The Experts below are selected from a list of 32661 Experts worldwide ranked by ideXlab platform
Lucas B Sullivan - One of the best experts on this subject based on the ideXlab platform.
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free Asparagine or die cancer cells require proteasomal protein breakdown to survive Asparagine depletion
Cancer Discovery, 2020Co-Authors: Lucas B Sullivan, Kristian DavidsenAbstract:The chemotherapeutic enzyme asparaginase depletes systemic Asparagine to kill cancers; however, its efficacy thus far is limited to a subset of leukemias. Hinze and colleagues identify that inhibiting proteasomal release of Asparagine can sensitize colorectal cancers to Asparagine depletion, providing a potential avenue to repurpose asparaginase for treatment of solid tumors.See related article by Hinze et al., p. 1690.
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aspartate is an endogenous metabolic limitation for tumour growth
Nature Cell Biology, 2018Co-Authors: Lucas B Sullivan, Alba Luengo, Laura V Danai, Lauren N Bush, Frances F Diehl, Aaron M Hosios, Allison N Lau, Sarah Elmiligy, Scott E MalstromAbstract:Defining the metabolic limitations of tumour growth will help to develop cancer therapies1. Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired2–4; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid Asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert Asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from Asparagine5, confers the ability to use Asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer.
Nigel G Halford - One of the best experts on this subject based on the ideXlab platform.
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free amino acids and sugars in rye grain implications for acrylamide formation
Journal of Agricultural and Food Chemistry, 2010Co-Authors: Tanya Y Curtis, M A J Parry, Peter R Shewry, Stephen J Powers, Dimitrios P Balagiannis, Stephen J Elmore, Donald S Mottram, Mariann Rakszegi, Zoltan Bedo, Nigel G HalfordAbstract:Acrylamide forms from free Asparagine and sugars during cooking, and products derived from the grain of cereals, including rye, contribute a large proportion of total dietary intake. In this study, free amino acid and sugar concentrations were measured in the grain of a range of rye varieties grown at locations in Hungary, France, Poland, and the United Kingdom and harvested in 2005, 2006, and 2007. Genetic and environmental (location and harvest year) effects on the levels of acrylamide precursors were assessed. The data showed free Asparagine concentration to be the main determinant of acrylamide formation in heated rye flour, as it is in wheat. However, in contrast to wheat, sugar, particularly sucrose, concentration also correlated both with Asparagine concentration and with acrylamide formed. Free Asparagine concentration was shown to be under genetic (G), environmental (E), and integrated (G x E) control. The same was true for glucose, whereas maltose and fructose were affected mainly by environmental factors and sucrose was largely under genetic control. The ratio of variation due to varieties (genotype) to the total variation (a measure of heritability) for free Asparagine concentration in the grain was 23%. Free Asparagine concentration was closely associated with bran yield, whereas sugar concentration was associated with low Hagberg falling number. Rye grain was found to contain much higher concentrations of free proline than wheat grain, and less acrylamide formed per unit of Asparagine in rye than in wheat flour.
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effects of genotype and environment on free amino acid levels in wheat grain implications for acrylamide formation during processing
Journal of Agricultural and Food Chemistry, 2009Co-Authors: Tanya Y Curtis, M A J Parry, Peter R Shewry, Stephen J Powers, Stephen J Elmore, Donald S Mottram, Nira Muttucumaru, Simon Hook, Nigel G HalfordAbstract:Acrylamide forms from free Asparagine and reducing sugars during cooking, with Asparagine concentration being the key parameter determining the formation in foods produced from wheat flour. In this study free amino acid concentrations were measured in the grain of varieties Spark and Rialto and four doubled haploid lines from a Spark x Rialto mapping population. The parental and doubled haploid lines had differing levels of total free amino acids and free Asparagine in the grain, with one line consistently being lower than either parent for both of these factors. Sulfur deprivation led to huge increases in the concentrations of free Asparagine and glutamine, and canonical variate analysis showed clear separation of the grain samples as a result of treatment (environment, E) and genotype (G) and provided evidence of G x E interactions. Low grain sulfur and high free Asparagine concentration were closely associated with increased risk of acrylamide formation. G, E, and G x E effects were also evident in grain from six varieties of wheat grown at field locations around the United Kingdom in 2006 and 2007. The data indicate that progress in reducing the risk of acrylamide formation in processed wheat products could be made immediately through the selection and cultivation of low grain Asparagine varieties and that further genetically driven improvements should be achievable. However, genotypes that are selected should also be tested under a range of environmental conditions.
