文章：

丝氨酸和癌症中的单碳代谢

Serine and one-carbon metabolism in cancer

原文发布日期：2016-09-16

DOI: 10.1038/nrc.2016.81

类型: Review Article

开放获取: 否

要点：

1. Serine is a non-essential amino acid that can be taken up by the cell or synthesized de novo from glycolytic intermediates through the serine synthesis pathway (SSP). Serine is used for many biosynthetic pathways, including the one-carbon cycle that supports nucleotide synthesis, methylation reactions and antioxidant defence.
2. Although one-carbon metabolism enzymes are expressed in both the mitochondria and cytosol, most cells generate formate in the mitochondria for use in cytosolic nucleotide synthesis. This directionality in the pathway can also provide mitochondrial NADH, NADPH and ATP.
3. Some cancer cells show amplification of the SSP enzymes, and their survival depends on the sustained expression of these enzymes, even under serine-fed conditions. This seems to reflect a requirement for serine synthesis to maintain nucleotide synthesis.
4. Cancer cells without amplification of the SSP tend to depend on exogenous serine for optimal growth. The switch to de novo serine synthesis under serine starvation leads to increased oxidative stress, which must be managed for successful adaptation.
5. Several oncogenes and tumour suppressor genes can regulate the serine synthesis and one-carbon cycle enzymes, with evidence that changes in their expression and activity can contribute to malignant development and progression.
6. Therapeutic approaches are being developed based on limiting exogenous serine or targeting serine synthesis or metabolism enzymes.

要点翻译：

1. 丝氨酸是一种非必需氨基酸，可通过细胞摄取或经丝氨酸合成途径（SSP）从糖酵解中间体从头合成。丝氨酸参与多种生物合成途径，包括支持核苷酸合成、甲基化反应和抗氧化防御的一碳循环。
2. 尽管一碳代谢酶在线粒体和细胞质中均有表达，但大多数细胞在线粒体中生成甲酸盐用于胞质核苷酸合成。该通路的定向性还能产生线粒体NADH、NADPH和ATP。
3. 部分癌细胞的SSP酶呈现扩增，其存活依赖于这些酶的持续表达——即使在丝氨酸充足条件下亦如此。这似乎反映了维持核苷酸合成对丝氨酸合成的内在需求。
4. 未发生SSP扩增的癌细胞往往依赖外源丝氨酸以实现最佳生长。在丝氨酸匮乏时转向从头合成会导致氧化应激加剧，必须有效调控该过程才能成功适应。
5. 多种癌基因和抑癌基因可调控丝氨酸合成及一碳循环相关酶类，有证据表明其表达与活性的变化会促进恶性肿瘤的发生发展。
6. 目前正在研发基于限制外源丝氨酸或靶向丝氨酸合成/代谢酶的治疗策略。

英文摘要：

The non-essential amino acid serine supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, amino acid and glutathione synthesis. As an important one-carbon donor to the folate cycle, serine contributes to nucleotide synthesis, methylation reactions and the generation of NADPH for antioxidant defence. Many cancer cells are highly dependent on serine, a trait that provides several novel therapeutic opportunities, either through the inhibition of de novo serine synthesis or by limiting the availability or uptake of exogenous serine.

摘要翻译： 

非必需氨基酸丝氨酸支持多种代谢过程，这些过程对增殖细胞的生长和生存至关重要，包括蛋白质、氨基酸和谷胱甘肽的合成。作为叶酸循环的重要一碳供体，丝氨酸有助于核苷酸合成、甲基化反应以及生成用于抗氧化防御的NADPH。许多癌细胞高度依赖丝氨酸，这一特性提供了多种新的治疗机会，可通过抑制从头合成丝氨酸或限制外源性丝氨酸的可用性或摄取来实现。

原文链接：

Serine and one-carbon metabolism in cancer