1, also controls autophagy (Algret et al, 2014;Graef and Nunnari, 2011;Kira et al, 2014;Laxman et al, 2014;Sutter et al, 2013;Wu and Tu, 2011); there are some indications this is also the case in mammals (Kira et al, 2014). So far, the effects of SEACIT have only been described for a specific form of autophagy, non-nitrogen-starvation (NNS)-induced autophagy Sutter et al, 2013;Wu and Tu, 2011).…”

Section: Molecular Basis Of Sea/gator-mediated Regulation Of Torc1mentioning

confidence: 99%

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Dokudovskaya

Rout

2015

Journal of Cell Science

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Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 -the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases.

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“…Ammonia assimilation in yeast has a fundamental role in supporting growth and proliferation (31, 32). Because ammonia was not toxic to tumor cells (Fig.…”

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confidence: 99%

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Spinelli

Yoon

Ringel

et al. 2017

Science

322

325

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Ammonia is a ubiquitous by-product of cellular metabolism, however the biological consequences of ammonia production are not fully understood, especially in cancer. We find that ammonia is not merely a toxic waste product, but is recycled into central amino acid metabolism to maximize nitrogen utilization. Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment, and was used directly to generate amino acids through GDH activity. These data show that ammonia not only is a secreted waste product, but a fundamental nitrogen source that can support tumor biomass.

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Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites

Cited by 47 publications

References 68 publications

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

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