Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal...

Metabolic network plasticity helps organisms survive change, including dietary fluctuations, transitions between developmental stages and genetic perturbations. To maintain a robust supply of resources under these conditions, metabolic networks must rebalance flux across individual pathways. However, how pathways coordinate their activity to support homeostasis remains poorly understood. Here, we use metabolomics, dietary supplementation, and genetic screening to investigate how the network compensates for the loss of phosphoglycerate dehydrogenase PHDH-1, the rate-limiting enzyme in serine biosynthesis. We find that PHDH-1 dysfunction causes developmental delay and substantially alters the metabolome of C. elegans embryos, but not that of adult animals. Despite these perturbations, Δphdh-1 mutant embryos remain viable through the compensatory activity of enzymes that we identified through a genetic interaction screen. The identified PHDH-1 interactions span the metabolic network and are alleviated by maternal serine supplementation, revealing wide-ranging functional links between serine metabolism and distant pathways. We further demonstrate how the joint action of PHDH-1, the glycine cleavage system and the maternal diet sustains embryonic one-carbon metabolism. Overall, our results reveal how metabolic networks buffer the supply of one-carbon units to compensate for enzyme dysfunction and support robust development.