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Asparagine in plants
Annals of Applied Biology, 2007Co-Authors: Peter J Lea, Ladaslav Sodek, M A J Parry, Peter R Shewry, Nigel G HalfordAbstract:Interest in plant Asparagine has rapidly taken off over the past 5 years following the report that acrylamide, a neurotoxin and potential carcinogen, is present in cooked foods, particularly carbohydrate-rich foods such as wheat and potatoes which are subjected to roasting, baking or frying at high temperatures. Subsequent studies showed that acrylamide could be formed in foods by the thermal degradation of free Asparagine in the presence of sugars in the Maillard reaction. In this article, our current knowledge of Asparagine in plants and in particular its occurrence in cereal seeds and potatoes is reviewed and discussed in relation to acrylamide formation. There is now clear evidence that soluble Asparagine accumulates in most if not all plant organs during periods of low rates of protein synthesis and a plentiful supply of reduced nitrogen. The accumulation of Asparagine occurs during normal physiological processes such as seed germination and nitrogen transport. However, in addition, stress-induced Asparagine accumulation can be caused by mineral deficiencies, drought, salt, toxic metals and pathogen attack. The properties and gene regulation of the enzymes involved in Asparagine synthesis and breakdown in plants are discussed in detail.
Akira Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Impact of the Disruption of ASN3-Encoding Asparagine Synthetase on Arabidopsis Development
Agronomy, 2016Co-Authors: Laure Gaufichon, Anne Marmagne, Tadakatsu Yoneyama, Toshiharu Hase, Gilles Clément, Marion Trassaert, Maryam Shakibaei, Amina Najihi, Akira SuzukiAbstract:The aim of this study was to investigate the role of ASN3-encoded Asparagine synthetase (AS, EC 6.3.5.4) during vegetative growth, seed development and germination of Arabidopsis thaliana. Phenotypic analysis of knockout (asn3-1) and knockdown (asn3-2) T-DNA insertion mutants for the ASN3 gene (At5g10240) demonstrated wild-type contents of Asparagine synthetase protein, chlorophyll and ammonium in green leaves at 35 days after sowing. In situ hybridization localized ASN3 mRNA to phloem companion cells of vasculature. Young siliques of the asn3-1 knockout line showed a decrease in Asparagine but an increase in glutamate. The seeds of asn3-1 and asn3-2 displayed a wild-type nitrogen status expressed as total nitrogen content, indicating that the repression of ASN3 expression had only a limited effect on mature seeds. An analysis of amino acid labeling of seeds imbibed with (N-15) ammonium for 24 h revealed that asn3-1 seeds contained 20% less total Asparagine while N-15-labeled Asparagine ((2-N-15)Asparagine, (4-N-15)Asparagine and (2,4-N-15)Asparagine) increased by 12% compared to wild-type seeds. The data indicate a fine regulation of Asparagine synthesis and hydrolysis in Arabidopsis seeds.
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Asparagine metabolic pathways in arabidopsis
Plant and Cell Physiology, 2016Co-Authors: Laure Gaufichon, Steven J Rothstein, Akira SuzukiAbstract:Inorganic nitrogen in the form of ammonium is assimilated into Asparagine via multiple steps involving glutamine synthetase (GS), glutamate synthase (GOGAT), aspartate aminotransferase (AspAT) and Asparagine synthetase (AS) in Arabidopsis. The Asparagine amide group is liberated by the reaction catalyzed by asparaginase (ASPG) and also the amino group of Asparagine is released by Asparagine aminotransferase (AsnAT) for use in the biosynthesis of amino acids. Asparagine plays a primary role in nitrogen recycling, storage and transport in developing and germinating seeds, as well as in vegetative and senescence organs. A small multigene family encodes isoenzymes of each step of Asparagine metabolism in Arabidopsis, except for Asparagine aminotransferase encoded by a single gene. The aim of this study is to highlight the structure of the genes and encoded enzyme proteins involved in Asparagine metabolic pathways; the regulation and role of different isogenes; and kinetic and physiological properties of encoded enzymes in different tissues and developmental stages.
