D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain.
D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain.
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D-半胱氨酸是哺乳动物大脑中神经祖细胞动力学的内源性调节剂。
DOI：
10.1073/pnas.2110610118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Roychaudhuri,Robin
中科院分区：
文献类型：
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作者：
Semenza,EvanR;Harraz,MagedM;Abramson,Efrat;Malla,AdarshaP;Vasavda,Chirag;Gadalla,MoatazM;Kornberg,MichaelD;Snyder,SolomonH;Roychaudhuri,Robin
D-氨基酸越来越被认为是哺乳动物中枢神经系统中重要的信号分子。然而，d-立体异构体的氨基酸与最快的自发外消旋率在体外，半胱氨酸，还没有被检查在哺乳动物。使用手性高效液相色谱和立体特异性荧光素酶测定，我们确定内源性半胱氨酸在哺乳动物大脑。丝氨酸消旋酶（serine racemase，SR）产生N-甲基-d-天冬氨酸（N-methyl-d-aspartate，NMDA）谷氨酸受体的凝血因子d-丝氨酸，是半胱氨酸的候选生物合成酶，d-半胱氨酸在胚胎小鼠脑中的富集程度是成年小鼠脑的20倍以上，d-半胱氨酸可使培养的小鼠胚胎神经前体细胞（neural progenitor cells，NPC）的增殖减少约50%，这是d-丝氨酸或l-半胱氨酸所不具有的作用。d-半胱氨酸的抗增殖作用由转录因子FoxO 1和FoxO 3a介导。d-半胱氨酸对NPC增殖的选择性影响反映在新生SR敲除小鼠大脑皮质的过度生长和异常分层中。最后，我们进行了一个公正的屏幕for-cysteine-binding蛋白在NPC免疫沉淀与广告-半胱氨酸特异性抗体，然后通过质谱。这种方法确定豆蔻酰丙氨酸丰富的C-激酶底物（MARCKS）作为一个假定的半胱氨酸结合蛋白。总之，这些结果建立了内源性半胱氨酸，并暗示它作为一种生理调节NPC稳态发育中的大脑。
d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, thed-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenousd-cysteine in the mammalian brain. We identify serine racemase (SR), which generates theN-methyl-d-aspartate (NMDA) glutamate receptor coagonistd-serine, as a candidate biosynthetic enzyme ford-cysteine.d-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain.d-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared withd-serine orl-cysteine. The antiproliferative effect ofd-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence ofd-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen ford-cysteine–binding proteins in NPCs by immunoprecipitation with ad-cysteine–specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putatived-cysteine–binding protein. Together, these results establish endogenous mammaliand-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.