2013
DOI: 10.1126/science.1228771
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Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis

Abstract: The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first thre… Show more

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Cited by 448 publications
(422 citation statements)
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“…Aspartate derived from glutamine via the TCA cycle and transamination (Figures 2,3) serves as a crucial source of carbon for purine and pyrimidine synthesis 84,85 , and provision of aspartate can rescue cell cycle arrest caused by glutamine deprivation 86 . Additionally, glutamine dependent mTOR signaling may activate the enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the incorporation of glutamine derived nitrogen into pyrimidine precursors 118,121,122 . It has been suggested that NADPH produced downstream of glutamine metabolism and flux through the malic enzymes can further support nucleotide synthesis 31 .…”
Section: Nucleotide Biosynthesismentioning
confidence: 99%
“…Aspartate derived from glutamine via the TCA cycle and transamination (Figures 2,3) serves as a crucial source of carbon for purine and pyrimidine synthesis 84,85 , and provision of aspartate can rescue cell cycle arrest caused by glutamine deprivation 86 . Additionally, glutamine dependent mTOR signaling may activate the enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the incorporation of glutamine derived nitrogen into pyrimidine precursors 118,121,122 . It has been suggested that NADPH produced downstream of glutamine metabolism and flux through the malic enzymes can further support nucleotide synthesis 31 .…”
Section: Nucleotide Biosynthesismentioning
confidence: 99%
“…It has been reported that the multienzyme, CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) which is essential for CMP synthesis, is activated by serum stimulation. 30,31 Therefore, the production of dCTP from CMP through the subsequent action of CMPK, RNR and NDPK is serum-sensitive and responsive to CMPK depletion. In serumdeprived cells, however, depletion of CMPK protein did not reduce the dCTP pool.…”
Section: Discussionmentioning
confidence: 99%
“…Additionally, the practical feedback for extracellular validation was obtained as significant structural indices of polysaccharide components (Tables 1 and 4). On the other hand, the overexpressed performance of some kinases, such as tyrosine protein kinase, is based on the stability of either a de novo managing system [29] or a cellular damage bioplatform [30] and can maintain metabolic balance over an entire process of closed WSMB (Table 2). Furthermore, in order to support the cellular differentiation based on the long-term cultivation bioprocess, the pentose phosphate pathway, e.g., ribose 5-phosphate isomerase, may be activated rather than lignocellulolytic cascades in spite of ligninolytic maximization.…”
Section: Proteomic Evaluation Of Advanced Wsmb Biosystem: Nonspecificmentioning
confidence: 99%