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Biological functions of Asparagine synthetase in plants
Plant Science, 2010Co-Authors: Laure Gaufichon, Michèle Cren-reisdorf, Fabien Chardon, Steven J Rothstein, Akira SuzukiAbstract:Ammonium is a form of inorganic nitrogen derived from several metabolic pathways, and is assimilated into glutamine, glutamate, Asparagine and carbamoylphosphate. These molecules play important roles in nitrogen assimilation, recycling, transport and storage in plants. Ammonium assimilation into Asparagine is catalyzed by ammonia-dependent Asparagine synthetase encoded by asnA (EC 6.3.1.1) or glutamine-dependent Asparagine synthetase encoded by asnB (EC 6.3.5.4) in prokaryotes and eukaryotes. These organisms display a distinct distribution of these two forms of Asparagine synthetase. Gene and primary protein structure for Asparagine synthetase-A and -B from prokaryotes and eukaryotes is examined. Using nucleotide sequences, we constructed a phylogenetic tree that distinguished two major classes (classes I and II) for ASN genes from a range of organisms. Only the glutamine-dependent Asparagine synthetases-B have been identified, and are encoded by a small multigene family in plants. The isoenzyme encoded by each member of the gene family provides Asparagine at specific phases of development. These include the nitrogen mobilization in germinating seeds, nitrogen recycling in vegetative organs in response to stress, and nitrogen remobilization during seed embryogenesis. The expression of genes for Asparagine synthetase is regulated by light and metabolites. Genetic and molecular data using mutants and transgenic plants have provided insights into the light perception by the photoreceptors, carbon and nitrogen sensing and signal transduction mechanism in the asn regulation. Global analysis of carbon and nitrogen metabolites supports the impact of asn regulation in the synthesis and transport of Asparagine in plants.
Abigail S. Krall - One of the best experts on this subject based on the ideXlab platform.
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Asparagine couples mitochondrial respiration to atf4 activity and tumor growth
Cell Metabolism, 2021Co-Authors: Abigail S. Krall, Peter J Mullen, Felicia Surjono, Milica Momcilovic, Ernst W Schmid, Christopher J Halbrook, Apisadaporn Thambundit, Steven D Mittelman, Costas A Lyssiotis, David B ShackelfordAbstract:Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived Asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous Asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that Asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor Asparagine synthesis, and either asparaginase or dietary Asparagine restriction, which limit tumor Asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental Asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that Asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
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Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth
bioRxiv, 2020Co-Authors: Abigail S. Krall, Peter J Mullen, Felicia Surjono, Milica Momcilovic, Ernst W Schmid, Christopher J Halbrook, Apisadaporn Thambundit, Steven D Mittelman, Costas A Lyssiotis, David B ShackelfordAbstract:Abstract Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived Asparagine and impairs mTORC1 activity. Providing exogenous Asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour Asparagine synthesis, and either asparaginase or dietary Asparagine restriction, which limit tumour Asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental Asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo, our findings suggest that Asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that Asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism.
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Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor
Nature Communications, 2016Co-Authors: Abigail S. Krall, Thomas G Graeber, Shili Xu, Daniel Braas, Heather R ChristofkAbstract:Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for Asparagine as an amino acid exchange factor: intracellular Asparagine exchanges with extracellular amino acids. Through Asparagine synthetase knockdown and altering of media Asparagine concentrations, we show that intracellular Asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, Asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that Asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that Asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular Asparagine levels is critical for cancer cell growth. Collectively, our results indicate that Asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.
Laure Gaufichon - One of the best experts on this subject based on the ideXlab platform.
