As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid

Pavlova Natalya N.; Hui Sheng; Ghergurovich Jonathan M.; Fan Jing; Intlekofer Andrew M.; White Richard M.; Rabinowitz Joshua D.; Thompson Craig B.; Zhang Ji

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As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid

机译：由于细胞外谷氨酰胺水平下降，天冬酰胺成为必需的氨基酸

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When mammalian cells are deprived of glutamine, exogenous asparagine rescues cell survival and growth. Here we report that this rescue results from use of asparagine in protein synthesis. All mammalian cell lines tested lacked cytosolic asparaginase activity and could not utilize asparagine to produce other amino acids or biosynthetic intermediates. Instead, most glutamine-deprived cell lines are capable of sufficient glutamine synthesis to maintain essential amino acid uptake and production of glutamine-dependent biosynthetic precursors, with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine and increase tricarboxylic acid cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted medium in vitro and severely compromised the in vivo growth of tumor xenografts. These results suggest that the lack of asparaginase activity represents an evolutionary adaptation to allow mammalian cells to survive pathophysiologic variations in extracellular glutamine.

机译：当哺乳动物细胞被剥夺谷氨酰胺时，外源天冬酰胺拯救细胞存活和生长。在这里，我们报告说，这种救援是通过在蛋白质合成中使用天冬酰胺。所有哺乳动物细胞系缺乏胞岩天冬酰胺酶活性，不能利用天冬酰胺生产其他氨基酸或生物合成中间体。相反，大多数谷氨酰胺剥夺的细胞系能够足够的谷氨酰胺合成，以维持必要的氨基酸摄取和产生谷氨酰胺依赖性生物合成前体，除去天冬酰胺。虽然细胞溶质天冬酰胺酶的实验引入可以增强谷氨酰胺的合成并增加三羧酸循环的术语，但核苷酸前体的合成，胞岩天冬酰胺酶在体外体外抑制谷氨酰胺耗尽培养基中细胞的生长和存活率，并且严重损害了肿瘤的体内生长异种移植物。这些结果表明，缺乏天冬酰胺酶活性代表进化适应，以允许哺乳动物细胞存活细胞外谷氨酰胺的病理物理学变化。

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《Cell metabolism》 |2018年第2期|共16页
作者
Pavlova Natalya N.; Hui Sheng; Ghergurovich Jonathan M.; Fan Jing; Intlekofer Andrew M.; White Richard M.; Rabinowitz Joshua D.; Thompson Craig B.; Zhang Ji;
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作者单位

Mem Sloan Kettering Canc Ctr Dept Canc Biol &

Genet New York NY 10065 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Mem Sloan Kettering Canc Ctr Human Oncol &

Pathogenesis Program New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Dept Canc Biol &

Genet New York NY 10065 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Mem Sloan Kettering Canc Ctr Dept Canc Biol &

Genet New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Dept Canc Biol &

Genet New York NY 10065 USA;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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1. As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid [J] . Pavlova Natalya N., Hui Sheng, Ghergurovich Jonathan M., Cell metabolism . 2018,第2期

机译：由于细胞外谷氨酰胺水平下降，天冬酰胺成为必需的氨基酸
2. Synthesis and characterization of four new manganese(III) complexes and amino acid (L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine) Schiif bases [J] . Iffet Sakiyan Transition Metal Chemistry . 2007,第1期

机译：四种新型锰（III）配合物和氨基酸（L-天冬氨酸，L-天冬酰胺，L-谷氨酸，L-谷氨酰胺）Schiif碱的合成与表征
3. Synthesis and characterization of four new manganese(III) complexes and amino acid (L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine) Schiff bases [J] . ?ffet ?ak?yan Transition Metal Chemistry . 2007,第1期

机译：四种新型锰（III）配合物和氨基酸（L-天冬氨酸，L-天冬酰胺，L-谷氨酸，L-谷氨酰胺）席夫碱的合成与表征
4. The Levels of Serum Free Amino Acids: L-Glutamine, L-Arginine, L-Citrulline, in Women With Intrauterine Growth Retardation [C] . M.B. Wawrzycka, A. Haratym-Maj, B. Wawrzycki European Congress of Perinatal Medicine . 2006

机译：血清游离氨基酸的水平：L-谷氨酰胺，L-精氨酸，L-瓜氨酸，宫内生长迟缓的妇女
5. Responses of Two Strains of Broilers to Diets Varying in Essential Amino Acid Density and Energy Levels. [D] . Clark, Tyler James. 2015

机译：两种肉鸡对必需氨基酸密度和能级变化的日粮的反应。
6. As Extracellular Glutamine Levels Decline Asparagine Becomes an Essential Amino Acid [O] . Natalya N. Pavlova, Sheng Hui, Jonathan M. Ghergurovich, -1

机译：随着细胞外谷氨酰胺水平的下降天冬酰胺成为必需氨基酸
7. As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid [O] . Natalya N. Pavlova, Sheng Hui, Jonathan M. Ghergurovich, 2018

机译：由于细胞外谷氨酰胺水平下降，天冬酰胺成为必需的氨基酸
8. Plasma and Urinary Levels of L-Asparaginase, L-Asparagine, L-Glutamine, Aspartic Acid and Plasma Ammonia Levels in a Beagle Dog Treated with 1,000 I.U./Kg/Day X 5 of L-Asparaginase [R] . Rakieten, N., Cooney, D. A., Davis, R. D. 1970

机译：用1,000 I.U./Kg/Day X 5 L-天冬酰胺酶处理的Beagle犬血浆和尿液中L-天冬酰胺酶，L-天冬酰胺，L-谷氨酰胺，天冬氨酸和血浆氨水平

As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid

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