Hamano Momoko, Haraguchi Yurina, Sayano Tomoko, Zyao Chong, Arimoto Yashiho, Kawano Yui, Moriyasu Kazuki, Udono Miyako, Katakura Yoshinori, Ogawa Takuya, Kato Hisanori, Furuya Shigeki
Laboratory of Functional Genomics and Metabolism Department of Innovative Science and Technology for Bio-industry Kyushu University Fukuoka Japan.
International College of Arts and Sciences Fukuoka Women's University Fukuoka Japan.
FEBS Open Bio. 2018 May 8;8(6):914-922. doi: 10.1002/2211-5463.12429. eCollection 2018 Jun.
l-Serine (l-Ser) is a necessary precursor for the synthesis of proteins, lipids, glycine, cysteine, d-serine, and tetrahydrofolate metabolites. Low l-Ser availability activates stress responses and cell death; however, the underlying molecular mechanisms remain unclear. l-Ser is synthesized from 3-phosphoglycerate with 3-phosphoglycerate dehydrogenase (Phgdh) catalyzing the first reaction step. Here, we show that l-Ser depletion raises intracellular HO levels and enhances vulnerability to oxidative stress in Phgdh-deficient mouse embryonic fibroblasts. These changes were associated with reduced total glutathione levels. Moreover, levels of the inflammatory markers thioredoxin-interacting protein and prostaglandin-endoperoxide synthase 2 were upregulated under l-Ser-depleted conditions; this was suppressed by the addition of -acetyl-l-cysteine. Thus, intracellular l-Ser deficiency triggers an inflammatory response via increased oxidative stress, and l-Ser synthesis suppresses oxidative stress damage and inflammation when the external l-Ser supply is restricted.
L-丝氨酸（L-Ser）是蛋白质、脂质、甘氨酸、半胱氨酸、D-丝氨酸和四氢叶酸代谢产物合成所必需的前体。L-丝氨酸供应不足会激活应激反应和细胞死亡；然而，其潜在的分子机制仍不清楚。L-丝氨酸由3-磷酸甘油酸合成，3-磷酸甘油酸脱氢酶（Phgdh）催化第一步反应。在这里，我们表明L-丝氨酸耗竭会提高细胞内HO水平，并增强Phgdh缺陷型小鼠胚胎成纤维细胞对氧化应激的易感性。这些变化与总谷胱甘肽水平降低有关。此外，在L-丝氨酸耗竭条件下，炎症标志物硫氧还蛋白相互作用蛋白和前列腺素内过氧化物合酶2的水平上调；添加N-乙酰-L-半胱氨酸可抑制这种上调。因此，细胞内L-丝氨酸缺乏通过增加氧化应激触发炎症反应，当外部L-丝氨酸供应受限 时，L-丝氨酸合成可抑制氧化应激损伤和炎症。
