As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid.
As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid.
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DOI：
10.1016/j.cmet.2017.12.006
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发表时间：
2018-02-06
期刊：
影响因子：
29
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Pavlova NN;Hui S;Ghergurovich JM;Fan J;Intlekofer AM;White RM;Rabinowitz JD;Thompson CB;Zhang J
当哺乳动物细胞被剥夺谷氨酰胺时，外源性天冬酰胺拯救细胞存活和生长。在这里，我们报告说，这种救援的结果使用天冬酰胺在蛋白质合成。所有测试的哺乳动物细胞系都缺乏胞质天冬酰胺酶活性，不能利用天冬酰胺产生其他氨基酸或生物合成中间体。相反，大多数谷氨酰胺剥夺细胞系能够充分合成谷氨酰胺以维持必需氨基酸摄取和谷氨酰胺依赖性生物合成前体的产生-天冬酰胺除外。虽然实验性引入胞质天冬酰胺酶可以增强谷氨酰胺的合成，增加TCA循环回补和核苷酸前体的合成，但胞质天冬酰胺酶抑制细胞在体外谷氨酰胺耗尽培养基中的生长和存活，并严重损害肿瘤异种移植物的体内生长。这些结果表明，天冬酰胺酶活性的缺乏代表了一种进化适应，使哺乳动物细胞在细胞外谷氨酰胺的病理生理变化中生存。外源性天冬酰胺可以挽救谷氨酰胺剥夺细胞的生长和存活。XXX等人表明，天冬酰胺不被分解代谢以产生其他氨基酸或生物合成中间体，而是维持蛋白质合成。天冬酰胺酶的引入抑制了谷氨酰胺耗尽的细胞的生长和存活，并损害了肿瘤异种移植物的生长。
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 the glutamine-dependent biosynthetic precursors – with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine, increase TCA cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted media 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. Exogenous asparagine can rescue growth and survival of glutamine-deprived cells. XXX et al show that asparagine is not catabolized to produce other amino acids or biosynthetic intermediates but rather maintains protein synthesis. Introduction of asparaginase suppressed the growth and survival of glutamine-depleted cells and compromised the growth of tumor xenografts.
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