Serine chirality guides metabolic flow between one-carbon metabolism and neuromodulator synthesis

Neural development requires metabolic adaptations that coincide with a functional shift from differentiation to neurotransmission. Serine metabolism provides essential metabolites for cellular growth and proliferation, and also produces neurotransmitters. However, how serine metabolism coordinates functional development of neurons remains unclear. Here, we report that neurons undergo metabolic transitions through an enantiomeric shift of serine during functional maturation. Developmental alterations of neural transcriptional profiles and serine enantiomers indicated that L- to D-serine conversion is a signature of neural maturation. Metabolomic analysis of neural progenitors revealed that D-serine decreases glycine synthesis, thereby suppressing one-carbon metabolism, in which L-serine is a crucial carbon donor. D-serine inhibits one-carbon metabolism by competing with transport of cytosolic L-serine to mitochondria, which restrains proliferation and triggers apoptosis of neural progenitors as well as neural tumor cells, but not mature neurons, in vitro and ex vivo. Thus, our findings suggest that the metabolic transition from L- to D-serine during neural maturation inhibits one-carbon metabolism essential for proliferation of immature neural cells, leading to acquisition of characteristics tailored to functional development toward neurotransmission.