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      Metabolic flux analysis of the neural cell glycocalyx reveals differential utilization of monosaccharides

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          Abstract

          Saccharides in our diet are major sources of carbon for the formation of biomass such as proteins, lipids, nucleic acids and glycans. Among the dietary monosaccharides, glucose occupies a central role in metabolism, but human blood contains regulated levels of other monosaccharides as well. Their influence on metabolism and how they are utilized have not been explored thoroughly. Applying metabolic flux analysis on glycan synthesis can reveal the pathways that supply glycosylation precursors and provide a snapshot of the metabolic state of the cell. In this study, we traced the incorporation of six 13C uniformly labeled monosaccharides in the N-glycans, O-glycans and glycosphingolipids of both pluripotent and neural NTERA-2 cells. We gathered detailed isotopologue data for hundreds of glycoconjugates using mass spectrometry methods. The contributions of de novo synthesis and direct incorporation pathways for glucose, mannose, fructose, galactose, N-acetylglucosamine and fucose were determined based on their isotope incorporation. Co-feeding studies revealed that fructose incorporation is drastically decreased by the presence of glucose, while mannose and galactose were much less affected. Furthermore, increased sialylation slowed down the turnover of glycans, but fucosylation attenuated this effect. Our results demonstrated that exogenous monosaccharide utilization can vary markedly depending on the cell differentiation state and monosaccharide availability, and that the incorporation of carbons can also differ among different glycan structures. We contend that the analysis of metabolic isotope labeling of glycans can yield new insights about cell metabolism.

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            On the origin of cancer cells.

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              Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation.

              The energy requirements of the brain are very high, and tight regulatory mechanisms operate to ensure adequate spatial and temporal delivery of energy substrates in register with neuronal activity. Astrocytes-a type of glial cell-have emerged as active players in brain energy delivery, production, utilization, and storage. Our understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving an intense cooperativity between astrocytes and neurons. This review focuses on the cellular aspects of brain energy metabolism, with a particular emphasis on the metabolic interactions between neurons and astrocytes. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Glycobiology
                Glycobiology
                glycob
                Glycobiology
                Oxford University Press
                0959-6658
                1460-2423
                November 2020
                27 April 2020
                27 April 2020
                : 30
                : 11
                : 859-871
                Affiliations
                [1 ] Department of Chemistry , University of California , Davis, Davis, CA 95616, USA
                [2 ] Department of Anatomy , Physiology & Cell Biology, University of California , Davis, Davis, CA 95616, USA
                [3 ] Department of Pathology and Laboratory Medicine , UC Davis Medical Center , Sacramento, CA 95817, USA
                [4 ] Department of Nutrition , University of California , Davis, Davis, CA 95616, USA
                Author notes
                To whom correspondence should be addressed: E-mail: myuwong@ 123456ucdavis.edu
                Author information
                http://orcid.org/0000-0003-3851-2928
                Article
                cwaa038
                10.1093/glycob/cwaa038
                7581652
                32337579
                65efb39c-8508-47d2-a111-e2121751cc7d
                © The Author(s) 2020. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 2 December 2019
                : 31 March 2020
                : 15 April 2020
                : 15 April 2020
                Page count
                Pages: 13
                Funding
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: R01GM049077
                Award ID: R01AG062240
                Categories
                AcademicSubjects/SCI01000
                Analytical Glycobiology

                Biochemistry
                glycomics,mass spectrometry,metabolic flux analysis,neuron,stable isotope labeling
                Biochemistry
                glycomics, mass spectrometry, metabolic flux analysis, neuron, stable isotope labeling

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