Furuya Shigeki
Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, #315, The 3rd Building of School of Engineering, Hakozaki, Fukuoka City, Fukuoka 812-8581, Japan.
Asia Pac J Clin Nutr. 2008;17 Suppl 1:312-5.
L-serine plays a versatile role in intermediary metabolism in eukaryotic cells. The physiological significance of its de novo biosynthesis, however, remains largely unexplored. We demonstrated previously that neurons lose the ability to synthesize L-serine after their final differentiation and thus depend on astrocytes to supply this amino acid. This is due to a lack of neuronal expression of 3-phosphoglycerate dehydrogenase (Phgdh), which initiates de novo L-serine synthesis via the phosphorylated pathway from the glycolytic intermediate 3-phosphoglycerate. In rodent brain, Phgdh is expressed exclusively by the neuroepithelium/radial glia/astrocyte lineage. In humans, serine deficiency disorders can result from a deficiency of Phgdh or other enzymes involved in serine biosynthesis in the phosphorylated pathway. Patients with such disorders have lower serine levels in plasma and cerebrospinal fluid; they exhibit severe neurological symptoms including congenital microcephaly, feeding disabilities, and psychomotor retardation. L-serine supplementation can attenuate developmental defects in these patients. To define the physiological importance of de novo L-serine production, we generated Phgdh knockout mice using targeted gene disruption technique. Phgdh deletion drastically reduced serine and glycine levels in the body. Phgdh knockout mice exhibited overall growth retardation with severe brain malformation, culminating in embryonic lethality. These observations highlight the vital role of de novo L-serine synthesis in the formation and function of the mammalian central nervous system. Furthermore, the embryonic lethal phenotype of Phgdh knockouts indicates that L-serine must be synthesized endogenously in mouse (and probably humans) during embryonic development.
L-丝氨酸在真核细胞的中间代谢中发挥着多种作用。然而，其从头合成的生理意义在很大程度上仍未得到探索。我们之前证明，神经元在最终分化后失去了合成L-丝氨酸的能力，因此依赖星形胶质细胞来提供这种氨基酸。这是由于缺乏3-磷酸甘油酸脱氢酶（Phgdh）的神经元表达，该酶通过糖酵解中间产物3-磷酸甘油酸的磷酸化途径启动L-丝氨酸的从头合成。在啮齿动物大脑中，Phgdh仅由神经上皮/放射状胶质细胞/星形胶质细胞谱系表达。在人类中，丝氨酸缺乏症可能源于Phgdh或磷酸化途径中参与丝氨酸生物合成的其他酶的缺乏。患有此类疾病的患者血浆和脑脊液中的丝氨酸水平较低；他们表现出严重的神经症状，包括先天性小头畸形、喂养障碍和精神运动发育迟缓。补充L-丝氨酸可以减轻这些患者的发育缺陷。为了确定从头合成L-丝氨酸的生理重要性，我们使用靶向基因破坏技术生成了Phgdh基因敲除小鼠。Phgdh基因缺失显著降低了体内丝氨酸和甘氨酸水平。Phgdh基因敲除小鼠表现出整体生长迟缓，并伴有严重的脑畸形，最终导致胚胎致死。这些观察结果突出了从头合成L-丝氨酸在哺乳动物中枢神经系统的形成和功能中的重要作用。此外，Phgdh基因敲除小鼠的胚胎致死表型表明，在小鼠（可能还有人类）胚胎发育过程中，L-丝氨酸必须内源性合成。
