L-serine is a nonessential amino acid in eukaryotic cells, used for protein synthesis and in producing phosphoglycerides, glycerides, sphingolipids, phosphatidylserine, and methylenetetrahydrofolate. Moreover, L-serine is the precursor of two relevant coagonists of NMDA receptors: glycine (through the enzyme serine hydroxymethyltransferase), which preferentially acts on extrasynaptic receptors and D-serine (through the enzyme serine racemase), dominant at synaptic receptors. The cytosolic “phosphorylated pathway” regulates de novo biosynthesis of L-serine, employing 3-phosphoglycerate generated by glycolysis and the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, and phosphoserine phosphatase (the latter representing the irreversible step). In the human brain, L-serine is primarily found in glial cells and is supplied to neurons for D-serine synthesis. Serine-deficient patients show severe neurological symptoms, including congenital microcephaly, psychomotor retardation, and intractable seizures, thus highlighting the relevance of de novo production of this amino acid in brain development and morphogenesis. Indeed, the phosphorylated pathway is strictly linked to cancer. Moreover, L-serine has been suggested as a ready-to-use treatment, as also recently proposed for Alzheimer’s disease. Here, we present our current state of knowledge concerning the three mammalian enzymes of the phosphorylated pathway and known mutations related to pathological conditions: although the structure of these enzymes has been solved, how enzyme activity is regulated remains largely unknown. We believe that an in-depth investigation of these enzymes is crucial to identify the molecular mechanisms involved in modulating concentrations of the serine enantiomers and for studying the interplay between glial and neuronal cells and also to determine the most suitable therapeutic approach for various diseases.

L-丝氨酸是真核细胞中的一种非必需氨基酸，用于蛋白质合成和生产磷酸甘油酯、甘油酯、鞘脂、磷脂酰丝氨酸和亚甲基四氢叶酸。此外，L-丝氨酸是 NMDA 受体的两个相关共激动剂的前体：甘氨酸（通过丝氨酸羟甲基转移酶），优先作用于突触外受体；D-丝氨酸（通过丝氨酸消旋酶），在突触受体上占主导地位。胞质“磷酸化途径”利用糖酵解产生的 3-磷酸甘油酸以及 3-磷酸甘油酸脱氢酶、磷酸丝氨酸转氨酶和磷酸丝氨酸磷酸酶（后者代表不可逆步骤）调节 L-丝氨酸的从头生物合成。在人脑中，L-丝氨酸主要存在于神经胶质细胞中，并供应给神经元进行 D-丝氨酸合成。丝氨酸缺陷患者表现出严重的神经系统症状，包括先天性小头畸形、精神运动迟缓和顽固性癫痫发作，从而凸显了这种氨基酸从头产生在大脑发育和形态发生中的相关性。事实上，磷酸化途径与癌症密切相关。此外，L-丝氨酸已被建议作为一种即用型治疗方法，最近也被建议用于治疗阿尔茨海默病。在这里，我们介绍了我们目前对磷酸化途径的三种哺乳动物酶和与病理条件相关的已知突变的了解：尽管这些酶的结构已经解决，但酶活性如何调节仍然很大程度上未知。 我们相信，对这些酶的深入研究对于确定调节丝氨酸对映体浓度的分子机制、研究神经胶质细胞和神经元细胞之间的相互作用以及确定各种疾病的最合适的治疗方法至关重要。