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Impact of the Disruption of ASN3-Encoding Asparagine Synthetase on Arabidopsis Development
Agronomy, 2016Co-Authors: Laure Gaufichon, Anne Marmagne, Tadakatsu Yoneyama, Toshiharu Hase, Gilles Clément, Marion Trassaert, Maryam Shakibaei, Amina Najihi, Akira SuzukiAbstract:The aim of this study was to investigate the role of ASN3-encoded Asparagine synthetase (AS, EC 6.3.5.4) during vegetative growth, seed development and germination of Arabidopsis thaliana. Phenotypic analysis of knockout (asn3-1) and knockdown (asn3-2) T-DNA insertion mutants for the ASN3 gene (At5g10240) demonstrated wild-type contents of Asparagine synthetase protein, chlorophyll and ammonium in green leaves at 35 days after sowing. In situ hybridization localized ASN3 mRNA to phloem companion cells of vasculature. Young siliques of the asn3-1 knockout line showed a decrease in Asparagine but an increase in glutamate. The seeds of asn3-1 and asn3-2 displayed a wild-type nitrogen status expressed as total nitrogen content, indicating that the repression of ASN3 expression had only a limited effect on mature seeds. An analysis of amino acid labeling of seeds imbibed with (N-15) ammonium for 24 h revealed that asn3-1 seeds contained 20% less total Asparagine while N-15-labeled Asparagine ((2-N-15)Asparagine, (4-N-15)Asparagine and (2,4-N-15)Asparagine) increased by 12% compared to wild-type seeds. The data indicate a fine regulation of Asparagine synthesis and hydrolysis in Arabidopsis seeds.
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Asparagine metabolic pathways in arabidopsis
Plant and Cell Physiology, 2016Co-Authors: Laure Gaufichon, Steven J Rothstein, Akira SuzukiAbstract:Inorganic nitrogen in the form of ammonium is assimilated into Asparagine via multiple steps involving glutamine synthetase (GS), glutamate synthase (GOGAT), aspartate aminotransferase (AspAT) and Asparagine synthetase (AS) in Arabidopsis. The Asparagine amide group is liberated by the reaction catalyzed by asparaginase (ASPG) and also the amino group of Asparagine is released by Asparagine aminotransferase (AsnAT) for use in the biosynthesis of amino acids. Asparagine plays a primary role in nitrogen recycling, storage and transport in developing and germinating seeds, as well as in vegetative and senescence organs. A small multigene family encodes isoenzymes of each step of Asparagine metabolism in Arabidopsis, except for Asparagine aminotransferase encoded by a single gene. The aim of this study is to highlight the structure of the genes and encoded enzyme proteins involved in Asparagine metabolic pathways; the regulation and role of different isogenes; and kinetic and physiological properties of encoded enzymes in different tissues and developmental stages.
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Biological functions of Asparagine synthetase in plants
Plant Science, 2010Co-Authors: Laure Gaufichon, Michèle Cren-reisdorf, Fabien Chardon, Steven J Rothstein, Akira SuzukiAbstract:Ammonium is a form of inorganic nitrogen derived from several metabolic pathways, and is assimilated into glutamine, glutamate, Asparagine and carbamoylphosphate. These molecules play important roles in nitrogen assimilation, recycling, transport and storage in plants. Ammonium assimilation into Asparagine is catalyzed by ammonia-dependent Asparagine synthetase encoded by asnA (EC 6.3.1.1) or glutamine-dependent Asparagine synthetase encoded by asnB (EC 6.3.5.4) in prokaryotes and eukaryotes. These organisms display a distinct distribution of these two forms of Asparagine synthetase. Gene and primary protein structure for Asparagine synthetase-A and -B from prokaryotes and eukaryotes is examined. Using nucleotide sequences, we constructed a phylogenetic tree that distinguished two major classes (classes I and II) for ASN genes from a range of organisms. Only the glutamine-dependent Asparagine synthetases-B have been identified, and are encoded by a small multigene family in plants. The isoenzyme encoded by each member of the gene family provides Asparagine at specific phases of development. These include the nitrogen mobilization in germinating seeds, nitrogen recycling in vegetative organs in response to stress, and nitrogen remobilization during seed embryogenesis. The expression of genes for Asparagine synthetase is regulated by light and metabolites. Genetic and molecular data using mutants and transgenic plants have provided insights into the light perception by the photoreceptors, carbon and nitrogen sensing and signal transduction mechanism in the asn regulation. Global analysis of carbon and nitrogen metabolites supports the impact of asn regulation in the synthesis and transport of Asparagine in plants.
